Survival Differences in Women with and without Autologous Breast Reconstruction after Mastectomy for Breast Cancer

Background: Breast reconstruction (BR) is an option for women who are treated with mastectomy; however, there has been concern regarding the oncologic safety of BR. In this study, we evaluated recurrences and mortality in women treated with mastectomy and compared outcomes in those treated with mastectomy alone to those with mastectomy plus transverse rectus adbominis (TRAM) flap BR. Methods: The prospective cohort study included women treated with mastectomy at Women's College Hospital from 1987 to 1997. Women with TRAM flap BR were matched to controls based on age and year of diagnosis, stage, and nodal status. Patients were followed from the date of diagnosis until death or date of last follow-up. Hazard ratios were generated to compare cases and controls for outcome variables using Cox's proportional hazards models. Results: Of 443 women with invasive breast cancer, 85 subjects had TRAM flap BR. Sixty-five of these women were matched to 115 controls. The mean follow-up was 11.2 (0.4–26.3) years. There were no significant differences between those with and without BR with weight, height, or smoking status. Women with TRAM flap were less likely to experience a distant recurrence compared to women without a TRAM flap (relative risk, 0.42; P = 0.0009) and were more likely to be alive (relative risk, 0.54; P = 0.03). Conclusions: Women who elect for TRAM flap BR after an invasive breast cancer diagnosis do have lower rates of recurrences and mortality than women treated with mastectomy alone. This cannot be explained by differences in various clinical or lifestyle factors.

http://ift.tt/2qR2RRg

An Innovative Risk-Reducing Approach to Postmastectomy Radiation Delivery after Autologous Breast Reconstruction

Introduction: Postmastectomy radiation therapy (PMRT) has known deleterious side effects in immediate autologous breast reconstruction. However, plastic surgeons are rarely involved in PMRT planning. Our institution has adopted a custom bolus approach for all patients receiving PMRT. This offers uniform distribution of standard radiation doses, thereby minimizing radiation-induced changes while maintaining oncologic safety. We present our 8-year experience with the custom bolus approach for PMRT delivery in immediate autologous breast reconstruction. Methods: All immediate autologous breast reconstruction patients requiring PMRT after 2006 were treated with the custom bolus approach. Retrospective chart review was performed to compare the postirradiation complications, reconstruction outcomes, and oncologic outcomes of these patients with those of previous patients at our institution who underwent standard bolus, and to historical controls from peer-reviewed literature. Results: Over the past 10 years, of the 29 patients who received PMRT, 10 were treated with custom bolus. Custom bolus resulted in fewer radiation-induced skin changes and less skin tethering/fibrosis than standard bolus (0% vs 10% and 20% vs 35%, respectively), and less volume loss and contour deformities compared with historical controls (10% vs 22.8% and 10% vs 30.7%, respectively). Conclusions: Custom bolus PMRT minimizes radiation delivery to the internal mammary vessels, anastomoses, and skin; uniformly doses the surgical incision; and provides the necessary radiation dose to prevent recurrence. Because custom bolus PMRT may reduce the deleterious effects of radiation on reconstructive outcomes while maintaining safe oncologic results, we encourage all plastic surgeons to collaborate with radiation oncologists to consider this technique.

http://ift.tt/2qQz0bC

Low-grade Cribriform Cystadenocarcinoma: A Review of the Literature and Case Report

Summary: Low-grade cribriform cystadenocarcinoma (LGCCC) is a rare tumor of the salivary gland that most often arises from the parotid gland. A 51-year-old man developed a small mass on the right parotid gland 5 years ago. A preoperative magnetic resonance image showed abnormal intensity, an atypical characteristic for such a tumor; therefore, the diagnosis was difficult. Thus, a superficial parotidectomy was performed as a total excisional biopsy to remove the tumor. Histopathological analyses revealed that the tumor was composed of a single cyst comprising cells containing mucosal fluid, with proliferation of large cells. Also, proliferation of the tumor epithelium showed a papillary cribriform pattern of proliferation with a partial ring form, and the tissue inside the tumor was replaced by a hematoma. Mild cellular atypia was observed. Immunostaining for S-100 was positive, and the Ki-67 ratio was

http://ift.tt/2puIGnI

A Novel Needle Structure that Can Avoid Intravascular Injection of Any Filler

Summary: With increasing use of dermal fillers, more and more adverse effects are reported. The most devastating one is intravascular injection. We propose a novel needle prototype that allows physicians to prevent intravascular injection.

http://ift.tt/2qQNAjD

Prediction of Skin Necrosis after Mastectomy for Breast Cancer Using Indocyanine Green Angiography Imaging

Background: In immediate tissue expander reconstruction following total mastectomy for breast cancer, indocyanine green angiography (ICGA)–guided skin trimming is useful for the prevention of complications. However, instances of unclear ICGA contrast can occur with this method, which are difficult to judge as to whether preventive trimming is warranted. To further improve the mastectomy flap necrosis rate, more accurate objective parameters are necessary. Methods: The degree of clinical improvement was compared between 81 patients trimmed according to the surgeon's judgment (non-ICGA group) and 100 patients with ICGA-guided trimming (ICGA group). We then retrospectively measured 3 parameters [relative perfusion (RP); time (T) to reach RPmax; and slope (S = RP/T) reflecting the rate of increase to RPmax] by using region of interest analysis software and examined their relationships with skin necrosis. Results: The rate of grade III necrosis (reaching the subcutaneous fat layer) was significantly lower in the ICGA group (4.8%) than in the non-ICGA group (17.8%; P

http://ift.tt/2qQOqNb

Composite Arteriovenous Radial Conduit Flap for Lower Limb Reconstruction

In complex lower limb trauma, the healthy recipient vessels can be far from the defect to be reconstructed due to the usually high-energy injury sustained. The use of vein grafts, either directly or in the form of arteriovenous loops, is the usual solution in these cases. In the vein graft donor–depleted patient, other options are required; the composite arteriovenous radial conduit flap may be a useful resort in these situations.

http://ift.tt/2qQX6mL

A New Local Flap Nipple Reconstruction Technique Using Dermal Bridge and Preoperatively Designed Tattoo

Background: Nipple–areolar reconstruction is the final step in breast reconstruction. Reconstruction using local flaps and tattooing is useful in cases of bilateral reconstruction, a small nipple–areolar complex (NAC) as the donor site, and avoiding disturbance of the normal side and other body parts. However, this method can cause projection loss and color fading of the nipple. Moreover, the breast mound is reconstructed with an implant. Methods: We performed nipple–areolar reconstruction of 90 nipples using clover-designed flaps oriented at 120 degrees and tattooing after breast silicone implantation in 64 women. The tattoo was designed before flap operation and stained darker. Following donor site closure, a dermal flap was made as a bridge for nipple support. The nipple space was separated by the dermal flap from the breast mound and was filled with subcutaneous tissue. The size of the reconstructed nipple projection was measured postoperatively and 1 year later. The projection maintenance rate was calculated. Results: The heights of the nipple projection were 11.3 ± 1.8 mm (95% confidence interval [CI]: 10.9–11.7) just after the operation and 6.09 ± 2.4 mm (95% CI: 5.6–6.6) 1 year later. The actual range of nipple projection between these 2 heights was 5.2 ± 2.4 mm (95% CI: 4.7–5.7). The maintenance rate of the reconstructed nipple projection after 12 months was 54.1 ± 20.9 (95% CI: 49.7–58.5). The nipple color was maintained for over a year. Conclusions: Our nipple–areolar reconstruction technique could maintain the projection and color of the reconstructed nipple for a long period. Good outcomes were obtained in this implant-based breast reconstruction.

http://ift.tt/2qR2O82

Chronological Order of Lipofilling during Implant Exchange

No abstract available

http://ift.tt/2qQSNYA

Difference in Success Treating Proximal Interphalangeal and Metacarpophalangeal Joints with Collagenase: Results of 208 Treatments

Background: Dupuytren disease (DD) is a fibroproliferative disorder of the palmar fasciae causing extension deficit and impaired hand function. Treatment with injection of collagenase clostridium histolyticum (CCH) is a nonsurgical treatment method. The aim of this study was to evaluate the difference in efficiency and recurrence at 12-month follow-up when treating metacarpophalangeal (MP) and proximal interphalangeal (PIP) joints with CCH. None of the patients had received previous treatments of their condition. Methods: This study is a prospective study of a consecutive series of patients with DD presenting with an extension deficit greater than 20° affecting the MP or PIP joint. Results: We found a mean reduction in extension deficit of 47° (91%) for MP joints and 47° (76%) for PIP joints. Full correction (max 5° deficit) was achieved in 76% of MP and 28% of PIP joints. Skin rupture was seen in 34% of treatments. The 1-year relapse rate was 15% for MP and 67% for PIP joints. The reduction in quickDASH score was only statistically significant for MP joints at 1 year. Eighty-one percent of all patients reported being satisfied or very satisfied. No major adverse events were recorded. Conclusion: Excellent results can be achieved in the treatment of MP-joint contractures, whereas the success rate is significantly lower and recurrence rate is greater for PIP joints.

http://ift.tt/2qQXamj

Aging and Sexual Differences of the Human Skull

Background: The aging process of the face comprises all layers: skin, subcutaneous fat, muscles, and skeleton, and the signs of aging depend mainly on which layer is mostly affected. Objective: To evaluate the aging facial skeleton, as well as establish the sexual differences, areas with a strong predisposition to resorption, and aesthetic repercussion for better treatment approach. Methods: Skulls from the Forensic Anthropology Department of the Institute of Forensic Medicine of Belo Horizonte, Brazil, were classified according to gender and age group (i.e., 50 years). Structural changes were classified according to gender and age group. Results: Of the 241 skulls included, 192 were male skulls and 49 female. Sexual dimorphism and age-related peculiarities are described herein. Conclusions: The knowledge of the anatomy of the aging face, taking into consideration all the layers (skin, fat pads, muscles, and bones), as a whole, for the treatment of folds and shadows is vital for a better and more natural final aesthetic outcome.

