Exendin-4 inhibits structural remodeling and improves Ca2+ homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway

Publication date: Available online 24 February 2017
Source:Peptides
Author(s): Jingjing Chen, Dandan Wang, Fangai Wang, Shaobo Shi, Yuting Chen, Bo Yang, Yanhong Tang, Congxin Huang
The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 is a long-acting analogue of GLP-1, which stimulates insulin secretion and is clinically used in the treatment of type 2 diabetes. Previous studies have demonstrated that GLP-1 agonists and analogues serve as cardioprotective factors in various conditions. Disturbances in calcium cycling are characteristic of heart failure (HF); therefore the aim of this study was to investigate the effect of exendin-4 (a GLP-1 mimetic) on the regulation of calcium handling and identify the underlying mechanisms in a heart failure (HF) rat model after myocardial infarction (MI). Rats underwent surgical ligation of the left anterior descending coronary artery or sham surgery prior to infusion with vehicle, exendin-4, or exendin-4 and exendin9-39 for four weeks. Exendin-4 treatment decreased MI size, suppressed chamber dilation, myocyte hypertrophy and fibrosis, and improved in vivo heart function in the rats subjected to MI. Exendin-4 resulted in an increase in circulating GLP-1, and GLP-1R in ventricular tissues. Additionally, exendin-4 activated the eNOS/cGMP/PKG signaling pathway and inhibited the Ca²⁺/calmodulin-dependent kinase II (CaMKII) pathways. Myocytes isolated from exendin-4-treated hearts displayed higher Ca²⁺ transients, higher sarcoplasmic reticulum Ca²⁺ content and higher L-type Ca²⁺ current densities than MI hearts. Exendin-4 treatment restored the protein expression of sarcoplasmic reticulum Ca²⁺ uptake ATPase (SERCA2a), phosphorylated phospholamban (PLB) and Cav1.2 and decreased the levels of phosphorylated ryanodine receptor (RyR). Moreover, the favorable effects of exendin-4 were significant inhibited by exendin9-39 (a GLP-1 receptor antagonist). Exendin-4 treatment of a HF rat model after MI inhibited cardiac and cardiomyocytes progressive remodeling. In addition, Ca²⁺ handling and its molecular modulation were also improved by exendin-4 treatment. The beneficial effects of exendin-4 on cardiac remodeling may be mediated through activation of the eNOS/cGMP/PKG pathway.



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Gastric bypass in the pig increases GIP levels and decreases active GLP-1 levels

Publication date: Available online 24 February 2017
Source:Peptides
Author(s): Andreas Lindqvist, Mikael Ekelund, Stefan Pierzynowski, Leif Groop, Jan Hedenbro, Nils Wierup
Gastric bypass surgery results in remission of type 2 diabetes in the majority of patients. The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been implicated in the observed remission. Most knowledge so far has been generated in obese subjects. To isolate the surgical effects of gastric bypass on metabolism and hormone responses from the confounding influence of obesity, T2D or food intake, we performed gastric bypass in lean pigs, using sham-operated and pair-fed pigs as controls. Thus, pigs were subjected to Roux-en-Y gastric bypass (RYGB) or sham-surgery and oral glucose tolerance tests (OGTT). RYGB- and sham-pigs exhibited similar basal and 120-minute glucose levels in response to the OGTT. However, RYGB-pigs had approximately 1.6-fold higher 30-min glucose (p<0.01). Early insulin release (EIR) was enhanced approximately 3.5-fold in the RYGB-pigs (p<0.01). Furthermore, GIP release, both the acute and sustained release (p<0.001 and p<0.01, respectively) were increased approximately 2.5-fold and 1.4-fold, respectively, in RYGB-pigs. While total GLP-1 release increased approximately 2.1-fold after RYGB (p<0.001), active GLP-1 was 33% lower (p<0.01). Interestingly basal DPP4-activity was approximately 3.2-fold higher in RYGB-pigs (p<0.001).In conclusion, RYGB in lean pigs increases the response of GIP, total GLP-1 and insulin, but reduces levels of active GLP-1 in response to an oral glucose load. These data challenge the role of active GLP-1 as a contributor to remission from diabetes after RYGB.



