Persistent Intracellular Staphylococcus aureus in Keratinocytes Lead to Activation of the Complement System with Subsequent Reduction in the Intracellular Bacterial Load.

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Persistent Intracellular Staphylococcus aureus in Keratinocytes Lead to Activation of the Complement System with Subsequent Reduction in the Intracellular Bacterial Load.

Front Immunol. 2018;9:396

Authors: Abu-Humaidan AH, Elvén M, Sonesson A, Garred P, Sørensen OE

Abstract
The complement system is an ancient part of the innate immune system important for both tissue homeostasis and host defense. However, bacteria like Staphylococcus aureus (SA) possess elaborative mechanisms for evading both the complement system and other parts of the immune system. One of these evasive mechanisms-important in causing chronic and therapy resistant infections-is the intracellular persistence in non-immune cells. The objective of our study was to investigate whether persistent intracellular SA infection of epidermal keratinocytes resulted in complement activation. Using fluorescence microscopy, we found that persistent SA, surviving intracellularly in keratinocytes, caused activation of the complement system with formation of the terminal complement complex (TCC) at the cell surface. Skin samples from atopic dermatitis patients analyzed by bacterial culture and microscopy, demonstrated that SA colonization was associated with the presence of intracellular bacteria and deposition of the TCC in epidermis in vivo. Complement activation on keratinocytes with persistent intracellular bacteria was found with sera deficient/depleted of the complement components C1q, Mannan-binding lectin, or complement factor B, demonstrating involvement of more than one complement activation pathway. Viable bacterial counts showed that complement activation at the cell surface initiated cellular responses that significantly reduced the intracellular bacterial burden. The use of an inhibitor of the extracellular signal-regulated kinase (ERK) abrogated the complement-induced reduction in intracellular bacterial load. These data bridge the roles of the complement system in tissue homeostasis and innate immunity and illustrate a novel mechanism by which the complement system combats persistent intracellular bacteria in epithelial cells.

PMID: 29545804 [PubMed]

http://ift.tt/2tT7Jby

Comparative and molecular analysis of MRSA isolates from infection sites and carrier colonization sites.

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Comparative and molecular analysis of MRSA isolates from infection sites and carrier colonization sites.

Ann Clin Microbiol Antimicrob. 2018 Mar 15;17(1):7

Authors: Alkharsah KR, Rehman S, Alkhamis F, Alnimr A, Diab A, Al-Ali AK

Abstract
BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) constitutes a major global health concern causing hospital and community acquired infections. A wide diversity of MRSA genotypes are circulating in geographically related regions. Therefore understanding the molecular epidemiology of MRSA is fundamental to design control and clearance measures.
METHODS: A total of 106 MRSA isolates from infection (51) and carrier colonization sites (55) are characterized genetically based on SCCmec and MLST genotyping methods in addition to detection of PVL, TSST-1 and enterotoxins.
RESULTS: Sccmec-IV was the most frequently detected genotype (77.3%) followed by genotype V (13.2%) and III (9.4%). SCCmec-IVa was more prevalent among the carrier group (p value 0.002). CC80 was the most commonly identified clonal complex (CC). CC6 and CC22 were significantly more prevalent among the carrier group (p value 0.02 and 0.01, respectively). PVL was highly prevalent among the isolates (58.5%). PVL was detected in 70.6% of isolates from infection sites and 47.3% of isolates from carriers. All strains were sensitive to vancomycin, however, MRSA strains isolated from infection sites had significantly higher MICs compared to strains isolated from carrier colonization sites (p value 0.021). Five new sequence types mainly from the carrier group were identified and described in the study.
CONCLUSIONS: MRSA population is genetically very diverse among carriers and infected individuals. With SCCmec type IV being most prevalent, this suggests a community origin of most MRSA strains. Therefore very well designed surveillance and clearance strategies should be prepared to prevent emergence and control spread of MRSA in the community.

PMID: 29544544 [PubMed - in process]

http://ift.tt/2FKOQNi

Analyzing the antiseptic capacity of silver-functionalized poly(ethylene glycol)-heparin hydrogels after human whole blood exposure.

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Analyzing the antiseptic capacity of silver-functionalized poly(ethylene glycol)-heparin hydrogels after human whole blood exposure.

Biomater Sci. 2018 Mar 15;:

Authors: Schulz S, Maitz M, Hänsel S, Renner LD, Werner C

Abstract
Advanced blood contacting biomaterials are designed to combine antiseptic and anticoagulant functionalities. Here, we present a new in vitro methodology for the analysis of bacterial adhesion and growth after the preceding human whole blood incubation of the tested materials. Poly(styrene) surfaces as well as thrombin-responsive and non-responsive poly(ethylene glycol)-heparin hydrogel coatings, with and without silver functionalization, were analyzed with this approach using freshly drawn human whole blood and various human pathogens (Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli). Adsorbed blood proteins and adherent immune cells were observed to suppress bacterial colonization on poly(styrene) surfaces. Silver functionalization of responsive and non-responsive poly(ethylene glycol)-heparin hydrogels had no influence on microbial attachment but decreased bacterial proliferation and viability. Whole blood pre-incubation did not affect the antimicrobial properties of the tested silver-modified hydrogels. In sum, our introduced multistage incubation test revealed the antibacterial effects as well as antiseptic-permissive characteristics of blood-borne interfacial layers on polymeric biomaterials.

PMID: 29542739 [PubMed - as supplied by publisher]

http://ift.tt/2tT7D3G

Effect of Lactobacillus rhamnosus HN001 on carriage of Staphylococcus aureus: results of the impact of probiotics for reducing infections in veterans (IMPROVE) study.

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Effect of Lactobacillus rhamnosus HN001 on carriage of Staphylococcus aureus: results of the impact of probiotics for reducing infections in veterans (IMPROVE) study.

BMC Infect Dis. 2018 Mar 14;18(1):129

Authors: Eggers S, Barker AK, Valentine S, Hess T, Duster M, Safdar N

Abstract
BACKGROUND: Infection by Staphylococcus aureus (S. aureus) is a major cause of morbidity and mortality. Colonization by S. aureus increases the risk of infection. Little is known about decolonization strategies for S. aureus beyond antibiotics, however probiotics represent a promising alternative. A randomized controlled trial was conducted to determine the efficacy of Lactobacillus rhamnosus (L. rhamnosus) HN001 in reducing carriage of S. aureus at multiple body sites.
METHODS: One hundred thirteen subjects, positive for S. aureus carriage, were recruited from the William S. Middleton Memorial Medical Center, Madison, WI, USA, and randomized by initial site of colonization, either gastrointestinal (GI) or extra-GI, to 4-weeks of oral L. rhamnosus HN001 probiotic, or placebo. Nasal, oropharyngeal, and axillary/groin swabs were obtained, and serial blood and fecal samples were collected. Differences in prevalence of S. aureus carriage at the end of the 4-weeks of treatment were assessed.
RESULTS: The probiotic and placebo groups were similar in age, gender, and health history at baseline. S. aureus colonization within the stool samples of the extra-GI group was 15% lower in the probiotic than placebo group at the endpoint of the trial. Those in the probiotic group compared to the placebo group had 73% reduced odds (OR 0.27, 95% CI 0.07-0.98) of methicillin-susceptible S. aureus presence, and 83% reduced odds (OR 0.17, 95% CI 0.04-0.73) of any S. aureus presence in the stool sample at endpoint.
CONCLUSION: Use of daily oral L. rhamnosus HN001 reduced odds of carriage of S. aureus in the GI tract, however it did not eradicate S. aureus from other body sites.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01321606 . Registered March 21, 2011.

PMID: 29540160 [PubMed - in process]

http://ift.tt/2Gzt1gZ

Lipoteichoic Acid Inhibits Staphylococcus aureus Biofilm Formation.

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Lipoteichoic Acid Inhibits Staphylococcus aureus Biofilm Formation.

Front Microbiol. 2018;9:327

Authors: Ahn KB, Baik JE, Yun CH, Han SH

Abstract
A biofilm is an aggregate of microorganisms in which cells adhere to biological or non-biological surfaces and is responsible for various infectious diseases. Infections caused by Staphylococcus aureus, including pneumonia, endocarditis, and osteomyelitis, are often associated with colonization and biofilm formation. Although lipoteichoic acid (LTA) is involved in biofilm formation, the specific role of LTA is not clearly understood. In this study, we demonstrated that LTA released from Lactobacillus plantarum could inhibit S. aureus biofilm formation and aggregation without affecting the growth of S. aureus in various in vitro and in vivo models. L. plantarum LTA (Lp.LTA) also inhibited biofilm formation of S. aureus clinical isolates, including a methicillin-resistant strain. Remarkably, Lp.LTA not only interfered with S. aureus biofilm formation, but it also disrupted a pre-formed biofilm. Mechanism studies demonstrated that Lp.LTA inhibited expression of the ica-operon, which is responsible for the production of poly-N-acetylglucosamine, a key molecule required for S. aureus biofilm development. Lp.LTA increased the release of autoinducer-2 from S. aureus, which contributed to the inhibition of S. aureus biofilm formation. Moreover, Lp.LTA treatment enhanced susceptibility of the biofilm to various antibiotics and to macrophages. Interestingly, Lp.LTA without D-alanine moieties was not able to inhibit biofilm formation by S. aureus. In conclusion, the present study suggests that LTA can inhibit S. aureus biofilm formation, and therefore could be applied for preventing and/or treating infectious diseases caused by S. aureus biofilms.

PMID: 29535693 [PubMed]

http://ift.tt/2u4QuEj

Predominance of methicillin-resistant Staphylococcus aureus in the residents and environments of long-term care facilities in Taiwan.

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Predominance of methicillin-resistant Staphylococcus aureus in the residents and environments of long-term care facilities in Taiwan.