http://ift.tt/2qQZxpw

Contracted Nose Correction with Dermofat and Conchal Cartilage

No abstract available

http://ift.tt/2qQG4VK

Ulnar Head Reconstruction with Microvascular Second Metatarsal

Background: The distal radioulnar joint along with the interosseous ligament of the forearm and the proximal radioulnar joint, form a functionally integrated system responsible for the pronation–supination of the hand. The distal ulna, the so-called ulnar head, is an integral part of this system. Apart from its well-known role in forearm rotation, the ulnar head is essential in transverse load transmission through the distal radioulnar joint upon resisted elbow flexion. Autologous reconstruction of ulnar head would theoretically be beneficial with respect to prostheses. Methods: Three cases of ulnar head reconstruction with microvascular second metatarsal are reported herein including trauma, oncological, and congenital ethiologies. Results: The clinical result was good without complaints of instability. Conclusions: The cases included in this series, although heterogeneous, indicate that this treatment may be feasible also in postoncological resections and in congenital cases.

http://ift.tt/2qQSOLW

Absence of Ulnar Artery Inflow Detected by Allen’s Test Prior to Radial Forearm Free Flap

Summary: Radial forearm free flaps are commonly used for soft-tissue reconstruction after resection of head and neck cancer. It is perfused by the radial artery, leaving the ulnar artery for perfusion of the hand and digits. The absence of distal ulnar artery and associated superficial palmar arch, however, has not been reported in cadaveric dissection. We report a case of unilateral ulnar artery flow absence, detected by Allen's test, during preoperative preparation for a radial forearm free flap. Based on the simplicity, safety, and ease, we recommend Allen's test to be performed preoperatively on every patient for whom such a flap is a consideration.

http://ift.tt/2qQNsk9

Inferior Limb Salvage by Combined Free-tissue Transfer and the Crane Principle Revisited

Summary: Aggressive treatment of ischemia of the lower extremities has decreased the number of amputations in both diabetic and nondiabetic patients; combined vascular reconstruction and microvascular free-flap transfer has been used to improve distal perfusion and cover large tissue defects caused by the critical limb ischemia during the past 30 years. We present our experience with a 71-year-old diabetic patient who underwent revascularization with a vascular bypass and a simultaneous microvascular flap reconstruction for limb salvage after domestic trauma. An extension of the "crane" principle was used to solve bypass exposure due to wound late complication. After 1-year follow-up, the patient was able to walk without pain. Combining 3 well-established methods of arterial revascularization and free-flap transfer and the old "crane principle," we achieved limb salvage, offering an alternative to below-knee amputation.

http://ift.tt/2qQG48c

Establishing Content Validity of the CLEFT-Q: A New Patient-reported Outcome Instrument for Cleft Lip/Palate

Background: The CLEFT-Q is a new patient-reported outcome instrument designed to measure outcomes that matter to patients. The aim of this qualitative study was to establish content validity of the CLEFT-Q in patients who differ by age and culture. Methods: Patients aged between 6 and 29 years were recruited from plastic surgery clinics in Canada, India, Ireland, the Philippines, the Netherlands and the United States. Healthcare providers and other experts participated in a focus group or provided individual feedback. Input was sought on all aspects of the CLEFT-Q (item wording, instructions, and response options), and to identify missing content. Patient interviews and expert feedback took place between September 2013 and September 2014. Results: Sixty-nine patients and 44 experts participated. The first draft of the CLEFT-Q consisted of 163 items measuring 12 constructs. The first round of feedback identified 92 items that required revision. In total, 3 rounds of interviews, and the involvement of an artist to create pictures for 17 items, were needed to establish content validity. At the conclusion of cognitive interviews, the CLEFT-Q consisted of 13 scales (total 171 items) that measure appearance, health-related quality of life, and facial function. The mean Flesch-Kincaid readability statistic for items was 1.4 (0 to 5.2). Conclusion: Cognitive interviews and expert review allowed us to identify items that required re-wording, re-conceptualizing, or to be removed, as well as any missing items. This process was useful for refining the CLEFT-Q scales for further testing.

http://ift.tt/2qQX9Ph

Technical Tip: Mark Scarpa's Fascia to Facilitate Proper Abdominal Closure During Autologous Breast Reconstruction

No abstract available

http://ift.tt/2qQX2n1

Surgical Factors Associated with Prolonged Hospitalization after Reconstruction for Oncological Spine Surgery

Background: Posterior trunk reconstruction is increasingly possible as a result of advances in spinal instrumentation, reconstructive approaches, and perioperative critical care. Extensive cases often require a muscle flap or complex closure to obliterate dead space. Postsurgical wound complications and subsequent reoperations can lead to neural injury, higher hospital costs, and longer hospitalizations. We aim to identify risk factors that are associated with increased length of stay (LOS) for patients receiving flaps to close a spinal defect. Methods: A single institution, retrospective cohort study was performed on all patients from 2002 to 2014 who received a muscle flap to close a spine defect. Medical and perioperative variables that were significantly associated with LOS (P

http://ift.tt/2qQOjkJ

Efficacy of Autologous Platelet-rich Plasma Glue in Weight Loss Sequelae Surgery and Breast Reduction: A Prospective Study: Erratum

No abstract available

http://ift.tt/2pv0EWX

Distally Based Sural Artery Peroneus Flap (DBSPF) for Foot and Ankle Reconstruction

Background: Reconstruction of soft-tissue defects in lower third of leg, ankle, and foot has been a challenge and reconstructive surgeons have been trying to innovate different flaps. To solve this issue, we propose a distally based sural artery peroneus flap (DBSPF) in which we include superficial portion of the peroneus brevis muscle and its blood supply with the peroneal artery distally. The aim of this study was to evaluate the functional outcome and its usefulness over conventional distal sural artery flap or other local options available. Methods: This is a case series of 20 patients that include a DBSPF that was done for defects around ankle, distal leg, and foot caused by trauma or tumor ablation within the period of June 2013 to March 2015 in Kasralainy Hospital, Cairo. All cases were evaluated according to flap vascularity, distal reach of flap, aesthetic outcome, and donor-site morbidity. Results: All flaps survived. One flap developed venous congestion that subsided spontaneously with limb elevation. The flap dimension ranged from 42 cm to 442 cm2, and it reached the midfoot easily. The pivot point was kept as low as 2–6 cm from lateral malleolus according to location of perforators. The ankle stability was maintained, and the desired aesthetic outcome was achieved. Conclusions: The DBSPF is an addition to the armamentarium in plastic surgery for defects around ankle, distal leg, and foot. It is an easy and swift procedure as compared with complex microsurgical reconstruction.

http://ift.tt/2puI4hJ

Reverse Radial Forearm Flap

No abstract available

http://ift.tt/2puEhku

Def1 and Dst1 play distinct roles in repair of AP lesions in highly transcribed genomic regions

Publication date: Available online 10 May 2017
Source:DNA Repair
Author(s): Norah Owiti, Christopher Lopez, Shivani Singh, Andrei Stephenson, Nayun Kim
Abasic or AP sites generated by spontaneous DNA damage accumulate at a higher rate in actively transcribed regions of the genome in S. cerevisiae and are primarily repaired by base excision repair (BER) pathway. We have demonstrated that transcription-coupled nucleotide excision repair (NER) pathway can functionally replace BER to repair those AP sites located on the transcribed strand much like the strand specific repair of UV-induced pyrimidine dimers. Previous reports indicate that Rad26, a yeast homolog of transcription-repair coupling factor CSB, partly mediates strand-specific repair of UV-dimers as well as AP lesions. Here, we report that Def1, known to promote ubiquitination and degradation of stalled RNA polymerase complex, also directs NER to AP lesions on the transcribed strand of an actively transcribed gene but that its function is dependent on metabolic state of the yeast cells. We additionally show that Dst1, a homolog of mammalian transcription elongation factor TFIIS, interferes with NER-dependent repair of AP lesions while suppressing homologous recombination pathway. Overall, Def1 and Dst1 mediate very different outcomes in response to AP-induced transcription arrest.



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Human somatic cells deficient for RAD52 are impaired for viral integration and compromised for most aspects of homology-directed repair

Publication date: Available online 10 May 2017
Source:DNA Repair
Author(s): Yinan Kan, Nizar N. Batada, Eric A. Hendrickson
Homology-directed repair (HDR) maintains genomic integrity by eliminating lesions such as DNA double-strand breaks (DSBs), interstrand crosslinks (ICLs) and stalled replication forks and thus a deficiency in HDR is associated with genomic instability and cancer predisposition. The mechanism of HDR is best understood and most rigorously characterized in yeast. The inactivation of the fungal radiation sensitive 52 (RAD52) gene, which has both recombination mediator and single-strand annealing (SSA) activities in vitro, leads to severe HDR defects in vivo. Confusingly, however, the inactivation of murine and chicken RAD52 genes resulted in mouse and chicken cells, respectively, that were largely aphenotypic. To clarify this issue, we have generated RAD52 knockout human cell lines. Human RAD52-null cells retain a significant level of SSA activity demonstrating perforce that additional SSA-like activities must exist in human cells. Moreover, we confirmed that the SSA activity associated with RAD52 is involved in, but not absolutely required for, most HDR subpathways. Specifically, a deficiency in RAD52 impaired the repair of DNA DSBs and intriguingly decreased the random integration of recombinant adeno-associated virus (rAAV). Finally, an analysis of pan-cancer genome data from The Cancer Genome Atlas (TCGA) revealed an association between aberrant levels of RAD52 expression and poor overall survival in multiple cancers. In toto, our work demonstrates that RAD52 contributes to the maintenance of genome stability and tumor suppression in human cells.