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Letter From the Guest Editors

Publication date: February 2017
Source:Seminars in Ultrasound, CT and MRI, Volume 38, Issue 1
Author(s): Olivier Helenon, Nicolas Grenier




http://ift.tt/2lFux8c

Ghrelin and Cancer Progression

Publication date: Available online 24 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Tsung-Chieh Lin, Michael Hsiao
Ghrelin is a small peptide with 28 amino acids, and has been characterized as the ligand of the growth hormone secretagogue receptor (GHSR). In addition to its original function in stimulating pituitary growth hormone release, ghrelin is multifunctional which plays role in the regulation of energy balance, gastric acid release, appetite, insulin secretion, gastric motility and the turnover of gastric and intestinal mucosa. The discovery of ghrelin and GHSR expression beyond normal tissues suggests its role other than physiological function. Emerging evidences has reveal ghrelin's function in regulating several processes related to cancer progression, especially in metastasis and proliferation. We further show the relative GHRL and GHSR expression in pan-cancers from The Cancer Genome Atlas (TCGA), suggesting the potential pathological role of the axis in cancers. This review focuses on ghrelin's biological function in cancer progression, and reveals its clinical significance especially the impact on cancer patient outcome.



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Autophagy as a potential target for sarcoma treatment

Publication date: Available online 24 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Li Min, Edwin Choy, Raphael E. Pollock, Chongqi Tu, Francis Hornicek, Zhenfeng Duan
Autophagy is a constitutively active, evolutionary conserved, catabolic process for maintaining homeostasis in cellular stress responses and cell survival. Although its mechanism has not been fully illustrated, recent work on autophagy in various types of sarcomas has demonstrated that autophagy exerts an important role in sarcoma cell growth and proliferation, in pro-survival response to therapies and stresses, and in therapeutic resistance of sarcoma. Thus, the autophagic process is being seen as a possibly novel therapeutic target of sarcoma. Additionally, some co-regulators of autophagy have also been investigated as promising biomarkers for the diagnosis and prognosis of sarcoma. In this review, we summarize contemporary advances in the role of autophagy in sarcoma and discuss the potential of autophagy as a new target for sarcoma treatment.



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A comprehensive in vitro biological investigation of metal complexes of tolfenamic acid

Publication date: Available online 24 February 2017
Source:Alexandria Journal of Medicine
Author(s): Md. Mahabob Ullah Mazumder, Abhijit Sukul, Sajal Kumar Saha, Asif Alam Chowdhury, Yasir Mamun
ObjectiveThe inquisitive objective of the study was to observe the antimicrobial, cytotoxicity, and antioxidant activities of some newly synthesized metal complexes of tolfenamic acid.MethodsWhile antimicrobial activity was studied by disk diffusion method, cytotoxicity was studied by performing brine shrimp lethality bioassay. Moreover, DPPH radical scavenging potential was observed to determine the antioxidant property of the complexes.ResultsFrom the disk diffusion antimicrobial screening of tolfenamic acid and its metal complexes, it was found out that considerable antimicrobial activity in terms of zone of inhibition against the tested organisms had been demonstrated by Cu and Zn complex of tolfenamic acid. In addition, the brine shrimp lethality bioassay corroborated that tolfenamic acid and Cu, Co, Zn complexes of the parent NSAID exhibited cytotoxicity with LC50 values 1.23±0.91μg/ml, 1.12±0.12μg/ml, 1.17±0.56μg/ml, 1.35±0.24μg/ml respectively, compared to the vincristine sulfate had LC50 value of 0.82±0.09μg/ml. Furthermore, 1,1-diphenyl-2-picrylhydrazyl assay revealed that in comparison with standard BHT had IC50 of 11.84±0.65, Cu and Co complex of tolfenamic acid exhibited significant antioxidant or radical-scavenging properties with IC50 values 13.61±0.58μg/ml and 15.38±0.09μg/ml, respectively.ConclusionIt can be postulated that metal complexes of tolfenamic acid have auspicious pharmacological effects: antimicrobial, cytotoxicity, and antioxidant potency. Hence, these complexes might have better therapeutic responses in future; notwithstanding, it needs further detailed analysis in other pharmacological perspectives.