J Microbiol Immunol Infect. 2018 Feb 21;:

Authors: Liu CY, Lai CC, Chiang HT, Lu MC, Wang LF, Tsai TL, Kang MY, Jan YN, Lo YT, Ko WC, Tseng SH, Lee CM, Hsueh PR, Infection Control Society of Taiwan

Abstract
BACKGROUND/PURPOSE: This study investigated the distribution and persistence of multidrug resistant organisms (MDROs) including methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and multidrug-resistant Acinetobacter baumannii (MDRAB) in six long-term care facilities (LTCFs).
METHODS: We investigated the distribution of MDROs in residents of six LTCFs and their environments from January to December 2016 (intervention period). Active surveillance of colonization of MDROs was performed by culturing rectal and nasal swab samples from the residents every three months. Multilocus sequence typing (MLST) was conducted, and genes for panton-valentine leukocidin (PVL) from MRSA isolates were determined.
RESULTS: A total of 521 samples were positive for MDROs, and MRSA was the most common organism (65.1%), followed by MDRAB (11.3%), carbapenem-resistant Klebsiellapneumoniae (11.1%), carbapenem-resistant Escherichiacoli (4.6%), and carbapenem-resistant P. aeruginosa (2.1%, n = 11). By a linear regression model, positive MRSA isolates from the environment were found to be statistically significant and associated with the number of colonized LTCF residents (p = 0.01), while the timing of the surveillance culture was not (p = 0.227). The main MLST types associated with PVL-production were sequence type (ST) 59, (40.0%, 24/60), ST30 (21.4%, 3/14), ST8 (87.5%, 14/16), and ST45 (3.6%, 1/28). The susceptibility rates of tetracycline (96.7%), trimethoprim-sulfamethoxazole (96.7%), and ciprofloxacin (81.7%) were statistically significant and higher in MRSA ST59, compared to the rates in MRSA ST45 isolates.
CONCLUSIONS: MRSA was the most commonly colonized MDRO, both in the LTCF residents and in the environment, followed by MDRAB and carbapenem-resistant K. pneumoniae.

PMID: 29530709 [PubMed - as supplied by publisher]

http://ift.tt/2FJy8Ou

Molecular epidemiology and virulence characteristics of Staphylococcus aureus nasal colonization in medical laboratory staff: comparison between microbiological and non-microbiological laboratories.

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Molecular epidemiology and virulence characteristics of Staphylococcus aureus nasal colonization in medical laboratory staff: comparison between microbiological and non-microbiological laboratories.

BMC Infect Dis. 2018 03 12;18(1):122

Authors: Xie X, Dai X, Ni L, Chen B, Luo Z, Yao Y, Wu X, Li H, Huang S

Abstract
BACKGROUND: Medical laboratory staff are a high-risk population for colonization of Staphylococcus aureus (S. aureus) due to direct and dense contact with the pathogens; however, there is limited information about this colonization. This study sought to determine the prevalence and molecular characteristics of nasal colonization by S. aureus in medical laboratory staff in Guangzhou, southern China, and to compare the differences between microbiological laboratory (MLS) and non-microbiological laboratory (NMLS) staff.
METHODS: S. aureus colonization was assessed by nasal swab cultures from 434 subjects, including 130 MLSs and 304 NMLSs from 33 hospitals in Guangzhou. All S. aureus isolates underwent the antimicrobial susceptibility test, virulence gene detection and molecular typing.
RESULTS: The overall prevalence of S. aureus carriage was 20.1% (87/434), which was higher in MLSs than in NMLSs (26.2% vs. 17.4%, P < 0.05), while the prevalence of Methicillin-resistant S. aureus (MRSA) was similar. Living with hospital staff was associated with S. aureus carriage. The majority of the isolates harboured various virulence genes, and those in MLSs appeared less resistant to antibiotics and more virulent than their counterparts. A total of 37 different spa types were detected; among these, t338, t437, t189 and t701 were the most frequently encountered types. T338 was the main spa type contributing to nasal colonization Methicillin-sensitive S. aureus (MSSA) (13.0%), and t437-SCCmec IV was predominant in MRSA isolates (40%).
CONCLUSIONS: These findings provide insight into the risk factors, molecular epidemiology and virulence gene profiles of S. aureus nasal carriage among the medical laboratory staff in Guangzhou.

PMID: 29529992 [PubMed - in process]

http://ift.tt/2tYwBP2

Colonization of long-term care facility residents in three Italian Provinces by multidrug-resistant bacteria.

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Colonization of long-term care facility residents in three Italian Provinces by multidrug-resistant bacteria.

Antimicrob Resist Infect Control. 2018;7:33

Authors: Nucleo E, Caltagirone M, Marchetti VM, D'Angelo R, Fogato E, Confalonieri M, Reboli C, March A, Sleghel F, Soelva G, Pagani E, Aschbacher R, Migliavacca R, Pagani L, AMCLI – GLISTer Group, ESCMID Study Group Elderly Infections – ESGIE

Abstract
Background: Rationale and aims of the study were to compare colonization frequencies with MDR bacteria isolated from LTCF residents in three different Northern Italian regions, to investigate risk factors for colonization and the genotypic characteristics of isolates. The screening included Enterobacteriaceae expressing extended-spectrum β-lactamases (ESβLs) and high-level AmpC cephalosporinases, carbapenemase-producing Enterobacteriaceae, Pseudomonas aeruginosa or Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
Methods: Urine samples and rectal, inguinal, oropharyngeal and nasal swabs were plated on selective agar; resistance genes were sought by PCR and sequencing. Demographic and clinical data were collected.
Results: Among the LTCF residents, 75.0% (78/104), 69.4% (84/121) and 66.1% (76/115) were colonized with at least one of the target organisms in LTCFs located in Milan, Piacenza and Bolzano, respectively. ESβL producers (60.5, 66.1 and 53.0%) were highly predominant, mainly belonging to Escherichia coli expressing CTX-M group-1 enzymes. Carbapenemase-producing enterobacteria were found in 7.6, 0.0 and 1.6% of residents; carbapemenase-producing P. aeruginosa and A. baumannii were also detected. Colonization by MRSA (24.0, 5.7 and 14.8%) and VRE (20.2, 0.8 and 0.8%) was highly variable. Several risk factors for colonization by ESβL-producing Enterobacteriaceae and MRSA were found and compared among LTCFs in the three Provinces. Colonization differences among the enrolled LTCFs can be partially explained by variation in risk factors, resident populations and staff/resident ratios, applied hygiene measures and especially the local antibiotic resistance epidemiology.
Conclusions: The widespread diffusion of MDR bacteria in LTCFs within three Italian Provinces confirms that LTCFs are an important reservoir of MDR organisms in Italy and suggests that future efforts should focus on MDR screening, improved implementation of infection control strategies and antibiotic stewardship programs targeting the complex aspects of LTCFs.

PMID: 29527303 [PubMed - in process]

http://ift.tt/2FJlPl9

Cytocompatibility, biofilm assembly and corrosion behavior of Mg-HAP composites processed by extrusion.

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Cytocompatibility, biofilm assembly and corrosion behavior of Mg-HAP composites processed by extrusion.

Mater Sci Eng C Mater Biol Appl. 2017 Sep 01;78:667-673

Authors: Del Campo R, Savoini B, Jordao L, Muñoz A, Monge MA

Abstract
In this work the cytocompatibility of pure magnesium and Mg-xHAP composites (x=5, 10 and 15wt%) fabricated by powder metallurgy routes has been investigated. The materials were produced from raw HAP powders with particle mean sizes of 6μm (S-xHAP) or 25μm (L-xHAP). The biocompatibility study has been performed for MC3T3 cells (osteoblasts/osteoclasts) and L929 fibroblasts. The results indicate that S-Mg (pure magnesium), S-10HAP and L-10HAP composites are the materials with the best biocompatibility. The ability of S. aureus bacteria to assemble biofilms was also evaluated. Biofilm formation assays showed that these materials are not particular prone to colonization and biofilm assembly is strain dependent. The corrosion resistance of S-Mg, S-10HAP and L-10HAP materials immersed in the media used for the cells culture has also been analyzed. Different trends in the corrosion resistance have been found: S-Mg and S-10HAP show a very high resistance to corrosion whereas the corrosion of L-10HAP steadily increases with time.

PMID: 28576036 [PubMed - indexed for MEDLINE]

http://ift.tt/2tSBZ64

Imidazolium-based titanium substrates against bacterial colonization.

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Imidazolium-based titanium substrates against bacterial colonization.

Biomater Sci. 2017 Feb 28;5(3):561-569

Authors: Cavoue T, Bounou Abassi H, Vayssade M, Nguyen Van Nhien A, Kang IK, Kwon GW, Pourceau G, Dubot P, Abbad Andaloussi S, Versace DL

Abstract
Nosocomial infections are often induced by the presence of pathogenic organisms on the surface of medical devices or hospital equipment. Chemical modifications of the surface are recognized as efficient strategies to prevent bacterial adhesion but they may have a negative impact on the material's interaction with living tissues. Here we have developed a photoactivated method for the modification of titanium substrates. A photoinduced technique employing a grafting-onto process has been successfully performed to covalently anchor an imidazolium-derivative siloxane onto titanium surfaces. Imidazolium surfaces showed higher bacteria-repellency performances than native titanium substrates, achieving more than 98% anti-adhesion efficiency against Escherichia coli after 24 h of incubation. In addition, these surfaces allowed for the adhesion and viability of osteoblasts cells without evidence of cytotoxicity.