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Thanks

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Heavy mite exposure in the environment can induce allergic systemic reactions.

http://alexsfakianakis.blogspot.com/2017/05/mite-hypersensitivity.html

Anaphylaxis

Anaphylaxis is an acute emergency that is potentially fatal and commonly related to an allergic and immunologic trigger requiring immediate effective life-saving treatment [151]. Heavy mite exposure in the environment can induce allergic systemic reactions. More recently, the induction of anaphylaxis through ingestion of mite-contaminated foods has been described [152].

Pancake anaphylaxis, also called oral mite anaphylaxis (OMA), is a relatively new syndrome characterized by severe allergic symptoms occurring immediately after eating foods, especially containing flours, contaminated with mites. These cooked foods contain thermoresistant mite allergens and contaminated wheat flour used to make pancakes is its most common presentation [152]. A variant clinical picture is provoked by physical exercise and is called dust mite ingestion-associated exercise-induced anaphylaxis [153]. OMA is more prevalent in tropical and subtropical areas of the globe where mites grow easily in their warm and humid environments [154]. There are reports in the literature of two fatalities associated with the ingestion of foods contaminated with mites [155, 156]. Mites responsible for OMA include domestic and storage species and can be present in any type of flours. There is an intriguing association of OMA and hypersensitivity to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) for which there is no good explanation yet and it is more prevalent in patients with house dust mite allergic rhinitis and/or asthma [157]. The higher the contaminated mite ingestion the greater the risk for anaphylaxis. OMA confirmation requires the microscopic documentation and identification of mites in the suspected flour. Alternatively the immunoassay for demonstration of the presence of mite allergens in the suspected flour can be used. It is imperative to try to prevent the worldwide OMA delineating predisposing genetic factors and determining if mite immunotherapy might be efficacious modifying the clinical course of this important variety of food anaphylaxis [152, 158].

Co-sensitization to cockroaches, some crustaceans (shrimp, crab, lobster), shellfish (clams, mussels), and mollusks (snails) is often described and likely due to the presence of allergens in the tropomyosins family, present in some crustaceans (major allergen of shrimp: Pen 1), insects (some flies, mosquitoes, cockroaches), gastropods and mites (Der f 10) [122].

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Prevention of Dust Mite and Dust Mite Allergen Exposure

http://alexsfakianakis.blogspot.com/2017/05/mite-hypersensitivity.html

Justification for Dust Mite Exposure Control

The decision to initiate environmental controls to reduce dust mite exposure can be complex. Total prevention of exposure to mite allergenic material to prevent IgE sensitization to mite allergens in genetically susceptible individuals requires strict, continuous avoidance of mite exposure, which is practically all but impossible [199]. Furthermore, to curtail development of all cross-reacting specific IgE, avoidance of all arthropods would probably be required [200]. The majority of the world's population lives on seacoasts [201] or along rivers [202] and these areas typically have adequate humidity to support growth of dust mites and storage mites during all parts of the year.

Much research has been conducted to determine if it is possible to reduce development of mite-specific IgE-mediated sensitization (primary prevention). Several studies comparing dust mite sensitization rates in children from areas endemically low and areas endemically high in dust mite allergen indicated that the prevalence and degree of sensitization to dust mite was strongly associated with the amount of exposure to mite allergens [203, 204]. A prospective study of mite allergen avoidance in Manchester, UK, [205, 206] using a combination of interventions, decreased Der p 1 from mattresses by 97% to the nanogram range during pregnancy and 12 months after birth in the active group [205]. However, with all possible dust mite exposures at homes of friends and family, on public transportation and in public places and at schools and day care centers, primary prevention of dust mite sensitization by mite allergen avoidance may not be possible [207, 208, 209].

Secondary prevention, or the attempt to reduce the risk of asthma in dust mite sensitized children has also received much attention. The link between asthma and dust mite exposure is one of the most extensively studied relationships between environmental exposure and disease development [210, 211, 212, 213]. In all climates conducive to the growth of dust mites, mite exposure may be one of the factors contributing to the development of asthma [112, 214]. Secondary prevention has also been the goal for many children with allergic rhinitis who are at risk of the subsequent development of asthma. However, to date there is no evidence-based information as to whether mite avoidance may be effective as a secondary preventive measure to prevent/delay asthma development among mite-sensitized individuals, or those with allergic rhinitis.

The relation of dust mite allergen exposure and the worsening of allergic respiratory symptoms is well documented [215]. In one study of 311 subjects both sensitized and exposed to high levels of indoor allergen including dust mite allergen there was significantly lower FEV1% predicted values (mean, 83.7% vs 89.3%; mean difference, 5.6%; 95% CI, 0.6%-10.6%; P = .03), higher eNO values (geometric mean [GM], 12.8 vs 8.7 ppb; GM ratio, 0.7; 95% CI, 0.5-0.8; P = .001), and more severe airways reactivity (PD20 GM, 0.25 vs 0.73 mg; GM ratio, 2.9; 95% CI, 1.6-5.0; P < .001) as compared with subjects not sensitized and exposed [216]. Adults in a 4-year study who were both sensitized and exposed to high levels of dust mite allergens had increased bronchial hyper-responsiveness [217]. Many additional links between dust mite exposure and allergic disease are documented in the recent environmental practice parameter on dust mites [198]. A reduction in the symptoms experienced by those with atopic dermatitis has also been linked to house dust-mite allergen avoidance [218].

Facilitative factors and Allergen Reservoirs

Controlling factors that facilitate the growth and reproduction of dust mites has been an often sought goal in exposure control. The dependence of dust mites on the water content of the air has been extensively documented [219, 220]. Arid climates have an intrinsically low abundance of dust mites, and the most effective method of controlling dust mite exposure is to live in a very dry climate such as the high desert of New Mexico in the US or the Altiplano or Bolivian Plateau, in west-central South America [202]. Since this is not a practical solution, mimicking these conditions in the home environment as much as possible provides an opportunity to control mite population growth.

Humidity control should be the mainstay of any mite control efforts. The most important factor facilitating dust mite growth, reproduction and allergen production is the availability of water in the surrounding environment [220]. Mites absorb moisture directly from their surroundings under conditions of high moisture and lose water when moisture is low. The mite moisture equilibrium therefore is not directly relative humidity dependent. It is instead dependent of the moisture situation of the local microenvironment and the moisture retention ability of the mite's immediate surroundings such as carpet dust reservoirs or bedding. A simple measurement of relative humidity may not assure an environment free of dust mite activity. Microenvironments that exist in bedding, in carpet next to concrete or in pet lounging areas may provide adequate moisture for mite survival in climates not expected to have a mite presence. A mite surrounded by a hygroscopic microenvironment as moist bedding can survive much dryer conditions than would be expected. Of note, exposure to a moisture rich environment for only a short period can provide enough moisture for growth and metabolism [221].

Although directly linked to water content of the air in the calculation of relative humidity, temperature is also a factor in dust mite survival. Conditions at the extreme ends of the temperature spectrum, either to cold or to hot can impact mite survival although elevated temperature conditions tend to be more lethal than freezing. Mites and their eggs survive poorly when exposed to hot water and clothes dryers but survive during short periods of freezing conditions. The exposure to direct sunlight is an often forgotten factor in the destruction of dust mites [222].

It is not enough to address mite factors facilitating mite population growth. Reservoirs of mite allergen must also be eliminated. House dust mites can be found in any area of the home, however they are most often associated with certain indoor environments including the bedroom carpet, mattresses and bedding, frequently occupied upholstered furniture and in pet lounging areas [223, 224]. Recent investigations have questioned the traditional concepts of the location of dust mite reservoirs indicating that significant exposure can occur in public transportation conveyances and associated with work environments as well as clothing [207].

Climate Factors

Although residents of cold and arid climates are less likely to be exposed to house dust mites, the large majority of the world population is exposed to house dust mites. Nearly half of the people in the world live within 200 km of the coast where humidity levels are typically higher. The rate of population growth in coastal areas is accelerating. In China alone over 400 million live in coastal cities. Dust mite exposures and the allergic problems related to those exposures are likely to increase [201].

Although many climates are naturally conducive to mite growth and allergen production, the artificial control of indoor climates is increasing. Even though it is energy intensive, the use of forced air heating and air conditioning is growing around the world and especially in more affluent economies. Dust mite allergen exposure control is therefore a viable option for large numbers of persons. In many areas seasonal heating requirements result in very dry indoor environments and subsequently dust mite exposure is a seasonal phenomenon. Low humidity conditions can also be obtained through use of air conditioning and dehumidification. Yet, in many areas of the world ambient humidity levels are high enough that producing low humidity levels sufficient to preclude dust mite growth is not practically achievable. The recent Cochrane study on dehumidification alone indicates that evidence of clinical benefits of dehumidification using mechanical ventilation with dehumidifiers is scanty [225]. Indeed, the meta-analysis of multiple dust mite control studies would lead the reader to believe that there is nothing that can be physically done to control dust mites and improve health. Yet, this conclusion is disputed by many experts in the field of allergy [226]. Furthermore, the nature of single source exposure control studies may preclude successful clinical improvement because allergen sensitization is typically to multiple agents.

A significant amount of work has been done on removal of mites and mite allergens through cleaning. It goes without saying that efforts to control mite infestations of the skin and remove mite infestations from clothing are essential in the maintenance of overall health [227]. Humans have been living with dust mites for generations and they might even be described as among our "old friends" [228]. But no physician would advocate for wearing mite infested clothing or sleeping in mite infested bedding. Mite sensitization is likely to occur in genetically susceptible individuals, therefore efforts to reduce instances of elevated mite exposure and thus reduce allergic symptoms are only prudent [229].

Since mite allergens are located in known areas of a typical house [229, 230] removing mite allergen reservoirs is a very effective way to reduce mite allergen exposure. Efforts to remove carpets, drapes, upholstered furniture and any other fabric covered objects from the living environment can effectively reduce mite allergen exposure. The extent to which these items are removed will ultimately be a matter of personal preference. Since mite allergens are known to be heavy and not aerodynamically suited for airborne disbursal [34] and high humidity microenvironments are known to exist in bedding it is logical to focus dust mite reduction efforts on bedding. Efforts to enclose mattresses, box springs and pillows in mite-impermeable covers are known to be very effective [231]. However, it is important to mention that the efficacy of allergen avoidance in patients with already established rhinitis or asthma is a matter of debate [232, 233, 234, 235].

Washing bedding in hot water and even with bleach and drying bedding in very hot conditions or even in direct sunlight are known to reduce both the presence of mite allergen and the mites themselves [236, 237]. Washing bedding and clothing removes mite allergens and kills mites. Most of the killing is through drowning, although washing in hotter water kills more mites. The temperature used to wash bedding has become an issue. Elevated temperatures are more energy intensive and hotter water is a scalding hazard. Experts agree that washing is better than not washing and washing with water that is 48° Celsius provides optimum mite killing and home safety [199].

Heat treatment can be effective in killing mites and their eggs. Treatment of cloth at 95° Celsius killed all mites present [238]. However, treatment at 40 °C under dry and wet conditions allowed approximately 80% of all mite eggs to survive. Under dry heat at 50 °C, the thermal death point of dust mite eggs occurred at 5 h and at 60 °C death occurred almost instantaneously [239]. Presumably the eggs survive heat better than the mites themselves. Homes treated with heat-steam over a period of months showed a sustained reduction of Der p 1 and Der p 2 compared to sham treated homes [240] However, mite allergens have been demonstrated to be stable even at elevated temperatures [241].

Although the practice has fallen into senescence in the modern world of appliances, there was a time when frequently placing bedding in direct sunlight for several hours was practiced in many cultures. It has been demonstrated that ultraviolet irradiation is lethal to many organisms including dust mites [242, 243].

Many harsh chemicals are known to kill dust mites or denature mite allergens in industrial and household settings. Agents like tannic acid, Benzyl benzoate, Disodium octaborate tetrahydrate, tri-n-butyl tin maleate, pirimiphos methyl and even "essential oils" like methyl eugenol have been described in the literature to effectively kill mites [244, 245, 246, 247, 248]. However, they are all dangerous at some concentration and cannot be recommended for use by patients or homeowners [199].

It has been suggested that freezing can be effective in killing dust mites and the recommendation to place small cloth items like stuffed animals in the freezer compartment of house hold refrigerators has been frequently given out by allergists. However, there is little evidence that this is effective. There may be some mite death due to desiccation in the dry environment of a household freezer. But, dust mite eggs have been shown to resist freezing at temperatures above −70° Celsius [222]. And, freezing is not effective in removing dust mite allergen from reservoirs because dust mite allergen is stable at low temperatures for extended periods of time [239].

Air conditioning would have a twofold impact on dust mite populations. The cool temperatures will slow mite metabolism and reproduction and reduce moisture need for mite survival. Microenvironments or increased humidity can be reduced using a dehumidifier and/or air conditioning. The absence of air conditioning has been shown to be a factor contributing to increased mite allergen levels in US homes [249]. Air conditioners must be operated for a long time to remove sufficient moisture from the air to effectively decrease room humidity. Mechanical ventilation heat pump recovery units in the UK failed to achieve the desired mite reduction results [250].

Evidence on clinical benefits of dehumidification using mechanical ventilation with dehumidifiers remains scanty [225]. Although dehumidification and air conditioning doubtlessly reduce overall dust mite exposure [251], the difficulty in using dehumidification alone in damp environments to decrease dust mite antigen exposure has been described in a recent Cochrane review [225].

Summary of current recommendations

Most publications on allergy and dust mite control would agree that a comprehensive program of personal hygiene, bed hygiene, properly fitted allergen-impermeable covers, cleaning, dehumidification or air conditioning and appropriate food storage in very damp climates can reduce exposure to house dust mite allergens. It is a stretch further to conclude that the above steps can improve symptoms in those already allergic to dust mites. However, depending on the sensitivity and life style of the allergic person, prudent efforts over an extended period of time are likely to result in gradual improvement in health. The fact that current studies do not provide sufficient evidence for critical reviews to conclude there is unequivocal benefit is no reason to abandon logical and prudent efforts to reduce mite exposure.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Mite Allergy Research The authors view the following as currently unmet needs in mite allergy research: Since mites constitute the most important allergen source worldwide the information contained in this document needs to be disseminated to all ranks of the medical establishment for educational purposes and to stimulate research Increased knowledge on the cellular basis of the immune responses to mites A better understanding of the link between mite sensitization and allergic diseases Better insights into the genetic influences controlling IgE responses to mite allergens. Effects of epigenetic factors Improved mite allergen standardization Development of purified mite allergens with defined clinically relevant epitopes for molecular diagnosis and evaluation of the response to immunotherapy Development of objective methods to assess allergen exposure and environmental control outcomes Better strategies for immunotherapy and immunoprophylaxis of mite allergy: recombinant allergens, h

http://alexsfakianakis.blogspot.com/2017/05/mite-hypersensitivity.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Rick factors for medical and allergic events during air travel An increase of passenger’s age Flight stress and anxiety, including increased security procedures Disruption of routine Changes in the cabin environment (temperature, humidity, air pressure) Decreased seat space Flight delays Alcohol/drug intake Longer flights Altered circadian rhythm Jet lag Pre-existing medical conditions

http://alexsfakianakis.blogspot.com/2017/05/in-flight-allergic-emergencies.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

In-flight treatment of allergic emergencies and asthma Treating medical emergencies during flight is a major challenge and air travel is an important concern for subjects with asthma and a history of a SAR. The resources to treat allergic emergencies are somewhat limited. In the United States, the Federal Aviation Administration requires the inclusion of epinephrine in medical kits carried on board [18]. These emergency medical kits typically contain the following medications [19]: Aqueous epinephrine (adrenaline) 1:10000 and 1:1000 dilution. Albuterol (salbutamol) for nebulization. Bronchodilator aerosol inhaler. Cortisol (hydrocortisone). Antihistamines tablets and injectable (commonly diphenhydramine). A recommendation from this World Allergy Organization (WAO) expert group for in-flight treatment of a SAR and AE is: a) For AE, inhaled bronchodilator and oxygen. Consider an oral, intramuscular or intravenous corticosteroid for moderate to severe symptoms and intramuscular epinephr

http://alexsfakianakis.blogspot.com/2017/05/in-flight-allergic-emergencies.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Measures that reduce the risk of an in-flight reaction to peanut and tree nuts 1. Passengers requesting any kind of special accommodation (e.g., peanut/tree nut snacks not be distributed, announcement to not eat items with peanut/tree nut, request special peanut/tree nut-free meal, buffer zone, pre-board, request to sit in a certain seat/zone). 2. Peanut/tree nut-free meals. 3. Wiping of tray tables 4. Avoidance of airline pillows or blankets 5. Buffer zones around which peanut or nut products cannot be consumed 6. Request other passengers not to consume peanut/tree nut-containing products 7. Announcement that passengers do not eat peanut/tree nut containing goods 8. Not consuming airline-provided food

http://alexsfakianakis.blogspot.com/2017/05/in-flight-allergic-emergencies.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Recommendations to prevent and manage in-flight allergic events • Promote the prevention of allergic diseases via passenger education • Medical consultation for high-risk passengers before traveling • Train and re-train aircrews • Promote general preventive measures during the flight: hydration, food allergen avoidance (especially peanuts, tree nuts, other foods, as necessary) • Provide an appropriate place for furry pets away from subjects with pet allergy • Provide for sufficient quantities of appropriate medications: epinephrine (adrenaline), β2 agonists for inhalation and nebulization, oral and injectable corticosteroids and antihistamines • Oxygen

http://alexsfakianakis.blogspot.com/2017/05/in-flight-allergic-emergencies.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

The efficacy of a lip balm containing pseudo-ceramide on the dry lips of sensitive skin-conscious subjects

Summary

Background

Many people use lip care products daily to prevent dry lips. However, some people, especially those with sensitive skin-consciousness, complain of various skin problems on their lips including contact dermatitis caused by lip care products. Dry lips have decreased water holding capacity and cutaneous barrier function as well as reduced stratum corneum ceramide levels. In this study, we investigated the usefulness of a newly formulated lip balm containing pseudo-ceramide for the dry lips of subjects with sensitive skin.

Method

Thirty subjects with dry lips and sensitive skin-consciousness used the test lip balm more than twice a day for 4 weeks. Lip conditions were evaluated before and after 2 and 4 weeks.

Result

Visual evaluation by a dermatologist showed that overall improvements were observed in all subjects as early as week 2. After 4 weeks of usage, 27% of the subjects were objectively judged as "markedly improved" and 60% of the subjects were judged as "improved". No adverse event developed throughout the test period, and all subjects were able to use the lip balm safely for 4 weeks. Usefulness was judged based on all evaluation items, and 27%, 70%, and 3% of the subjects were judged as "very useful," "useful," and "slightly useful," respectively. Ninety percentage of the subjects expressed improvement and acceptance of the lip balm.