PMID: 28138661 [PubMed - indexed for MEDLINE]

http://ift.tt/2GCMjC4

Topical Antibiotics for Infection Prevention: A Review of the Clinical Effectiveness and Guidelines

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Topical Antibiotics for Infection Prevention: A Review of the Clinical Effectiveness and Guidelines

Book. 2017 03 30

Authors: Banerjee S, Argáez C

Abstract
It is estimated that worldwide, 7% to 10% of hospitalized patients are affected by skin and soft tissue infections caused by microbial invasion of the skin and underlying soft tissues. Surgical site infections (SSIs) occur in approximately 2% to 5% of patients undergoing clean extra-abdominal surgeries and in up to 20% of patients undergoing intra-abdominal surgeries. Infections lead to delay in healing, increased morbidity, and prolonged hospital stay which will impact health care resources. The bacteria, Staphylococcus aureus (S. aureus) is one of the most common causes of health care-associated infections such as SSIs, exit site infections (ESIs) in dialysis patients, and infections in patients in intensive care units (ICU). It is estimated that 20% of healthy people are chronic carriers of S. aureus, 30% are intermittent carriers, and 50% are not susceptible. The risk of infection is reported to be 2 to 12 times higher in S. aureus nasal carriers compared to non-carriers. It has been reported that nasal decolonization of patients with S. aureus significantly reduces infections caused by S. aureus. It has been reported that 18% to 25% of patients undergoing elective orthopedic surgery are nasal carriers of S. aureus and carriers are more likely to experience SSIs. One systematic review has reported that 26% of patients undergoing hemodialysis are nasal carriers of S. aureus. For patients with nasal S. aureus carriage, who were undergoing dialysis, colonization with the same bacteria was reported at the dialysis catheter exit site. Patients with S. aureus colonization are at a greater risk of developing S. aureus infection in the ICU. Topical antibiotics assist in preventing infections caused by bacteria. A variety of topical antibiotics are available such as bacitracin, mupirocin, gramicidin, fusidic acid and gentamycin. There is however some concern regarding the use of antibiotics because of the possible development of antibacterial resistance in the long term. The purpose of this report is to review the existing evidence on the clinical effectiveness of prevention of skin or wound infection with the topical antibiotics: polymyxin B sulfate-bacitracin (Polysporin ointment), polymyxin B sulfate-gramicidin (Polysporin cream), polymyxin B sulfate-bacitracin-gramicidin (Polysporin triple ointment), bacitracin (Bacitin ointment), mupirocin (Bactroban cream/ointment), silver sulfadiazine (Flamazine cream), fusidic acid/fusidate sodium (Fucidin cream/ointment), and fusidic acid 2% with hydrocortisone (Fucidin H). Additionally, this report aims to review evidence-based guidelines for the prevention of skin or wound infection using these topical antibiotics.

PMID: 29533570

http://ift.tt/2tY1UcS

Infrequent organ involvement of IgG4-related diseases: a literature review.

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Infrequent organ involvement of IgG4-related diseases: a literature review.

Clin Rheumatol. 2018 Mar 03;:

Authors: Chang J, Zhang W

Abstract
IgG4-related disease (IgG4-RD) is a chronic and systemic disease that can involve multiple organs. The most commonly involved organs include the salivary glands, orbital adnexal structures, paranasal sinus, thyroid, lungs, breasts, aorta, pancreas, biliary ducts, kidneys, retroperitoneum, lymph nodes, prostate, pituitary, and endocranium. Due to increased disease research, several new site-specific nuances of IgG4-RD have been described. The authors have reviewed the recent literature and briefly summarize the infrequent organ involvement of IgG4-RD.

PMID: 29502226 [PubMed - as supplied by publisher]

http://ift.tt/2G5aew2

Targeting BCL-2 in Hematologic Malignancies

Abstract

Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma.

http://ift.tt/2G7KY66

Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naïve Patients: a Systematic Review and Network Meta-Analysis

Abstract

Background

Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC).

Objective

To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC.

Methods

We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC. The outcomes analyzed were overall survival (OS) and progression-free survival (PFS). A network meta-analysis (NMA) was conducted comparing OS and PFS hazard ratios (HRs).

Results

Thirteen studies were identified in the SLR to be eligible for inclusion in the NMA. The overall study populations were heterogeneous in terms of risk groups; some studies included favorable risk patients. In intermediate-risk patients, HRs (95% confidence interval) for PFS were 0.52 (0.33, 0.82), 0.46 (0.26, 0.80), 0.20 (0.12, 0.36), and 0.37 (0.20, 0.68) when cabozantinib was compared with sunitinib, sorafenib, interferon (IFN), or bevacizumab plus IFN, respectively. In poor-risk patients, the NMA also demonstrated significant superiority in terms of PFS for cabozantinib; HRs were 0.31 (0.11, 0.90), 0.22 (0.06, 0.87), 0.16 (0.04, 0.64), and 0.20 (0.05, 0.88), when cabozantinib was compared with sunitinib, temsirolimus, IFN, or bevacizumab plus IFN, respectively. When the overall study populations were compared, the results were similar to the subgroup analyses. OS HRs in all analyses favored cabozantinib, but were not statistically significant.

Conclusions

The results suggest that cabozantinib significantly increases PFS in intermediate-, and poor-risk subgroups when compared to standard-of-care comparators. Although overall populations included favorable risk patients in some studies, the results seen were consistent with the subgroup analyses.

http://ift.tt/2owmnjM

The Abscopal Effect in the Era of Cancer Immunotherapy: a Spontaneous Synergism Boosting Anti-tumor Immunity?

Abstract

Radiotherapy is one of the main treatment strategies used in cancer. Aside from the local control of the disease, which is mediated by a direct cytotoxic effect on tumor cells, radiotherapy has also been shown to exert immune-mediated local and systemic effects. Radiotherapy can elicit anti-tumor responses in distant sites from the radiation field; this phenomenon is known as the abscopal effect and has been described in patients previously treated with immune checkpoint blockade (ICB). Considering that the efficacy of immunotherapy has been demonstrated only in a subset of patients—who often benefit with lasting responses—efforts are ongoing to potentiate its activity with the development of new combination strategies. Radiotherapy might represent a potential candidate for a synergistic combination with immunotherapy, by improving the immunogenicity of tumors and by enhancing local and systemic immune effects. This review aims to summarize the current pre-clinical and clinical data on the immune effects of radiotherapy and their potential implications for cancer immunotherapy.

http://ift.tt/2CD6zje

Acute downregulation of miR-155 leads to a reduced collagen synthesis through attenuating macrophages inflammatory factor secretion by targeting SHIP1

Abstract

Fibrosis, tightly associated with fibroblasts collagen synthesis, is related closely with inflammatory response. Our previously study found that acute downregulation of miR-155 at wound sites leads to a reduced fibrosis, however its particular mechanism is unclear. Herein, we aimed to explore the mechanism of miR-155 in reducing fibrosis. We first found that down-regulation of miR-155 inhibited macrophages transforming growth factor-β1 (TGF-β1) and IL-1β secretion. Next, we found that co-cultured with macrophages increased the proliferation and collagen synthesis of fibroblasts, and downregulation of miR-155 in macrophages could effectively attenuate the accelerative effects. We further identified SH2 domain containing inositol-5-phosphatase 1 (SHIP1) as a direct target of miR-155 in macrophages, and the expression of SHIP1 was negatively correlated with the level of miR-155. We further confirmed that PI3K/Akt pathway was involved in this process. Last, we found that downregulation of miR-155 leads to a reduced fibrosis in sever burn rat. Taken together, these results indicate that down-regulation of miR-155 leads to a reduced fibroblasts proliferation and collagen synthesis through attenuating macrophages TGF-β1 and IL-1β secretion by targeting SHIP1 via PI3K/Akt pathway, suggesting its potential therapeutic effects on the treatment of skin fibrosis.

http://ift.tt/2DpMaA8

Reduced myofilament component in primary Sjögren’s syndrome salivary gland myoepithelial cells

Abstract

Primary Sjögren's syndrome (pSS) is a solitary poorly understood autoimmune inflammatory disease by involvement of the salivary and lacrimal glands resulting in dry mouth and dry eyes. Myoepithelial cells (MECs) are cells knowing for its hybrid epithelial and mesenchymal phenotype that are important components of the salivary gland (SGs) structure aiding the expulsion of saliva from acinar lobules. In this study we investigate possible alteration in the myofilament component of MECs in SGs specimens obtained from pSS patients in comparison with healthy subjects, to evaluate MECs hypothetical involvement in the pathogenesis of pSS. The expression of alpha-smooth muscle actin (α-SMA) and p63, as MECs markers, was evaluated in bioptic specimens from pSS and healthy labial SGs through immunohistochemistry and immunofluorescence analyses; the distribution of MECs markers was quantified using Aperio ScanScope and ImageScope software to provide quantitative assessments of staining levels. Our observations demonstrated that p63 nuclear labeling in pSS MECs is preserved whereas α-SMA cytoplasmic staining is strongly and significantly reduced when compared with healthy SGs; the digital images analysis quantification of the expression of labeled α-SMA and p63 protein in the healthy and pSS MECs salivary tissues, led to results suggesting a loss of mechanical support for acini and ducts in pSS, correlated, probably, with the reduction of salivary flow that features one important aspect of pSS disease.

http://ift.tt/2ESmCMD

The decreased expression of Stat3 and p-Stat3 in preeclampsia-like rat placenta

Abstract

This study aims to investigate the expression of Stat3 and p-Stat3 in the placenta of a preeclampsia-like rat model induced by Nωnitro-l-arginine methyl ester (l-NAME). Two-to three-month-old (20 males, 40 females) Sprague–Dawley rats were used in this study. After conception was confirmed by vaginal smears, on the thirteenth day of pregnancy, the animals were allocated into two groups: control (0.9% NaCl administered) group and l-NAME (75 mg/kg) group. After the treatment of l-NAME, there was a significant increase in systolic blood pressure (SBP) levels in the l-NAME group (148.5 ± 5.71 mmHg) on day 21 compared to the SBPs in the control group (117.5 ± 4.57 mmHg) (P < 0.001). There was also an increase in total proteinuria on day 21 in the l-NAME group (766.57 ± 17.7 mg/L), when compared to the control group (459.89 ± 20.1 mg/L) (P < 0.001). Moreover, we also found a decrease in fetal numbers and fetal weight in the PE group in comparison to the control group. After the rats were sacrificed, the placentas were obtained from both groups. We found that the l-NAME group exhibited fewer placentas compared with the control group. Furthermore, the immunohistochemistry (IHC) and Western blot results showed that decreased expression of Stat3 and p-Stat3 were detected in the placenta of the preeclampsia-like rat model compared to Stat3 and p-Stat3 in the control group. We found the expression and activation of Stat3 and p-Stat3 were decreased in the placenta of the l-NAME-induced preeclampsia rat model.