Conclusion

Based on these results, the newly formulated lip balm containing pseudo-ceramide is very useful for the lip care of sensitive skin-conscious subjects as well as for daily use by healthy subjects.

http://ift.tt/2qpvRjo

Ca2+ Release Channels Join the ‘Resolution Revolution’

Publication date: Available online 9 May 2017
Source:Trends in Biochemical Sciences
Author(s): Ran Zalk, Andrew R. Marks
Ryanodine receptors (RyRs) are calcium release channels expressed in the sarcoendoplasmic reticula of many cell types including cardiac and skeletal muscle cells. In recent years Ca²⁺ leak through RyRs has been implicated as a major contributor to the development of diseases including heart failure, muscle myopathies, Alzheimer's disease, and diabetes, making it an important therapeutic target. Recent mammalian RyR1 cryoelectron microscopy (cryo-EM) structures of multiple functional states have clarified longstanding questions including the architecture of the transmembrane (TM) pore and cytoplasmic domains, the location and architecture of the channel gate, ligand-binding sites, and the gating mechanism. As we advance toward complete models of RyRs this new information enables the determination of domain–domain interfaces and the location and structural effects of disease-causing RyR mutations.



http://ift.tt/2q247QI

Found in Translation: Applying Lessons from Model Systems to Strigolactone Signaling in Parasitic Plants

Publication date: Available online 9 May 2017
Source:Trends in Biochemical Sciences
Author(s): Shelley Lumba, Asrinus Subha, Peter McCourt
Strigolactones (SLs) are small molecules that act as endogenous hormones to regulate plant development as well as exogenous cues that help parasitic plants to infect their hosts. Given that parasitic plants are experimentally challenging systems, researchers are using two approaches to understand how they respond to host-derived SLs. The first involves extrapolating information on SLs from model genetic systems to dissect their roles in parasitic plants. The second uses chemicals to probe SL signaling directly in the parasite Striga hermonthica. These approaches indicate that parasitic plants have co-opted a family of α/β hydrolases to perceive SLs. The importance of this genetic and chemical information cannot be overstated since parasitic plant infestations are major obstacles to food security in the developing world.



http://ift.tt/2q4PoCR

Mechanisms and Dynamics of T Cell-Mediated Cytotoxicity In Vivo

Publication date: Available online 9 May 2017
Source:Trends in Immunology
Author(s): Stephan Halle, Olga Halle, Reinhold Förster
Cytotoxic T lymphocytes (CTLs) are critical in the elimination of infected or malignant cells and are emerging as a major therapeutic target. How CTLs recognize and kill harmful cells has been characterized in vitro but little is known about these processes in the living organism. Here we review recent insights into CTL-mediated killing with an emphasis on in vivo CTL biology. Specifically, we focus on the possible rate-limiting steps determining the efficiency of CTL-mediated killing. We also highlight the need for cell-based datasets that permit the quantification of CTL dynamics, including CTL location, migration, and killing rates. A better understanding of these factors is required to predict protective CD8 T cell immunity in vivo and to design optimized vaccination protocols.



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Dolichoectatic internal carotid artery presenting as a sellar-suprasellar mass with symptomatic hydrocephalus

Anita Jagetia, Ketan Patel, Deepashu Sachdeva, Lavlesh Rathore

Neurology India 2017 65(3):681-682



http://ift.tt/2q1GZSs

1892 and the tribulations of Joseph Babinski

Kalyan B Bhattacharyya

Neurology India 2017 65(3):468-470

In the early 1880s, Joseph Babinski was appointed as Chef de Clinique under Jean-Martin Charcot at Salpétrière, Paris, in France. He appeared for the post of Professeur Agrégé, the pinnacle of academic distinction in France in 1892. Charles Bouchard, the earliest pupil of Charcot, who described the Charcot-Bouchard aneurysm along with his master, was the Chief of the Board of Jury. Charcot and Bouchard did not see eye to eye in the later period, and when German Sée, an external examiner did not join the board of examiners following illness, Bouchard, instead of seeking the assistance of an alternate examiner, employed the special right of Vote of Absence. Babinski and all other pupils of Charcot were unsuccessful, while those of Bouchard, came out with flying colors. An embittered Babinski, along with some of the other unsuccessful candidates, appeared before the Ministry of Public Assistance after a protracted legal battle for nearly 2 years but lost the case. They were even ordered by the court to pay on behalf of the the successful candidates for the legal battle. Babinski never sat for the examination again and this is the story of one of the most ignominious episodes in an examination anywhere.

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Post-discectomy annular pseudocyst: A rare cause of failed back syndrome

G Lakshmi Prasad, Girish R Menon

Neurology India 2017 65(3):650-652



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Random reflections

Devika Nag

Neurology India 2017 65(3):456-459



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Two founders of Bombay neurosciences: Dr. Ramchandra G. Ginde and Dr. Menino De Souza

Sunil Pandya

Neurology India 2017 65(3):460-467



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Dengue fever triggering hemiconvulsion hemiplegia epilepsy in a child

Lokesh Saini, Biswaroop Chakrabarty, Harsh Pastel, Anil Israni, Atin Kumar, Sheffali Gulati

Neurology India 2017 65(3):636-638



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Dengue encephalitis: “Double doughnut” sign

Amith S Kumar, Sahil Mehta, Paramjeet Singh, Vivek Lal

Neurology India 2017 65(3):670-671



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Pediatric thoracolumbar spinal injuries: A rare and unique clinical scenario

Ajoy Prasad Shetty, Siddharth N Aiyer

Neurology India 2017 65(3):482-484



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Endoscopic management of intracranial cysts: Need of the hour

NK Venkataramana

Neurology India 2017 65(3):471-472



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Full-field perimetry in pituitary tumors

N Venugopal

Neurology India 2017 65(3):690-690



http://ift.tt/2q28V8O

Role of neuro-endoscopy and fenestration in the management of brain cysts

Iype Cherian

Neurology India 2017 65(3):473-474



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Cerebral venous thrombosis due to pheochromocytoma in a patient with Von Hippel Lindau mutation

Vivek K Nambiar, S Sajitha, Naveen Viswanath, VP Praveen, MR Bindhu

Neurology India 2017 65(3):643-645



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Clinical and health policy-related challenges of pediatric spinal cord injuries

Mario Ganau, Michael G Fehlings

Neurology India 2017 65(3):475-476



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Cost effective, technically simpler, and aesthetically promising cranioplasty in developing countries

Manish Baldia, Suryaprakash A Sharma, Krishna Prabhu, Santosh Koshy

Neurology India 2017 65(3):660-663



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Surgical considerations in the management of pediatric thoracolumbar fractures

So Kato, Stephen J Lewis

Neurology India 2017 65(3):477-479



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Central pontine myelinolysis associated with hypokalemia in a diabetic patient with sepsis

Sweety V Shinde

Neurology India 2017 65(3):674-675



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Pediatric thoracolumbar fractures: Salient points in management

Shankar Acharya

Neurology India 2017 65(3):480-481



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Clinicopathological conferences: The fading art of playing Sherlock Holmes

George C Vilanilam, Anita Mahadevan, Praveen Kumar John, Joe M Das

Neurology India 2017 65(3):685-688



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Movement disorders in anti-NMDA receptor encephalitis

Emilie Servais, Sophie Fastre, Philippe Hantson

Neurology India 2017 65(3):632-633



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Epilepsy surgery in children

Sita Jayalakshmi, Sudhindra Vooturi, Swapan Gupta, Manas Panigrahi

Neurology India 2017 65(3):485-492

Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In approximately 15% of these patients, the seizures are not adequately controlled with anticonvulsive drugs, and such patients are potential candidates for surgical treatment and majority are children. Epilepsy surgery in children, who have been carefully chosen, can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-third of children with intractable seizures. In the multimodality presurgical evaluation approach, sufficient concordance should be established among various independent investigations, thus identifying the location and extent of the epileptogenic zone with a high degree of confidence. Early surgery improves the quality of life and cognitive and developmental outcome of the child. Surgically remediable epilepsies in children should be identified early and include temporal lobe epilepsy with focal lesions, lesional extratemporal epilepsies, hemispherical epilepsies, and gelastic epilepsy with hypothalamic hamartoma, and can be treated by resective or disconnection surgery. Palliative procedures include corpus callosotomy and vagal nerve stimulation for children with diffuse and multifocal epilepsies, who are not candidates for resective surgery. Deep brain stimulation in patients with epilepsy is still under evaluation. For children with "surgically remedial epilepsy," surgery should be offered as a procedure of choice rather than as a treatment of last resort.

http://ift.tt/2pxvcbA

Radioactive iodine (RAI) therapy for metastatic differentiated thyroid cancer

Publication date: Available online 9 May 2017
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Frederik A. Verburg, Heribert Hänscheid, Markus Luster
Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. It usually has a comparatively benign course. If properly executed, radioiodine therapy can provide an effective treatment of even advanced, metastatic DTC. A major problem in determining the right RAI for a patient with metastatic disease is a comparative lack of evidence. There are no reports on randomized controlled trials in this patient group which can aid us in determining which way to treat which patient. Few non-randomized prospective observational studies have been performed. Most available evidence is based on retrospective analyses which, although often informative, still are hampered by the selection bias inherent to retrospective studies on a small, preselected sample of the total DTC population. The aim of the present review is to provide an overview of the relevant literature on the issues pertinent to the execution of RAI.Radioiodine therapy of metastatic DTC in patients can be an effective treatment modality which will contribute significantly to a patients' life expectancy. However, much is unclear in the management of this malignancy, including which activity to use, how to determine this activity (empiric vs. dosimetric approach) as well as the potential long-term complications. In pediatric patients, special considerations apply with regard to weight-adaptation of activities as well the risk of pulmonary fibrosis in patients with diffuse miliary metastases.



http://ift.tt/2q22gM3

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

Publication date: Available online 10 May 2017
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Valentina De Falco, Francesca Carlomagno, Hong-yu Li, Massimo Santoro
RET receptor tyrosine kinase acts as a mutated oncogenic driver in several human malignancies and it is over-expressed in other cancers. Small molecule compounds with RET tyrosine kinase inhibitory activity are being investigated for the targeted treatment of these malignancies. Multi-targeted compounds with RET inhibitory concentration in the nanomolar range have entered clinical practice. This review summarizes mechanisms of RET oncogenic activity and properties of new compounds that, at the preclinical stage, have demonstrated promising anti-RET activity.



http://ift.tt/2q4uTGc

Stimulus Expectation Prolongs Rather Than Shortens Perceived Duration: Evidence From Self-Generated Expectations.