http://ift.tt/2G0jZZB

Localization of epithelial sodium channel (ENaC) and CFTR in the germinal epithelium of the testis, Sertoli cells, and spermatozoa

Abstract

Spermatogenesis starts within the seminiferous tubules of the testis by mitotic division of spermatogonia that produces spermatocytes. Meiotic division of these spermatocytes produces haploid spermatids that differentiate into spermatozoa. In this study, we examined the expression of ENaC and CFTR (a Cl⁻ channel) in rat testicular sections using confocal microscopic immunofluorescence. The structural integrity of the seminiferous tubule sections was verified by precise phalloidin staining of the actin fibers located abundantly at both basal and adluminal tight junctions. The acrosome forming regions in the round spermatids were stained using an FITC coupled lectin (wheat germ agglutinin). In all phases of the germ cells (spermatogonia, spermatocytes, and spermatids) ENaC was localized in cytoplasmic pools. Prior to spermiation, ENaC immunofluorescence appeared along the tails of the spermatids. In spermatozoa isolated from the epididymis, ENaC was localized at the acrosome and a central region of the sperm flagellum. The mature sperm are transcriptionally silent. Hence, we suggest that ENaC subunits in cytoplasmic pools in germ cells serve as the source of ENaC subunits located along the tail of spermatozoa. The locations of ENaC is compatible with a possible role in the acrosomal reaction and sperm mobility. In contrast to ENaC, CFTR immunofluorescence was most strongly observed specifically within the Sertoli cell nuclei. Based on the nuclear localization of CFTR we suggest that, in addition to its role as an ion channel, CFTR may have an independent role in gene regulation within the nuclei.

http://ift.tt/2pk4zru

Cyclophilin a increases CD68 + cell infiltration in rat experimental periodontitis

Abstract

Cyclophilin A (CyPA) is a potent chemokine, which can directly induce leukocyte chemotaxis and contribute to the pathogenesis of inflammation-mediated diseases. This study is to observe the expression and distribution of CyPA and CD68⁺ cells in the histopathogenesis of rat ligation-induced experimental periodontitis, and assess the role of CyPA in CD68⁺ cell infiltration in rat experimental periodontitis. Experimental periodontitis was induced by ligation according to our previous method. CyPA expression in gingival tissues was detected by western blotting. Immunohistochemistry was applied for CyPA and CD68 distribution. For further certifying the role of CyPA in CD68⁺ cell infiltration, the right mandibular first molar received 0.1 μM CyPA locally by gingival injection every 2 days (L + C group), while the left mandibular first molar received saline as a control group (L group). The number of CD68⁺ cells in the experimental periodontitis was observed by immunohistochemistry. Alveolar bone destruction was assessed by micro-computerized tomography (micro-CT). Osteoclast was observed through TRAP staining. Nuclear factor (NF)-κB phospho-p65 (p p65) and phosphor-IκBα (p IκBα) expressions were detected to investigate NF-κB activation. CyPA showed an increasing trend at 1–6 weeks after ligation. CyPA and CD68⁺ cells were present in the gingival inflammatory infiltration, and participated in alveolar bone destruction. In the L + C group, the number of CD68⁺ cells was increased compared with the L group, and greater alveolar bone destruction was observed. NF-κB p p65 and p IκBα expressions were upregulated in the L + C group compared with the L group indicating NF-κB activation. CyPA increases CD68⁺ cell infiltration in rat experimental periodontitis, suggesting CyPA might be an anti-inflammatory therapeutic target.

http://ift.tt/2CMvsu0

miR-484/MAP2/c-Myc-positive regulatory loop in glioma promotes tumor-initiating properties through ERK1/2 signaling

Abstract

Glioma is the most common intracranial malignant tumor. Cancer stem cells (CSCs) are resistant to chemotherapy and radiotherapy, and are closely related to cancer metastasis and recurrence. In this study, we aimed to explore the effect of miR-484 on glioma stemness and the underlying mechanism involved. miR-484 enhanced glioma tumor-initiating properties in vitro and in vivo. Moreover, miR-484 was shown to directly target MAP2, resulting in activation of ERK1/2 signaling and promotion of stemness in glioma. The ERK1/2 signaling facilitated the formation of a miR-484/MAP2/c-Myc positive feedback loop in glioma. High miR-484 expression predicted a poor prognosis for glioma patients, and high MAP2 expression predicted a good prognosis for glioma patients. Low miR-484 expression and high MAP2 expression was associated with the best prognosis in glioma. Our study suggests that miR-484 and MAP2 can be utilized as predictors for the clinical diagnosis and prognosis of glioma, and miR-484 and MAP2 are potential targets for the treatment of glioma.

http://ift.tt/2Ixw8Xl

Capillary rarefaction and altered renal development: the imbalance between pro- and anti-angiogenic factors in response to angiotensin II inhibition in the developing rat kidney

Abstract

Proper and timely assembly of the kidney vasculature with their respective nephrons is crucial during normal kidney development. In this study, we investigated the effects of enalapril (angiotensin-converting enzyme inhibitor) on angiogenesis-related gene expression and microvascular endothelium related to glomeular and tubular changes in the neonatal rat kidney. Enalapril-treated rats had higher tubular injury scores and lower glomerular maturity grades than those of untreated rats. In the enalapril-treated group, intrarenal angiopoietin-2, Tie-2, and thrombospondin-1 protein expression increased, whereas intrarenal angiopoietin-1 protein expression decreased. JG12-positive glomerular and peritubular capillary staining was reduced in the enalapril-treated rat kidney. The number of JG12-positive capillary endothelial cells was directly correlated with glomerular maturation grade and was inversely related with the tubular injury. Our findings suggest the imbalance between pro- and anti-angiogenic factors may be implicated in the loss of capillaries in associated with impaired nephrogenesis after angiotensin II blockade in the developing rat kidney.

http://ift.tt/2ppQGbF

Expression pattern of YAP and TAZ during orthodontic tooth movement in rats

Abstract

Orthodontic tooth movement (OTM) is a periodontal tissue remodeling and regeneration process that is caused by bio-mechanical stimulation. This mechanical–chemical transduction process involves a variety of biological factors and signaling pathways. It has been shown that the Hippo-YAP/TAZ signaling pathway plays a pivotal role in the mechanical–chemical signal transduction process. Moreover, YAP and TAZ proteins interact with RUNX family proteins via different mechanisms. To explore the regulation of the Hippo signaling pathway during periodontal tissue remodeling, we examined the upper first molar OTM model in rats. We examined YAP, TAZ and RUNX2 expression at 12 hours, 24 hours, 2 days (2d), 4 days, 7 days (7d) and 14 days (14d) after force application. Haemotoxylin and eosin staining, immunohistochemical staining and western blot analysis were used to examine the expression level and localization of these proteins. We found that YAP, TAZ and RUNX2 expression started increasing at 2d, YAP and TAZ expression was proportional to the orthodontic force applied until peaking at 7d, and at 14d the expression started to decrease. YAP and TAZ were observed in osteocytes, bone matrix and periodontal ligament cells during OTM. Furthermore, using double labeling immunofluorescence staining, we found that the increase in TAZ expression was associated with RUNX2 expression, however, YAP and RUNX2 showed different expression patterns. These results suggest that the Hippo-YAP/TAZ signaling pathway participates in periodontal tissue remodeling through various mechanisms; TAZ may adjust bone tissue remodeling through RUNX2 during OTM, while YAP may regulate periodontal cell proliferation and differentiation.

http://ift.tt/2DorUhC

Methylation of secreted frizzled-related protein 1 (SFRP1) promoter downregulates Wnt/β-catenin activity in keloids

Abstract

Keloid, a benign skin disorder, forms during wound healing in genetically susceptible individuals. To better control keloid and understand the molecular mechanisms, this study screened gene hypermethylations of GEO database microarray data on keloids and identified the hypermethylation of the secreted frizzled related protein-1 (SFRP1) promoter. Subsequently, hypermethylation and mRNA and protein levels were assessed in 57 cases of keloid vs. normal skin tissues. Fibroblasts from tissues were isolated for the assessment of gene regulation in vitro. The methods used were bioinformatic analysis, lentiviral infection carrying SFRP1 cDNA, qRT-PCR, western blot, immunohistochemistry, luciferase reporter assay, methylation-specific PCR and methylated DNA immunoprecipitation-qPCR, ELISA, and/or 5-Aza-2′-deoxycytidine treatment. The data revealed that the SFRP1 promoter was hypermethylated in keloid tissues, compared with that in normal skin tissues. The SFRP1 promoter methylation contributed to the downregulation of SFRP1 mRNA and protein in keloid tissues and keloid fibroblasts. The 5-Aza treatment significantly upregulated SFRP1 mRNA and protein level in keloid fibroblasts. Furthermore, the knockdown of DNMT1 expression, and not the expression of DNMT3a or DMNT3b, was responsible for the hypermethylation of the SFRP1 promoter and upregulation of SFRP1 mRNA and protein in keloid fibroblasts. In addition, the infection of lentivirus carrying SFRP1 cDNA significantly inhibited the signaling activity of Wnt/β-catenin and the mRNA and protein expression of β-catenin and α-SMA in keloid fibroblasts. In summary, the lost SFRP1 expression-induced Wnt/β-catenin signaling due to the hypermethylation of the SFRP1 promoter could associate with keloid development, suggesting that SFRP1 might be a therapeutic target for keloid treatment.

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c-Fos downregulation positively regulates EphA5 expression in a congenital hypothyroidism rat model

Abstract

The EphA5 receptor is well established as an axon guidance molecule during neural system development and plays an important role in dendritic spine formation and synaptogenesis. Our previous study has showed that EphA5 is decreased in the developing brain of congenital hypothyroidism (CH) and the EphA5 promoter methylation modification participates in its decrease. c-Fos, a well-kown transcription factor, has been considered in association with brain development. Bioinformatics analysis showed that the EphA5 promoter region contained five putative c-fos binding sites. The chromatin immunoprecipitation (ChIP) assays were used to assess the direct binding of c-fos to the EphA5 promoter. Furthermore, dual-luciferase assays showed that these three c-fos protein binding sites were positive regulatory elements for EphA5 expression in PC12 cells. Moreover, We verified c-fos positively regulation for EphA5 expression in CH model. Q-PCR and Western blot showed that c-fos overexpression could upregulate EphA5 expression in hippocampal neurons of rats with CH. Our results suggest that c-fos positively regulates EphA5 expression in CH rat model.

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SLC30A family expression in the pancreatic islets of humans and mice: cellular localization in the β-cells

Abstract

Zinc is a vital co-factor for insulin metabolism in the pancreatic β-cell, involved in synthesis, maturation, and crystallization. Two families of zinc transporters, namely SLC30A (ZNT) and SLC39A (ZIP) are involved in maintaining cellular zinc homeostasis in mammalian cells. Single nuclear polymorphisms or mutations in zinc transporters have been associated with insulin resistance and risk of type 2 diabetes (T2D) in both humans and mice. Thus, mice can be useful for studying the underlying mechanisms of zinc-associated risk of T2D development. To determine potential differences in zinc transporter expression and cellular localization in the pancreatic β-cells between humans and mice, we examined all members (ZNT1-10) of the ZNT family in pancreatic islets and in β-cell lines derived from both species using immunohistochemistry and immunofluorescence microscopic analysis. We found that there were no substantial differences in the expression of nine ZNT proteins in the human and mouse islets and β-cells with exception of ZNT3, which was only detected in human β-cells, but not in mouse β-cells. Moreover, we found that ZNT2 was localized on the cell surface of both human and mouse β-cells, suggesting a role of ZNT2 in direct export of zinc out of the β-cell. Together, our study suggests functional conservations of the ZNT proteins between humans and mice. We believe that our results are of interest for future studies in the association of zinc metabolism with risk of T2D in humans using mouse models.

http://ift.tt/2E8VqJG

Effect of preameloblast-conditioned medium and CPNE7 on root surfaces in dogs: a histologic and histomorphometric evaluation

Abstract

Preameloblast-conditioned medium (PACM) has been reported as a potent dentin regenerative material, but its effects as a mixture on periodontal regeneration and the role of CPNE7 in PACM are not known. The purpose of this study is to evaluate the histologic and histomorphometric effects of preameloblast-conditioned medium (PACM) and CPNE7 on periodontal tissue healing in dogs. Seventy-two mandibular premolar roots from ten dogs were extracted and randomly divided into six groups (n = 12 each): (1) positive control group; (2) negative control group; (3) cementum-removed and PACM-treated group; (4) cementum-preserved and PACM-treated group; (5) CPNE7-inactivated PACM-treated group; and (6) recombinant CPNE7-treated group. The extracted roots were replanted into extraction sockets for 4 and 8 weeks and analyzed histologically. Most of the root surfaces in the negative control group showed ankylosis; and those in the experimental groups showed newly formed PDL-like and cementum-like tissues. Histomorphometric analysis of horizontal sections showed that the mean length of the PDL on the roots of the positive controls was similar to those in cementum-removed or -preserved and PACM-treated group at 8 weeks (p = 1.08). Sagittal sections showed that the mean length of the new cementum on the roots in cementum-removed and PACM-treated group was significantly greater than that in CPNE7-inactivated PACM-treated group (p = 0.037). The mean length of the newly formed PDL on the roots in CPNE7- inactivated PACM-treated and rCPNE7-treated groups was significantly greater than that in the negative controls at 8 weeks (p = 0.037, p = 0.036). The use of PACM and CPNE7 in tooth replantation resulted in increased PDL and cementum formation, suggesting the beneficial role of PACM and CPNE7 in periodontal tissue healing.

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Activation of satellite glial cells in trigeminal ganglion following dental injury and inflammation

Abstract

Satellite glial cells (SGCs), a peripheral neuroglial cell, surround neurons and form a complete envelope around individual sensory neurons in the trigeminal ganglia (TG), which may be involved in modulating neurons in inflammation. The purpose of this study was to determine the effect of dental injury and inflammation on SGCs in the TG. Pulp exposure (PX) was performed on the first maxillary molar of 28 rats. The neurons innervating injured tooth in TG were labeled by the retrograde transport of fluoro-gold (FG). Specimens were collected at 1, 3, 7, 14, 21 and 28 days after PX and stained immunohistochemically for glial fibrillary acid protein (GFAP), a marker of SGCs activation, in the TG. We observed that GFAP-immunoreactivity (IR) SGCs enclosed FG-labeled neurons increased in a time-dependent manner after PX. The neurons surrounded by GFAP-IR SGCs were mainly small and medium in size. The GFAP-IR SGCs encircled neurons increased significantly in the maxillary nerve region of the TG at 7–28 days following PX. The results show that dental injury and inflammation induced SGCs activation in the TG. It indicates that activation of SGCs might be implicated in the peripheral mechanisms of pain following dental injury and inflammation.

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Endoscopy, histology and electron microscopy analysis of foetal membranes in pregnant South American plains vizcacha reveal unusual excrescences on the yolk sac

Abstract

The South American hystricognathe Lagostomus maximus is a fossorial rodent whose females show unique reproductive characteristics. They have a 155-day long gestation, show massive polyovulation and a selective process of embryonic resorption in the first half of gestation. In order to explore and perform an in-situ characterization of the reproductive tract, we visualized internal structures through ultrasonography and video-endoscopy in pregnant and non-pregnant females. We describe the finding of protruding structures that lie on the yolk sac and their histological and ultrastructural characterization. The placenta was covered with whitish, small pearl-shaped structures. These structures were also seen on the extra-embryonic space, being the amnion and the umbilical cord free of them. Pearl-shaped structures were composed with loose connective tissue, lacked blood vessels, and showed collagen fibers organized in a spiral form. They were anchored by pedicles to the villous surface of the extraembryonic membrane. We discuss the biological and evolutionary meaning of the pearl-shaped structures that relate L. maximus to the African origin of the South American hystricognathe fauna.

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Smad4 and epithelial–mesenchymal transition proteins in colorectal carcinoma: an immunohistochemical study

Abstract

Epithelial–mesenchymal transition (EMT) plays an important role in cancer metastasis. During EMT, tumor cells acquire the capacity to migrate and invade the stroma. Activation of the transforming growth factor-b (TGF-b) signaling pathway is of major importance for the initiation of EMT. Smad4, an essential protein of this pathway, is known to complex with multiple transcription factors (e.g. Snail-1, Slug, Twist-1), in various types of cancer, promoting the repression or activation of target genes. The role of Smad4 in colorectal cancer (CRC) is not straightforward so far. In the present study forty eight resected CRC tumor specimens were immunohistochemically examined in order to assess the expression of Smad4 and its association with E-cadherin, Snail-1, Slug, Twist-1 protein expression and with various pathological parameters. Smad4 was found to be positively correlated with Snail-1, Slug and Twist-1 expression (p < 0.001). On the other hand it was negatively correlated with the expression of E-cadherin (p < 0.001). Furthermore, lymphatic invasion could be clearly associated with Smad4 expression, a finding complying with the metastatic ability of EMT cells. In conclusion, Smad4 could be considered as a central component of EMT transition in human colorectal cancer that combines with transcriptional factors to reduce E-cadherin and alter the expression of the epithelial phenotype.

http://ift.tt/2IwLZp6

Occurrence and health risk assessment of organotins in waterworks and the source water of the Three Gorges Reservoir Region, China

Abstract

The occurrence and health risks of organotins (OTs) in the waterworks and source water in the Three Gorges Reservoir Region (TGRR), China were assessed in this study. Water samples were collected at four waterworks (A, B, C, and D) in March and July 2012 to analyze butyltins (BTs) and phenyltins (PTs) using a gas chromatography-mass spectrometry (GC-MS) system. Our results showed that both the waterworks and their nearby water sources were polluted by OTs, with PTs being the most dominant species. Monobutyltin (MBT), monophenyltin (MPT), diphenyltin (DPT), and triphenyltin (TPT) were detected in most of the analyzed water samples. The highest concentrations of OTs in influents, effluents, and source water in March were 52.81, 17.93, and 55.32 ng Sn L⁻¹, respectively. Furthermore, significant seasonal changes in OTs pollution were observed in all samples, showing pollution worse in spring compared with summer. The removal of OTs by the conventional treatment processes was not stable among the waterworks. The removal efficiency of OTs in July reached 100% at plant B, while that at plant C was only 38.8%. The source water and influents shared similar composition profiles, concentrations, and seasonal change of OTs, which indicated that OTs in the waterworks were derived from the source water. A health risk assessment indicated that the presence of OTs in the waterworks would not pose a significant health risk to the population, yet their presence should not be ignored.

http://ift.tt/2FM2YpG

Microarray expression profiling and co-expression network analysis of circulating LncRNAs and mRNAs associated with neurotoxicity induced by BPA

Abstract

A growing body of evidence has shown bisphenol A (BPA), an estrogen-like industrial chemical, has adverse effects on the nervous system. In this study, we investigated the transcriptional behavior of long non-coding RNAs (lncRNAs) and mRNAs to provide the information to explore neurotoxic effects induced by BPA. By microarray expression profiling, we discovered 151 differentially expressed lncRNAs and 794 differentially expressed mRNAs in the BPA intervention group compared with the control group. Gene ontology analysis indicated the differentially expressed mRNAs were mainly involved in fundamental metabolic processes and physiological and pathological conditions, such as development, synaptic transmission, homeostasis, injury, and neuroinflammation responses. In the expression network of the BPA-induced group, a great number of nodes and connections were found in comparison to the control-derived network. We identified lncRNAs that were aberrantly expressed in the BPA group, among which, growth arrest specific 5 (GAS5) might participate in the BPA-induced neurotoxicity by regulating Jun, RAS, and other pathways indirectly through these differentially expressed genes. This study provides the first investigation of genome-wide lncRNA expression and correlation between lncRNA and mRNA expression in the BPA-induced neurotoxicity. Our results suggest that the elevated expression of lncRNAs is a major biomarker in the neurotoxicity induced by BPA.