Author: Birngruber, Teresa; Schroter, Hannes; Schutt, Emanuel; Ulrich, Rolf

DOI: 10.1037/xhp0000433

Publication Date: POST AUTHOR CORRECTIONS, 8 May 2017

http://ift.tt/2qY0EQj

Audiovisual Integration in Social Evaluation.

Author: Mileva, Mila; Tompkinson, James; Watt, Dominic; Burton, A. Mike

DOI: 10.1037/xhp0000439

Publication Date: POST AUTHOR CORRECTIONS, 8 May 2017

http://ift.tt/2piAJGZ

Synthesis of novel acyl selenoureido benzensulfonamides as carbonic anhydrase I, II, VII and IX inhibitors

Publication date: Available online 9 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Andrea Angeli, Fabrizio Carta, Gianluca Bartolucci, Claudiu T. Supuran
A novel series of acyl selenoureido benzensulfonamides was evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, VII and IX, which are involved in a variety of diseases such as glaucoma, retinitis pigmentosa, epilepsy and tumors etc. These compounds showed excellent inhibitory activity for these isoforms, with several low nanomolar derivatives identified against all of them. Furthermore, the selenoureido group may provide an antioxidant activity to these enzyme inhibitors.

Graphical abstract

http://ift.tt/2r0kxqP

Succinamide derivatives of melampomagnolide B and their anti-cancer activities

Publication date: Available online 8 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Venumadhav Janganati, Jessica Ponder, Shraddha Thakkar, Craig T. Jordan, Peter A. Crooks
A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a-3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a-4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d-3i and dimers 4f-4g exhibited promising anti-cancer activity with GI50 values ranging from 0.28-33.5 µM against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI50 values in the nanomolar range (GI50 = 280-980 nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c-3l and 4b-4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h-3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1-8.1 μM. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1-109) of human IKKβ to inhibit the NFκB transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NFκB control.

Graphical abstract

http://ift.tt/2pi5ZFW

Design, Synthesis and Evaluation of Indole-2-carboxamides with Pan Anti-mycobacterial Activity

Publication date: Available online 8 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Nicholas D. Franz, Juan Manuel Belardinelli, Michael A. Kaminski, Louis C. Dunn, Vinicius Calado Nogueira de Moura, Michael A. Blaha, Dan D. Truong, Wei Li, Mary Jackson, E. Jeffrey North
Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.

Graphical abstract

http://ift.tt/2qZZRiR

Metabolic regulation and the anti-obesity perspectives of human brown fat

Publication date: August 2017
Source:Redox Biology, Volume 12
Author(s): Camilla Scheele, Søren Nielsen
Activation of brown adipose tissue (BAT) in adult humans increase glucose and fatty acid clearance as well as resting metabolic rate, whereas a prolonged elevation of BAT activity improves insulin sensitivity. However, substantial reductions in body weight following BAT activation has not yet been shown in humans. This observation raise the possibility for feedback mechanisms in adult humans in terms of a brown fat-brain crosstalk, possibly mediated by batokines, factors produced by and secreted from brown fat. Batokines also seems to be involved in BAT recruitment by stimulating proliferation and differentiation of brown fat progenitors. Increasing human BAT capacity could thus include inducing brown fat biogenesis as well as identifying novel batokines. Another attractive approach would be to induce a brown fat phenotype, the so-called brite or beige fat, within the white fat depots. In adult humans, white fat tissue transformation into beige has been observed in patients with pheochromocytoma, a norepinephrine-producing tumor. Interestingly, human beige fat is predominantly induced in regions that were BAT during early childhood, possibly reflecting that a presence of human beige progenitors is depot specific and originating from BAT. In conclusion, to utilize the anti-obesity potential of human BAT focus should be directed towards identifying novel regulators of brown and beige fat progenitor cells, as well as feedback mechanisms of BAT activation. This would allow for identification of novel anti-obesity targets.

Graphical abstract

http://ift.tt/2qPAYsM

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis

Publication date: 15 July 2017
Source:Toxicology and Applied Pharmacology, Volume 327
Author(s): Wei Yang, Jin Zhao, Yake Wang, Haiwei Xu, Zhenwei Wu, Yangyang Hu, Kunkun Jiang, Pengpeng Shen, Cuiyun Ma, Zhenzhen Guan, Yan Zhang, Jiahui Ma, Ning Shang, Guangming Yan, Zhenji Wang, Guifu Dai
It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.



http://ift.tt/2qQ4bDY

Function of microRNA-143 in different signal pathways in cancer: New insights into cancer therapy

Publication date: July 2017
Source:Biomedicine & Pharmacotherapy, Volume 91
Author(s): Leila Karimi, Behzad Mansoori, Dariush shanebandi, Ali Mohammadi, Mahyar Aghapour, Behzad Baradaran
MicroRNAs (miRNAs) are small non-coding RNAs which participate in the post-transcriptional regulation of gene expression. They play important roles in cellular events such as growth and differentiation. Deregulation of miRNAs is frequently evident in human cancers where their aberrant expression is associated with uncontrolled proliferation, metastasis, impaired cell cycle and DNA damage response. The miRNAs are important in cancer as ∼50% of miRNA genes are located in cancer-associated regions such as fragile sites of genome. MiRNA-143 is defined as an important tumor suppressor in a variety of neoplasms including solid tumors and B-cell malignancies. MiRNA-143 is involved in the pathogenesis of cancers by directly targeting several mRNAs such as Bcl-2, KRAS, HK2, DNMT3A, TP53 and MMP-13. In this study, an overview of the miRNA-143 function in different signaling pathways in cancer will be provided.



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27 Refractory Angina

Publication date: 2018
Source:Chronic Coronary Artery Disease
Author(s): E. Marc Jolicoeur, Timothy D. Henry




http://ift.tt/2mtQl5v

Index

Publication date: 2018
Source:Chronic Coronary Artery Disease





http://ift.tt/2mRTDSQ

Incorporation of BMP-2 loaded collagen conjugated BCP granules in calcium phosphate cement based injectable bone substitutes for improved bone regeneration

Publication date: 1 August 2017
Source:Materials Science and Engineering: C, Volume 77
Author(s): Gun Hee Lee, Preeti Makkar, Kallyanshis Paul, ByongTaek Lee
The objective of the present study was to incorporate surface modified porous multichannel BCP granule into CPC to enhance its in vivo biodegradation and bone tissue growth. The multichannel BCP granule (15wt%) was first coated with collagen subsequent to BMP-2 loading (ccMCG-B). It was then embedded into CPC to form CPC-ccMCG-B system. The newly developed CPC-ccMCG-B system was then examined for SEM, EDX, XRD, setting time, compressive strength, injectability, pH change, BMP-2 release, in vitro as well as in vivo studies and further compared with CPC. Optimized CPC (0.45mL/g) was found based on setting time and compressive strength studies. In vivo studies exhibited improved new bone formation and better degradation of CPC after 2 and 4weeks of implantation as compared to CPC as resulted from effective BMP-2 signaling. Our results suggest that CPC-ccMCG-B system might be used as a promising injectable bone substitutes in clinical applications.



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Embryonic vascular disruption adverse outcomes: Linking high-throughput signaling signatures with functional consequences

Publication date: August 2017
Source:Reproductive Toxicology, Volume 71
Author(s): Robert G. Ellis-Hutchings, Raja S. Settivari, Alene T. McCoy, Nicole Kleinstreuer, Jill Franzosa, Thomas B. Knudsen, Edward W. Carney
Embryonic vascular disruption is an important adverse outcome pathway (AOP) as chemical disruption of cardiovascular development induces broad prenatal defects. High-throughput screening (HTS) assays aid AOP development although linking in vitro data to in vivo apical endpoints remains challenging. This study evaluated two anti-angiogenic agents, 5HPP-33 and TNP-470, across the ToxCastDB HTS assay platform and anchored the results to complex in vitro functional assays: the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) assay. Both were identified as putative vascular disruptive compounds (pVDCs) in ToxCastDB and disrupted angiogenesis and embryogenesis in the functional assays. Differences were observed in potency and adverse effects: 5HPP-33 was embryolethal (WEC and ZET); TNP-470 produced caudal defects at lower concentrations. This study demonstrates how a tiered approach using HTS signatures and complex functional in vitro assays might be used to prioritize further in vivo developmental toxicity testing.



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Chapter 6 Neoplasia

Publication date: 2018
Source:Robbins Basic Pathology





http://ift.tt/2piqeDw

Core-shell hierarchical mesostructured silica nanoparticles for gene/chemo-synergetic stepwise therapy of multidrug-resistant cancer

Publication date: July 2017
Source:Biomaterials, Volume 133
Author(s): Lijun Sun, Dangge Wang, Yu Chen, Liying Wang, Ping Huang, Yaping Li, Ziwei Liu, Heliang Yao, Jianlin Shi
The design and synthesis of hierarchically nanoporous structures for the co-encapsulation and sequential releases of different cargos are still great challenges in biomedical applications. In this work, we report on the elaborate design and controlled synthesis of a unique core-shell hierarchical mesoporous silica/organosilica nanosystem, in which there are large and small mesopores separately present in the shell and core, facilitating the independent encapsulations of large (siRNA) and small (doxorubicin) molecules, respectively. Importantly, the framework of the organosilica shell is molecularly hybridized with disulfide bonds, which enables the unique responsiveness to the reductive tumor microenvironment for the controlled releasing of loaded gene molecules, followed by the subsequent doxorubicin release. The first released large siRNA molecules from the organosilica shell down-regulated the expression of P-gp in the cell membrane and reversed the MDR of cancer cells, thus enhancing the antitumor effect of subsequently released small DOX molecules from the silica core, and in such a synergetic way the MDR tumor growth can be efficiently inhibited. This work shows the significant advantages compared to the traditional small-mesoporous or large-mesoporous nanosystems for drug co-delivery.