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Graphical Abstracts

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Meet Our Editorial Board Member

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Genetic Signatures in Ischemic Stroke: Focus on Aspirin Resistance

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Implications of PEGylation of Carbon Nanotubes for Central Nervous System Bioavailability

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The 18-kDa Translocator Protein as a CNS Drug Target: Finding Our Way Through the Neuroinflammation Fog

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MicroRNA Dysregulation in Alzheimer's Disease

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Chromosomal Micro-aberration in a Saudi Family with Juvenile Myoclonic Epilepsy

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Natalizumab Changes the Peripheral Profile of the Th17 Panel in MS Patients: New Mechanisms of Action

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Identification of Electrophysiological Changes in Alzheimer's Disease: A Microarray Based Transcriptomics and Molecular Pathway Analysis Study

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Conference Report: 9th Clinical Trials on Alzheimer's Disease (CTAD)

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Book Review: “Dendrites- Third Edition”

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Pain, a Complex Challenge

Publication date: Available online 17 March 2018
Source:Hematology/Oncology Clinics of North America
Author(s): Janet L. Abrahm




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Rehabilitation Medicine Approaches to Pain Management

Publication date: Available online 17 March 2018
Source:Hematology/Oncology Clinics of North America
Author(s): Andrea L. Cheville, Sean Smith, Jeffrey R. Basford

Teaser

Rehabilitation medicine offers strategies that reduce musculoskeletal pain, targeted approaches to alleviate movement-related pain, and interventions to optimize patients' function despite the persistence of pain. These approaches fall into four categories: modulating nociception, stabilizing and unloading painful structures, influencing pain perception, and alleviating soft tissue musculotendinous pain. Incorporating these interventions into individualized, comprehensive pain management programs offers the potential to empower patients and limit pain associated with mobility and required daily activities. Rehabilitative approach may be particularly helpful for patients with refractory movement-associated pain and functional vulnerability, and for those who do not wish for, or cannot, tolerate pharmacoanalgesia.


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Radiation for Treatment of Painful Bone Metastases

Publication date: Available online 17 March 2018
Source:Hematology/Oncology Clinics of North America
Author(s): Ron Shiloh, Monica Krishnan

Teaser

Several variables may be considered when deciding on optimal modality of radiation therapy for each cancer patient with bone pain, including prognosis, tumor histology, location and extent of metastases, and association with cord compression. Hypofractionated external beam radiation therapy is as effective as a multiple fraction radiotherapy course in most cases, although retreatment rates are higher after a single dose of radiation. Stereotactic body radiation may be used in cases of oligometastatic disease, repeat irradiation, and radiation-resistant tumors. Radiopharmaceuticals may be used for pain from diffuse bone metastases and have an overall survival benefit in patients with castrate-resistant prostate cancer.


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Data on association of mitochondrial heteroplasmy and cardiovascular risk factors: Comparison of samples from Russian and Mexican populations

Publication date: June 2018
Source:Data in Brief, Volume 18
Author(s): Tatiana V. Kirichenko, Igor A. Sobenin, Zukhra B. Khasanova, Varvara A. Orekhova, Alexandra A. Melnichenko, Natalya A. Demakova, Andrey V. Grechko, Alexander N. Orekhov, Jorge L. Ble Castillo, Tatiana P. Shkurat
Despite the fact that the role of mitochondrial genome mutations in a number of human diseases is widely studied, the effect of mitochondrial heteroplasmy in the development of cardiovascular disease has not been adequately investigated. In this study, we compared the heteroplasmy levels of mtDNA from leukocytes for m.3256C>T, m.3336T>C, m.12315G>A, m.5178C>A, m.13513G>A, m.14459G>A, m.14846G>A, m.15059G>A, m.652insG and m.1555A>G mutations in CVD-free subjects and CVD patients in samples derived from Russian and Mexican populations. It was demonstrated that heteroplasmy level of m.5178C>A was associated with CVD in Russian men, and m.14459G>A – in Russian women. Mitochondrial heteroplasmy level of m.13513G>A and m.652insG were associated with CVD in Mexican men, and only m.652insG– in Mexican women. The levels of heteroplasmy for mitochondrial mutations m.3336T>C, m.5178C>A, m.14459G>A, m.14846G>A and m.1555A>G were significantly higher in CVD-free Mexican men, and for m.3256C>T, m.3336T>C, and m.14459G>A – in CVD-free Mexican women.



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Characterization of polymer-polymer type charge-transfer (CT) blend membranes for fuel cell application

Publication date: June 2018
Source:Data in Brief, Volume 18
Author(s): Shiyan Feng, Shoichi Kondo, Takahiro Kaseyama, Taichi Nakazawa, Takamasa Kikuchi, Roman Selyanchyn, Shigenori Fujikawa, Liana Christiani, Kazunari Sasaki, Masamichi Nishihara
The data presented in this article are related to polymer-polymer type charge-transfer blend membranes for fuel cell application. The visible spectra of the charge-transfer (CT) blend membranes indicated formation of CT complex in the blend membranes, and behavior of CT complex formation by polymers was clarified by Job plot of the visible spectra. The effect of fluorine for membrane property and fuel cell performance of CT blend membranes were evaluated by ¹⁹F NMR and overvoltage analysis, respectively.



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Data for inactivation of free-living nematode Rhabditida from water environment using ultraviolet radiation

Publication date: June 2018
Source:Data in Brief, Volume 18
Author(s): Hamed Biglari, Maryam Tatari, Mohammad Reza Narooie, Gholamreza Ebrahimzadeh, Hooshmand Sharafi
Sometimes free-living nematodes in conventional water treatment processes are not eliminated and cause adverse health effects in water consumer. So, the efficiency of UV lamps (125 W) with irradiation intensity 1020 μW cm⁻² on inactivation of free-living nematode Rhabditida released in water samples has been investigated along with the investigation of the effects of turbidity and change of temperature and exposure time in constant of pH 8 ± 0.2. The results showed that UV radiation could disabled the larval and adult nematodes after 12 and 15 min in the presence of turbidity 5 NTU, respectively. Also, increased turbidity up to 50 NTU decreased the inactivation efficiency of larval and adult nematodes from 100% to 73% and 64%, respectively. In addition, with increased temperature, the inactivation efficiency increased significantly in a short time. The results showed a significant relationship between increasing exposure time and temperature and turbidity reduction with UV radiation efficiency in the inactivation of the nematode (P < 0.00). It was also found that the efficiency of the lamp on nematode larvae was more than the adult nematode. Therefore, UV radiation can well inactivate larvae and then adult free-living nematode Rhabditida in water.



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Editorial Board

Publication date: March–April 2018
Source:Journal of Communication Disorders, Volume 72





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Polycomb/Trithorax group-dependent regulation of the neuronal gene Lim3 involved in Drosophila lifespan control

Publication date: Available online 17 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Olga Y. Rybina, Yakov M. Rozovsky, Ekaterina R. Veselkina, Elena G. Pasyukova
Molecular mechanisms governing gene expression and defining complex phenotypes are central to understanding the basics of development and aging. Here, we demonstrate that naturally occurring polymorphisms of the Lim3 regulatory region that are associated with variation in gene expression and Drosophila lifespan control are located exclusively in the Polycomb response element (PRE). We find that the Polycomb group (PcG) protein Polycomb (PC) is bound to the PRE only in embryos where Lim3 is present in both repressed and active states. In contrast, the Trithorax group (TrxG) protein absent, small, or homeotic discs 1 (ASH1) is bound downstream of the PRE, to a region adjacent to the Lim3 transcription start site in embryos and adult flies, in which Lim3 is in an active state. Furthermore, mutations in Pc and ash1 genes affect Lim3 expression depending on the structural integrity of the Lim3 PRE, thus confirming functional interactions between these proteins and Lim3 regulatory region. In addition, we demonstrate that the evolutionary conserved Lim3 core promoter provides basic Lim3 expression, whereas structural changes in the Lim3 PRE of distal promoter provide stage-, and tissue-specific Lim3 expression. Therefore, we hypothesize that PcG/TrxG proteins, which are directly involved in Lim3 transcription regulation, participate in lifespan control.