Graphical abstract

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39 Hypertension in Pregnancy

Publication date: 2018
Source:Hypertension: A Companion to Braunwald's Heart Disease
Author(s): Line Malha, Tiina Podymow, Phyllis August




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20 The Medical Treatment of Stable Angina

Publication date: 2018
Source:Chronic Coronary Artery Disease
Author(s): Lawrence Kwon, Clive Rosendorff




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35 Pulmonary Manifestations of Systemic Diseases

Publication date: 2018
Source:Pulmonary Pathology
Author(s): Haresh Mani, Dani S. Zander




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Angiogenesis in the atherosclerotic plaque

Publication date: August 2017
Source:Redox Biology, Volume 12
Author(s): Caroline Camaré, Mélanie Pucelle, Anne Nègre-Salvayre, Robert Salvayre
Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations.

Graphical abstract

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Chapter 5 Diseases of the Immune System

Publication date: 2018
Source:Robbins Basic Pathology





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Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity

Publication date: August 2017
Source:Redox Biology, Volume 12
Author(s): Shikha Prasad, Ravi K. Sajja, Mohammad Abul Kaisar, Jee Hyun Park, Heidi Villalba, Taylor Liles, Thomas Abbruscato, Luca Cucullo
Cigarette smoking (CS) is associated with vascular endothelial dysfunction in a causative way primarily related to the TS content of reactive oxygen species (ROS), nicotine, and inflammation. TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Herein we provide evidence of the role played by nuclear factor erythroid 2-related factor (Nrf2) in CS-induced cerebrobvascular/BBB impairments and how these cerebrovascular harmful effects can be circumvented by the use of metformin (MF; a widely prescribed, firstline anti-diabetic drug) treatment. Our data in fact revealed that MF activates counteractive mechanisms primarily associated with the Nrf2 pathway which drastically reduce CS toxicity at the cerebrovascular level. These include the suppression of tight junction (TJ) protein downregulation and loss of BBB integrity induced by CS, reduction of inflammation and oxidative stress, renormalization of the expression levels of the major BBB glucose transporter Glut-1 and that of the anticoagulant factor thrombomodulin. Further, we provide additional insights on the controversial interplay between Nrf2 and AMPK.

Graphical abstract

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Myricetin suppresses invasion and promotes cell death in human placental choriocarcinoma cells through induction of oxidative stress

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Changwon Yang, Whasun Lim, Fuller W. Bazer, Gwonhwa Song
Myricetin is a bioactive compound found in a variety of vegetables and fruits, and its anti-cancer effects are well known. In this study, we confirmed that myricetin reduced proliferation of two choriocarcinoma cell lines (JAR and JEG-3) and also promoted apoptosis and regulated cell cycle progression in a dose-dependent manner in JAR and JEG-3 cells. In addition, we found that invasive and pro-angiogenic properties of malignant JAR and JEG-3 trophoblast cells were attenuated by myricetin treatment via MAPK and PI3K/AKT signaling pathways. In addition, we found that ROS production, lipid peroxidation, glutathione depletion, and loss of mitochondrial membrane potentials were enhanced in JAR and JEG-3 cells treated with myricetin. Moreover, myricetin augmented cytosolic Ca²⁺ release from the endoplasmic reticulum associated with modulation of ER stress in JAR and JEG-3 cells. Our results also revealed that myricetin had synergistic antiproliferative effects with current chemotherapeutics, etoposide and cisplatin, on choriocarcinoma cells. Collectively, results of the present study provide strong evidence for the potential of myricetin to be an effective therapeutic for the prevention of human placental choriocarcinomas.



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Chapter 11 Heart

Publication date: 2018
Source:Robbins Basic Pathology





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Construction of three-dimensional vascularized functional human liver tissue using a layer-by-layer cell coating technique

Publication date: July 2017
Source:Biomaterials, Volume 133
Author(s): Kazuki Sasaki, Takami Akagi, Tadafumi Asaoka, Hidetoshi Eguchi, Yasunari Fukuda, Yoshifumi Iwagami, Daisaku Yamada, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Koichi Kawamoto, Yuichiro Doki, Masaki Mori, Mitsuru Akashi
The creation of artificial liver tissue is an active area of research due to the shortage of donors for liver transplantation. Here we investigated whether a simple and efficient cell coating technique developed in our laboratory could be used to generate functional vascularized liver tissue. This technique creates three-dimensional tissue by loading cells sterically onto other cells that have been coated with layer-by-layer (LbL) nanofilms of fibronectin and gelatin, two extracellular matrix proteins. We used this technique to construct homogenous, dense, well-vascularized liver tissue from cryopreserved human primary hepatocytes, human umbilical vein endothelial cells, and normal human dermal fibroblasts. Using LbL cell coating technique resulted in higher cellular function in terms of human albumin production (P < 0.01) and cytochrome P450 activity (P < 0.01) in vitro. Furthermore, after being transplanted subcutaneously into NOD/SCID mice, the vascularized liver tissue showed greater albumin production in the early stage than non-vascularized tissue or a hepatocyte suspension (P < 0.01). Histological examination demonstrated that compare to non-vascularized tissue, there were many less-morphologically changed and intact hepatocytes in the vascularized tissue. This cell coating technique would be applicable to the generation of vascularized functional liver tissue for regenerative medicine in the future.



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Scholar : These new articles for Acta Oncologica are available online

The online platform for Taylor & Francis Online content New for Acta Oncologica and online now on Taylor & Francis Online: LETTER TO THE EDITOR Metastatic melanoma in a 95 years old patient responding to treatment with talimogene laherparepvec followed by nivolumab Abdul R. Naqash, Geoffrey Stroud, Frances A. Collichio, Mahvish Muzaffar, Nitika Sharma & Paul Walker Pages: 1-4 | DOI: 10.1080/0284186X.2017.1324212 Free access World Diabetes Day research collection – Eyes on Diabetes. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

15 Cancer in Pregnancy

Publication date: 2018
Source:Clinical Gynecologic Oncology
Author(s): Krishnansu S. Tewari




http://ift.tt/2qPVjOF

Baseline carcinoembryonic antigen as a predictive factor of ramucirumab efficacy in RAISE, a second-line metastatic colorectal carcinoma phase III trial

Publication date: June 2017
Source:European Journal of Cancer, Volume 78
Author(s): Takayuki Yoshino, Radka Obermannová, György Bodoky, Rocio Garcia-Carbonero, Tudor Ciuleanu, David C. Portnoy, Tae Won Kim, Yanzhi Hsu, David Ferry, Federico Nasroulah, Josep Tabernero
BackgroundThe RAISE phase III clinical trial demonstrated that ramucirumab + (folinic acid plus 5-fluorouracil plus irinotecan) FOLFIRI significantly improved overall survival (OS) versus placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients failing bevacizumab- and oxaliplatin-based chemotherapy (hazard ratio [HR] = 0.84, 95% CI = 0.73–0.98, P = 0.022). Post hoc analyses of RAISE patient data examined the association of carcinoembryonic antigen (CEA) subgroups with efficacy parameters.MethodsCEA subgroups (≤10 versus >10 ng/ml) were based on 2X upper limit of normal (ULN) (5 ng/ml). The Kaplan–Meier method estimated the median OS and the progression-free survival (PFS). Log-rank test compared the survival distributions within the subgroups. Hazard ratio (HR) (95% confidence interval [CI]) and treatment-by-subgroup interaction p-values were calculated by Cox proportional hazards model.ResultsRamucirumab treatment prolonged survival for the CEA ≤10 subgroup (HR = 0.68; 95% CI = 0.50–0.92; P = 0.013) and CEA >10 subgroup (HR = 0.90; 95% CI = 0.76–1.07; P = 0.233). However, the ramucirumab OS benefit over placebo was greater for the CEA ≤10 subgroup than for the CEA >10 subgroup (median OS: 3.6 versus 0.8 months greater, respectively). The interaction P-value between CEA level and treatment effect on OS was 0.088. This trend was observed across randomisation strata and to a lesser extent for PFS (P = 0.594).ConclusionsAlthough patients in both high- and low-CEA subgroups derive OS and PFS benefits from ramucirumab treatment, the low baseline CEA level may identify a subgroup of patients with mCRC who obtain greater benefit from ramucirumab.



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Targeting tumor associated macrophages (TAMs) via nanocarriers

Publication date: 28 May 2017
Source:Journal of Controlled Release, Volume 254
Author(s): Yuvraj Singh, Vivek Kumar Pawar, Jaya Gopal Meher, Kavit Raval, Animesh Kumar, Richa Shrivastava, Smrati Bhadauria, Manish K. Chourasia
Recruitment of inflammatory cells to tumor has been well documented, with the most frequent inhabitants being macrophages termed as tumor associated macrophages, (TAMs). Their presence was thought to be an evidence of immune system initiating a fight response towards the tumor, i.e. immune surveillance. This is the case too initially, when TAMs majorly exhibit an M1 phenotype, but their continued presence in tumor microenvironment brings about their polarization to M2 phenotype, which not only participate in continued sustenance of existing tumor but also open up deleterious avenues for further progression and metastasis of cancer. Current perspective is built around this very premise and focuses specifically on TAMs and how they are being targeted by researchers working in annals of nanomedicine. To do so, we dwell into tumor microenvironment and focus on nanotechnology based drug delivery aspects which have either been already or can be potentially employed in the future to target tumor associated macrophages for improved immunoadjuvant therapy of cancer.

Graphical abstract

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11 Epithelial Ovarian Cancer

Publication date: 2018
Source:Clinical Gynecologic Oncology
Author(s): Eric L. Eisenhauer, Ritu Salani, Larry J. Copeland




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Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell

Publication date: June 2017
Source:Regenerative Therapy, Volume 6
Author(s): Yoshio Sakai, Masayuki Takamura, Akihiro Seki, Hajime Sunagozaka, Takeshi Terashima, Takuya Komura, Masatoshi Yamato, Masaki Miyazawa, Kazunori Kawaguchi, Alessandro Nasti, Hatsune Mochida, Soichiro Usui, Nobuhisa Otani, Takahiro Ochiya, Takashi Wada, Masao Honda, Shuichi Kaneko
IntroductionAdipose tissue stromal cells contain a substantial number of mesenchymal stem cells. As such, their application to regeneration of miscellaneous impaired organs has attracted much attention.MethodsWe designed a clinical study to investigate freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell (ADRC) therapy for liver cirrhosis and conducted treatment in four cirrhotic patients. ADRCs were isolated from autologous subcutaneous adipose tissue obtained by the liposuction method, followed with use of the Celution system adipose tissue dissociation device. The primary endpoint is assessment of safety one month after treatment. We also characterized the obtained ADRCs.ResultsTwo patients had type C cirrhosis, one had nonalcoholic steatohepatitis-cirrhosis, and one had type B cirrhosis. No serious adverse events were observed during the 1-month study period after freshly isolated ADRC infusion. Serum albumin concentrations were maintained or improved during this period as well as during the succeeding follow-up of approximately 1 year in two patients and 6 months in another patient. Liver regeneration-related factors, namely hepatocyte growth factor and interleukin-6, were elevated 1 day after ADRC treatment in all patients. The obtained freshly isolated ADRCs were expanded in culture and found to express mesenchymal stem cell markers. Gene expression profile analysis of ADRCs was shown to involve inflammatory features, suggesting that characteristics of the obtained ADRCs were related to immunomodulatory biological effects.ConclusionThis clinical study treatment for liver cirrhosis using ADRCs was proven to be safely conductible, and can be further investigated in future for regeneration/repair of liver cirrhosis.



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Mechanisms of sphingosine 1-phosphate receptor signalling in cancer

Publication date: June 2017
Source:Cellular Signalling, Volume 34
Author(s): Sathya Narayanan Patmanathan, Wei Wang, Lee Fah Yap, Deron R. Herr, Ian C. Paterson
S1P is a small bioactive lipid which exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P1–5. Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of S1P receptors (S1PRs) in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P. However, cooperativity between the individual S1PRs, functional interactions with receptor tyrosine kinases and the sub-cellular localisation of the S1PRs within tumour cells also appear to play a role in mediating the effects of S1PR signalling during carcinogenesis. Here we review what is known regarding the role of individual S1PRs in cancer and discuss the recent evidence to suggest cross-talk between the S1PRs and other cellular signalling pathways in cancer. We will also discuss the therapeutic potential of targeting the S1PRs and their downstream signalling pathways for the treatment of cancer.



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17 Basic Principles of Chemotherapy

Publication date: 2018
Source:Clinical Gynecologic Oncology
Author(s): Christina S. Chu, Stephen C. Rubin




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Osteonecrosis of jaw after antiangiogenic agent administration in a renal cell carcinoma patient

Publication date: June 2017
Source:Oral and Maxillofacial Surgery Cases, Volume 3, Issue 2
Author(s): Tae-Young Jung
A 62-year-old patient had characteristics corresponding to the diagnostic criteria of medication-related osteonecrosis of the jaw (MRONJ). She had been treated for renal cell carcinoma with radical nephrectomy and chemotherapy with pazopanib (Votrient^®) and everolimus (Afinitor^®) antiangiogenic agents. There was no history of radiation therapy, obvious metastatic disease or surgical treatment. Bone exposure was observed in both mandibular posterior regions. Bone necrosis had developed surrounding the #35=37 and 46, 47 implants installed 6 years prior. The lesions were diagnosed as MRONJ and the patient was treated by sequestrectomy, saucerization and reconstruction with a reconstruction plate. The clinical results were good.



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18 Targeted Therapy and Molecular Genetics

Publication date: 2018
Source:Clinical Gynecologic Oncology
Author(s): Shannon N. Westin, Anil K. Sood, Robert L. Coleman




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PDGFs and their receptors

Publication date: 30 May 2017
Source:Gene, Volume 614
Author(s): Andrius Kazlauskas
The platelet-derived growth factor (PDGF)/PDGFR receptor (PDGFR) family is essential for a vast array of physiological processes such as migration and proliferation of percityes that contribute to the formation and proper function of blood vessels. While ligand-dependent de-repression of the PDGFR's kinase activity is the major mode by which the PDGFR is activated, there are additional mechanisms to activate PDGFRs. Deregulated PDGFR activity contributes to various pathological conditions, and hence the PDGF/PDGFR family members are viable therapeutic targets. An increased appreciation of which PDGFR contributes to pathology, biomarkers that indicate the amplitude and mode of activation, and receptor-specific antagonists are necessary for the development of next-generation therapies that target the PDGF/PDGFR family.



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Chapter 1 The Cell as a Unit of Health and Disease

Publication date: 2018
Source:Robbins Basic Pathology





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3 Invasive Cervical Cancer

Publication date: 2018
Source:Clinical Gynecologic Oncology
Author(s): Krishnansu S. Tewari, Bradley J. Monk




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18 Cardiopulmonary Complications of Cirrhosis

Publication date: 2018
Source:Zakim and Boyer's Hepatology
Author(s): Moises I. Nevah, Asha C. Kuruvilla, Michael B. Fallon




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Targeting ligand–receptor interactions for development of cancer therapeutics

Publication date: June 2017
Source:Current Opinion in Chemical Biology, Volume 38
Author(s): Jun Woo Kim, Jennifer R Cochran
The biological importance and druggable properties of receptors and their cognate ligands have designated them as especially useful clinical targets. This significance continues to expand as new molecular insights underlying disease pathophysiology are uncovered. While both ligands and receptors have been exploited as drug targets, their differing biochemical properties require nuanced considerations for drug development, including where in the body they are located and how they are regulated on a cellular and molecular level. In this review we will discuss ligands and receptors as therapeutics targets, including their biodistribution and biological function. We provide examples of monoclonal antibodies (mAbs) used to modulate the activity of these targets, and discuss approaches for using engineered versions of ligands and receptors themselves for therapeutic intervention in cancer.

Graphical abstract

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64 Fibrocystic Diseases of the Liver

Publication date: 2018
Source:Zakim and Boyer's Hepatology
Author(s): Joost P.H. Drenth, Jesus M. Banales, Kalpana M. Devaraj, Steve M. Helmke, Gregory Thomas Everson




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Efficacy of bevacizumab therapy in recurrent malignant gliomas in relation to the prior recurrence pattern or tumor location

Publication date: June 2017
Source:Journal of Clinical Neuroscience, Volume 40
Author(s): Masahide Matsuda, Eiichi Ishikawa, Tetsuya Yamamoto, Hiroyoshi Akutsu, Shingo Takano, Akira Matsumura
Although promising preliminary results have been widely observed with bevacizumab for recurrent malignant gliomas, many unanswered questions remain to be resolved to achieve an optimal outcome. No predictive biomarkers of a survival benefit from bevacizumab have been established, and no consensus exists about the response or survival benefit regarding the prior recurrence pattern or tumor location. Here we retrospectively analyzed the clinical benefit from bevacizumab for recurrent malignant gliomas in relation to the prior recurrence pattern or tumor location. Thirty-one consecutive patients with recurrent malignant gliomas who were treated with bevacizumab were investigated. The treatment response and survival benefit from bevacizumab were analyzed in association with age, sex, Karnofsky performance status, prior pathological diagnosis, prior recurrence pattern, primary location of tumor, recurrence status, and expression of angiogenic and hypoxic markers. The group with leptomeningeal dissemination had a significantly shorter median overall survival with bevacizumab (OSBev) (6.0months, 95% confidence interval (CI) 1.4–10.7) compared to those in the local/distant group (11.8months, 95% CI 6.1–17.4). The median OSBev of the infratentorial tumor group and supratentorial tumor group were 9.2months (95% CI 5.0–13.4) and 10.4months (95% CI 6.6–14.3), respectively. With multivariate analysis, the prior recurrence pattern was the only independent prognostic factor of OSBev. Patients with leptomeningeal dissemination of recurrent malignant glioma experienced minimal benefit from bevacizumab. Therefore, in the context of cost effectiveness, bevacizumab is not recommended for patients with leptomeningeal dissemination.



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Recent advances in the development of novel protein scaffolds based therapeutics

Publication date: September 2017
Source:International Journal of Biological Macromolecules, Volume 102
Author(s): Asim Azhar, Ejaj Ahmad, Qamar Zia, Mohd. Ahmar Rauf, Mohammad Owais, Ghulam Md Ashraf
Antibodies occupy a central position when it comes to binding proteins with desired antigenic specificities. During the past decade, a plethora of recombinant or humanized versions of antibodies have entered clinical settings with outstanding accomplishments. Yet, they suffer from several drawbacks such as high molecular weight, limited tissue penetration, instability, high production cost, requirement for large doses and potential cytotoxicity. As a result, new generation of receptor proteins has been developed, that are derived from small and robust immunoglobulin (Ig) or non-immunoglobulin based "scaffolds". Combinatorial protein engineering has tremendous scope in the development of these protein scaffolds with immunoglobulin like specificity and/or prescribed binding functions. The advancement made in this regard can boast of developing various validated Ig based and non-Ig protein scaffolds with desirable therapeutic potential. The newly emerging technology has profound scope in translational biology and offer matching replacement for existing immunotherapeutic agents. Only few data from early clinical studies are available yet, but many more are likely to come in the near future. Here, we provide a glimpse of recent clinical advances in the field of existing protein scaffolds.



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Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Publication date: June 2017
Source:Pharmacological Research, Volume 120
Author(s): Maria Assunta Potenza, Carmela Nacci, Maria Antonietta De Salvia, Luca Sgarra, Massimo Collino, Monica Montagnani
The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelial-derived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

Graphical abstract

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