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Suberanilohydroxamic acid prevents TGF-β1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation

Publication date: Available online 17 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Alice Pasini, Oliver J. Brand, Gisli Jenkins, Alan J. Knox, Linhua Pang
Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE2, is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE2 have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in normal lung fibroblasts could be prevented by epigenetic inhibitors. We found that COX-2 protein expression and PGE2 production were markedly reduced by TGF-β1 and this was prevented by the pan-histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) and to a lesser extent by the DNA demethylating agent Decitabine (DAC), but not by the G9a histone methyltransferase (HMT) inhibitor BIX01294 or the EZH2 HMT inhibitor 3-deazaneplanocin A (DZNep). However, chromatin immunoprecipitation assay revealed that the effect of SAHA was unlikely mediated by histone modifications. Instead 3′-untranslated region (3′-UTR) luciferase reporter assay indicated the involvement of post-transcriptional mechanisms. This was supported by the downregulation by SAHA of the 3′-UTR mRNA binding protein TIA-1 (T-cell intracellular antigen-1), a negative regulator of COX-2 translation. Furthermore, TIA-1 knockdown by siRNA mimicked the effect of SAHA on COX-2 expression. These findings suggest SAHA can prevent TGF-β1-induced COX-2 repression in lung fibroblasts post-transcriptionally through a novel TIA-1-dependent mechanism and provide new insights into the mechanisms underlying its potential antifibrotic activity.Abbreviations



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Editorial Board

Publication date: May 2018
Source:Biomaterials, Volume 165





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Injectable and detachable heparin-based hydrogel micropatches for hepatic differentiation of hADSCs and their liver targeted delivery

Publication date: May 2018
Source:Biomaterials, Volume 165
Author(s): Youngmin Hwang, MeeiChyn Goh, Mihye Kim, Giyoong Tae
A micropatterned heparin-based hydrogel system that can provide sustained release of multiple growth factors upon one time loading was prepared via photopolymerization and lithography and it was employed as a culture matrix for differentiating hADSCs into hepatic lineage. Mature differentiation of hADSCs into hepatic lineage in terms of gene expression and immunofluorostaining of hepatic markers, and functional characteristics such as glycogen storage ability and production of albumin and urea was observed on the soft hydrogel (∼400 Pa) when the gel elasticity was modulated. This optimal heparin-based hydrogel was used to prepare micropatches containing hepatic-differentiated cells by 1) micropatterning of the gel on a polyelectrolyte multilayer (PEM), 2) seeding of hADSCs and inducing hepatic differentiation, and 3) electrochemical retrieval of cell-attached micropatches. Upon i.v. injection, the retrieved cell micropatches showed a prolonged retention in the liver and promoted function compared to single cell injection in a rat model. In conclusion, this injectable and detachable miropatterned heparin-based hydrogel system could serve as a total platform for the stem cell differentiation under well-controlled microenvironment in vitro and for targeted delivery of the differentiated cells in vivo.



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Hypoxia-inducible Factor-1α directs renal regeneration induced by decellularized scaffolds

Publication date: May 2018
Source:Biomaterials, Volume 165
Author(s): Yaling Yu, Haomin Cui, Chuan Chen, Gen Wen, Jia Xu, Binbin Zheng, Jianse Zhang, Chunyang Wang, Yimin Chai, Jin Mei
Although mammalian kidney regeneration has been reported to occur throughout life, mature kidneys in mammals are not thought to regenerate sufficiently, particularly glomeruli. In our previous work, we found that renal regeneration could be enhanced by decellularized renal scaffolds after partial nephrectomy. In this study, we verified that the enhanced renal regeneration mediated by decellularized scaffolds could be attributed to regenerated glomeruli, which were counted both indirectly and directly under a microscope. Using the isobaric tag for relative and absolute quantitation, we performed proteomics analysis and found that hypoxia-inducible factor (HIF)-1α may be a key factor involved in induced renal regeneration. Dimethyloxyallyl glycine (DMOG), a propyl hydroxylase inhibitor, was applied to stabilize constitutive expression of HIF-1α protein, and small interfering RNA was used to inhibit gene expression. Administration of DMOG to decellularized scaffold-grafted rats improved the induced renal regeneration, whereas siHif1α transfection decreased the regeneration capacity. These findings revealed the critical role of HIF-1α in renal regeneration and provided important insights into our understanding of kidney development and the treatment of various kidney diseases.



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Characterization and application of size-sorted zonal chondrocytes for articular cartilage regeneration

Publication date: May 2018
Source:Biomaterials, Volume 165
Author(s): Lu Yin, Yingnan Wu, Zheng Yang, Vinitha Denslin, Xiafei Ren, Ching Ann Tee, Zhangxing Lai, Chwee Teck Lim, Jongyoon Han, Eng Hin Lee
Current clinical approaches for articular cartilage repair have not been able to restore the tissue with zonal architecture, and its biomechanical and functional properties. Mimicking the zonal organization of articular cartilage in neo-tissue by implanting zonal chondrocyte subpopulations in multilayer construct could enhance the functionality of the graft, engineering of stratified tissue has not yet been realized due to lack of efficient and specific zonal chondrocyte isolation protocol. We show that by using a spiral microchannel device, the superficial, middle and deep zone chondrocytes can be separated based on cell size, and enriched from full thickness porcine cartilage in a high-throughput, label-free manner. The size-sorted cells show zone-specific characteristics in RT-PCR analysis of zonal cartilage markers. Both freshly sorted and two-passage expanded zonal chondrocytes formed cartilage tissue in 3D hydrogel, bearing respective zonal characteristics, indicated by RT-PCR, histology, extracellular matrix proteins, and mechanical compression test. In the proof-of-concept in vivo study using a rodent cartilage defect model, the size-sorted zonal chondrocytes when delivered in bi-layered hydrogel construct, facilitated better cartilage repair with mechanically enhanced cartilage tissue, in comparison to conventional chondrocytes implantation. This study provides an effective approach to obtain large numbers of zonal chondrocytes, and demonstrates the translational potential of stratified zonal chondrocyte implantation for clinical repair of critical size cartilage defects.



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Encapsulation of D-limonene in Alyssum homolocarpum seed gum nanocapsules by emulsion electrospraying: morphology characterization and stability assessment

Publication date: Available online 16 March 2018
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Khadije Khoshakhlagh, Mohebbat Mohebbi, Arash Koocheki, Alireza Allafchian
The main purpose of this research was nanoencapsulation of D-limonene with Alyssum homolocarpum seed gum (AHSG) using electrospraying process. For this purpose it was necessary to identify and optimize the factors affecting the morphology of electrosprayed nanocapsules. To this aim, D-limonene emulsions with various concentrations of AHSG and Tween 20 were homogenized by ultrasound or high speed homogenizer and electrosprayed under different process conditions including applied voltage and solution flow rate. Results indicated that the physical properties of emulsions, including viscosity, surface tension and electrical conductivity were greatly influenced by the concentrations of their ingredients, and also by the homogenization method. The physical properties of emulsion along with the processing parameters (voltage and flow rate) were the key factors affecting the morphology and size of the obtained structures (p<0.05). Briefly, round, smooth and compact capsules with an average diameter of 65.68 ± 8.80nm were obtained from electrospraying of high speed homogenized emulsion containing 0.5% gum (w/w), 20% D-limonene (w/w) and 0.1% surfactant (w/w) under the applied voltage of 20kV and flow rate of 0.1mL/h. These optimum nanocapsules showed 73.4% encapsulation efficiency. The stability of encapsulated D-limonene was also monitored for 90 days at 4°C and 25°C. Nanocapsules provided a relatively good storage stability and maintained 91.2 and 82.4 percentage of initial mass of the loaded D-limonene during 90 days of storage at 4°C and 25°C, respectively.

Graphical abstract

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New biomarkers for diagnosis and prognosis of localized prostate cancer

Publication date: Available online 31 January 2018
Source:Seminars in Cancer Biology
Author(s): Dimitry A. Chistiakov, Veronika A. Myasoedova, Andrey V. Grechko, Alexandra A. Melnichenko, Alexander N. Orekhov
The diagnostics and management of localized prostate cancer is complicated because of cancer heterogeneity and differentiated progression in various subgroups of patients. As a prostate cancer biomarker, FDA-approved detection assay for serum prostate specific antigen (PSA) and its derivatives are not potent enough to diagnose prostate cancer, especially high-grade disease (Gleason ≥7). To date, a collection of new biomarkers was developed. Some of these markers are superior for primary screening while others are particularly helpful for cancer risk stratification, detection of high-grade cancer, and prediction of adverse events. Two of those markers such as proPSA (a part of the Prostate Health Index (PHI)) and prostate specific antigen 3 (PCA3) (a part of the PCA3 Progensa test) were recently approved by FDA for clinical use. Other markers are not PDA-approved yet but are available from Clinical Laboratory Improvement Amendment (CLIA)-certified clinical laboratories. In this review, we characterize diagnostic performance of these markers and their diagnostic and prognostic utility for prostate cancer.



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New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling

Publication date: Available online 5 March 2018
Source:Seminars in Cancer Biology
Author(s): Keesha E. Erickson, Oleksii S. Rukhlenko, Richard G. Posner, William S. Hlavacek, Boris N. Kholodenko
RAS is the most frequently mutated gene across human cancers, but developing inhibitors of mutant RAS has proven to be challenging. Given the difficulties of targeting RAS directly, drugs that impact the other components of pathways where mutant RAS operates may potentially be effective. However, the system-level features, including different localizations of RAS isoforms, competition between downstream effectors, and interlocking feedback and feed-forward loops, must be understood to fully grasp the opportunities and limitations of inhibiting specific targets. Mathematical modeling can help us discern the system-level impacts of these features in normal and cancer cells. New technologies enable the acquisition of experimental data that will facilitate development of realistic models of oncogenic RAS behavior. In light of the wealth of empirical data accumulated over decades of study and the advancement of experimental methods for gathering new data, modelers now have the opportunity to advance progress toward realization of targeted treatment for mutant RAS-driven cancers.



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Genomics and emerging biomarkers for immunotherapy of colorectal cancer

Publication date: Available online 1 March 2018
Source:Seminars in Cancer Biology
Author(s): Jakob Nikolas Kather, Niels Halama, Dirk Jaeger
Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow.



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Oncogenic KRas mobility in the membrane and signaling response

Publication date: Available online 27 February 2018
Source:Seminars in Cancer Biology
Author(s): Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Ras signaling initiates at the plasma membrane. Thus, Ras behavior at the membrane and how it relates to its interactions with Raf and PI3Kα, are of immense interest. Here we review factors influencing Ras lateral diffusion. We then ask whether oncogenic Ras diffusion speed in the membrane is important for signaling response times and whether it affects ubiquitously all pathways. We suggest that if Ras expression is sufficiently high to dimerize (or form nanoclusters), signaling response of those pathways where dimers (or nanoclusters) are involved corresponds to the speed with which Ras molecules travel in the membrane. On average, the faster the rate at which Ras travels to dimerize, the shorter the time to MAPK signaling; but not PI3Kα. However, we argue that KRas speed may not play an important functional role because changes in mobility at this scale are unlikely to be significant. In line with this, despite the anchors' variability, lateral diffusion speeds of KRas and HRas are similar, as is that of Lck kinase; however, even though with similar anchor, Cdc42 mobility presents a different pattern, commensurate with its role in the positioning of the apical domain, suggesting that mobility evolved for function.



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P21 activated kinase signaling in cancer

Publication date: Available online 9 January 2018
Source:Seminars in Cancer Biology
Author(s): Chetan K. Rane, Audrey Minden
The p21 Activated Kinases (PAKs) are a family of serine threonine kinases, that consist of 6 members, PAKs 1–6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis. The PAKs were originally identified as protein kinases that function downstream of the Ras related Rho GTPases Cdc42 and Rac. PAK1 and PAK4, which belong to Group I and Group II PAKs, respectively, are most often associated with tumorigenesis. On account of their well characterized roles in cancer, several small molecule inhibitors are being developed to inhibit the PAKs, and there is interest in investigating their efficacy as either first line or adjuvant treatments for cancer. Studies to delineate PAK regulated signaling pathways as well as the long term effects of PAK overexpression on gene expression are beginning to shed light on the mechanism by which PAK proteins may lead to cancer when they are overexpressed or activated. This review will describe the association between PAK expression in cancer, with a focus on PAK1 and PAK4, which are most often associated with the disease. The current understanding of the molecular mechanisms by which the PAKs operate in cancer will be discussed. We will also review some of the potential drug candidates, and discuss which of them are currently being tested for their efficacy in cancer treatments.



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Targeting IκappaB kinases for cancer therapy

Publication date: Available online 24 February 2018
Source:Seminars in Cancer Biology
Author(s): Nikee Awasthee, Vipin Rai, Srinivas Chava, Palanisamy Nallasamy, Ajaikumar B. Kunnumakkara, Anupam Bishayee, Subhash C. Chauhan, Kishore B. Challagundla, Subash C. Gupta
The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed.



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Targeting the RAS-dependent chemoresistance: The Warburg connection

Publication date: Available online 9 February 2018
Source:Seminars in Cancer Biology
Author(s): Roberto Serna-Blasco, Marta Sanz-Álvarez, Óscar Aguilera, Jesús García-Foncillas
RAS protein family members (KRAS4A, KRAS4B, HRAS and NRAS) function as GDP–GTP-regulated on-off switches, which regulate cytoplasmic-nuclear signaling networks ruling diverse normal cellular processes. Constitutive activating mutations in RAS genes are found in up to 30% of human cancers, and remarkably, the oncogenic Ras mutations and mutations in other components of Ras/MAPK signaling pathways seem to be mutually exclusive in most tumors, pointing out that deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis. Up to 30% of solid tumors are known to have a mutated (abnormal) KRAS gene. Unfortunately, patients harboring mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy. Moreover, it remains unclear that patients with KRAS wild-type CRC will definitely respond to such therapies. Although some clinically designed-strategies to modulate KRAS aberrant activation have been designed, all attempts to target KRAS have failed in the clinical assays and K-RAS has been assumed to be invulnerable to chemotherapeutic attack. Recently, different encouraging publications reported that ascorbate may have a selective antitumoral effect on KRAS mutant cancer cells.In this review we aim to describe the prevalence and importance of KRAS mutation in cancer and associated problems for the clinical handling of patients harboring these tumors. We highlight the role of mutated KRAS in boosting and keeping the tumor associated aberrant cell metabolism stating that further in-depth studies on the molecular mechanism of ascorbate to bypass mutated KRAS-related metabolic alterations may constitute a new pathway to design novel molecules in order handle tumor resistance to anti EGFR-therapies.



http://ift.tt/2GBlUo9

RAS-mediated oncogenic signaling pathways in human malignancies

Publication date: Available online 7 March 2018
Source:Seminars in Cancer Biology
Author(s): Abdul Q. Khan, Shilpa Kuttikrishnan, Kodappully S. Siveen, Kirti S. Prabhu, Muralitharan Shanmugakonar, Hamda A. Al- Naemi, Mohammad Haris, Said Dermime, Shahab Uddin
Abnormally activated RAS proteins are the main oncogenic driver that governs the functioning of major signaling pathways involved in the initiation and development of human malignancies. Mutations in RAS genes and or its regulators, most frequent in human cancers, are the main force for incessant RAS activation and associated pathological conditions including cancer. In general, RAS is the main upstream regulator of the highly conserved signaling mechanisms associated with a plethora of important cellular activities vital for normal homeostasis. Mutated or the oncogenic RAS aberrantly activates a web of interconnected signaling pathways including RAF-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase), phosphoinositide-3 kinase (PI3K)/AKT (protein kinase B), protein kinase C (PKC) and ral guanine nucleotide dissociation stimulator (RALGDS), etc., leading to uncontrolled transcriptional expression and reprogramming in the functioning of a range of nuclear and cytosolic effectors critically associated with the hallmarks of carcinogenesis. This review highlights the recent literature on how oncogenic RAS negatively use its signaling web in deregulating the expression and functioning of various effector molecules in the pathogenesis of human malignancies.



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New weapons to penetrate the armor: Novel reagents and assays developed at the NCI RAS Initiative to enable discovery of RAS therapeutics

Publication date: Available online 9 February 2018
Source:Seminars in Cancer Biology
Author(s): Dominic Esposito, Andrew G. Stephen, Thomas J. Turbyville, Matthew Holderfield
Development of therapeutic strategies against RAS-driven cancers has been challenging due in part to a lack of understanding of the biology of the system and the ability to design appropriate assays and reagents for targeted drug discovery efforts. Recent developments in the field have opened up new avenues for exploration both through advances in the number and quality of reagents as well as the introduction of novel biochemical and cell-based assay technologies which can be used for high-throughput screening of compound libraries. The reagents and assays developed at the NCI RAS Initiative offer a suite of new weapons that could potentially be used to enable the next generation of RAS drug discovery efforts with the hope of finding novel therapeutics for a target once deemed undruggable.



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Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment

Publication date: Available online 31 January 2018
Source:Seminars in Cancer Biology
Author(s): F. Passiglia, C. Caglevic, E. Giovannetti, JA. Pinto, P. Manca, S. Taverna, A. Listì, I. Gil-Bazo, LE. Raez, A. Russo, C. Rolfo
Recent studies with immunomodulatory agents targeting both cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) have shown to be very effective in several cancers revealing an unexpected great activity in patients with both primary and metastatic brain tumors. Combining anti-CTLA4 and anti-PD1 agents as upfront systemic therapy has revealed to further increase the clinical benefit observed with single agent, even at cost of higher toxicity. Since the brain is an immunological specialized area it's crucial to establish the specific composition of the brain tumors' microenvironment in order to predict the potential activity of immunomodulatory agents. This review briefly summarizes the basis of the brain immunogenicity, providing the most updated clinical evidences in terms of immune-checkpoint inhibitors efficacy and toxicity in both primary and metastatic brain tumors with the final aim of defining potential biomarkers for immunomodulatory cancer treatment.



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Immuno-oncology-101: overview of major concepts and translational perspectives

Publication date: Available online 8 February 2018
Source:Seminars in Cancer Biology
Author(s): B. Allard, S. Aspeslagh, S. Garaud, F.A. Dupont, C. Solinas, M. Kok, B. Routy, C. Sotiriou, J. Stagg, L. Buisseret
Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments. Despite recent achievements, there remain a number of unresolved issues in order to successfully implement cancer immunotherapy in many cancers. Importantly, clinical biomarkers are still needed for better optimization of emerging combination immunotherapies and better treatment tailoring. In this review, we summarize the function of innate and adaptive immune cells in anti-tumor immunity and the general mechanisms exploited by tumor cells to escape and inhibit immune responses as well as therapeutic strategies developed to overcome these mechanisms and discuss emerging biomarkers in immuno-oncology.



http://ift.tt/2GBdwF6

Intratumor heterogeneity in epigenetic patterns

Publication date: Available online 31 January 2018
Source:Seminars in Cancer Biology
Author(s): Yassen Assenov, David Brocks, Clarissa Gerhäuser
Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. As a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. Profiling these variants contributes to understanding tumors' clonal origins and might help to better understand response to therapy. However, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity. Understanding epigenetic diversity across cancer cells provides important additional information about the functional state of subclones and therefore allows better understanding of tumor evolution and resistance to current therapies.



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Cancer Molecular Markers: A guide to cancer detection and Management.

Publication date: Available online 8 February 2018
Source:Seminars in Cancer Biology
Author(s): Meera Nair, Sardul Singh Sandhu, Anil Kumar Sharma
Cancer is generally caused by the molecular alterations which lead to specific mutations. Advances in molecular biology have provided an impetus to the study of cancers with valuable prognostic and predictive significance. Over the hindsight various attempts have been undertaken by scientists worldwide, in the management of cancer; where, we have witnessed a number of molecular markers which allow the early detection of cancers and lead to a decrease in its mortality rate. Recent advances in oncology have led to the discovery of cancer markers that has allowed early detection and targeted therapy of tumors. In this context, current review provides a detail outlook on various molecular markers for diagnosis, prognosis and management of therapeutic response in cancer patients.



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