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Longitudinal segmentation of age-related white matter hyperintensities

Publication date: Available online 24 February 2017
Source:Medical Image Analysis
Author(s): Carole H. Sudre, M.Jorge Cardoso, Sebastien Ourselin
Although white matter hyperintensities evolve in the course of ageing, few solutions exist to consider the lesion segmentation problem longitudinally. Based on an existing automatic lesion segmentation algorithm, a longitudinal extension is proposed. For evaluation purposes, a longitudinal lesion simulator is created allowing for the comparison between the longitudinal and the cross-sectional version in various situations of lesion load progression. Finally, applied to clinical data, the proposed framework demonstrates an increased robustness compared to available cross-sectional methods and findings are aligned with previously reported clinical patterns.

Graphical abstract

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Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center

Abstract

Purpose

Antithyroid drug (ATD)-induced agranulocytosis is a rare but life-threatening adverse drug reaction that occurs in patients during the treatment of Graves' disease. We aimed to comprehensively examine data for patients with this rare complication and to improve the clinical safety of ATDs.

Methods

We retrospectively reviewed the medical records of 64 hospitalized patients diagnosed with ATD-induced agranulocytosis between 2000 and 2015.

Results

Agranulocytosis occurred in 52 (81.3%) patients within the first 3 months after initiation of ATD therapy. Fever (84.4%) and sore throat (82.8%) were the most common symptoms. Although they experienced symptoms, 30 (46.9%) patients did not seek treatment immediately and delayed their diagnosis of agranulocytosis. The minimum granulocyte count was lower in the patients diagnosed after the appearance of symptoms than in those diagnosed before the appearance of symptoms (0.01 × 10⁹/L (0 × 10⁹/L − 0.06 × 10⁹/L) versus 0.26 × 10⁹/L (0.05 × 10⁹/L − 0.40 × 10⁹/L), P < 0.001). The interval days from the appearance of symptoms to the diagnosis of agranulocytosis were negatively correlated with the minimum granulocyte count (r = −0.348, P = 0.005). In addition, a lower minimum granulocyte count was associated with a longer recovery time (β = −11.899, 95% CI −15.304 to −8.496).

Conclusions

Our findings have demonstrated that delayed diagnosis of ATD-induced agranulocytosis is common in our population. Delayed diagnosis is associated with severe agranulocytosis and may prolong the recovery time from agranulocytosis. Monitoring of the white blood cell and granulocyte counts may be an effective way to establish an early diagnosis and prevent progression to severe agranulocytosis.

http://ift.tt/2kV3fMq

PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment

Abstract

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis usually manifesting as skin ulcers with undermined erythematous-violaceous borders. It may be isolated, associated with systemic conditions or occurring in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis) or PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis). From a physiopathological point of view, all these conditions share common mechanisms consisting of over-activation of the innate immune system leading to increased production of the interleukin (IL)-1 family and 'sterile' neutrophil-rich cutaneous inflammation. From a genetic point of view, a number of mutations affecting the proteins of the inflammasome complex (the molecular platform responsible for triggering autoinflammation) or the proteins that regulate inflammasome function have been described in these disorders. As these debilitating entities are all associated with the over-expression of IL-1 and tumour necrosis factor (TNF)-α, biological drugs specifically targeting these cytokines are currently the most effective treatments but, given the emerging role of IL-17 in the pathogenesis of these syndromes, IL-17 antagonists may represent the future management of these conditions.

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Resilience, work engagement and stress reactivity in a middle-aged manual worker population

Publication date: Available online 24 February 2017
Source:International Journal of Psychophysiology
Author(s): Julie K. Black, George M. Balanos, Anna C. Whittaker (previously Phillips)
Work stress is a growing problem in Europe. Together, the negative physiological effect of stress on health, and increasing age increases the risk of developing cardiovascular disease in those aged over 50years. Therefore, identifying older workers who may be at risk of work-related stress, and its physiological effects, is key to promoting their health and wellbeing in the workforce. The present study examined the relationship between perceived psychological resilience and work-related factors (work engagement and presenteeism) and the physiological response to acute psychological stress in older manual workers in the UK. Thirty-one participants, mean (SD) age 54.9 (3.78)years reported perceived levels of resilience, work engagement, and presenteeism using standardized questionnaires. Cardiovascular measurements (heart rate (HR) and blood pressure (BP) and salivary cortisol were used to assess their physiological response to an acute psychological stress task. Resilience was not associated with work-related factors or reactivity. However, workers with higher work engagement showed lower SBP (p=0.02) and HR (p=0.001) reactivity than those with lower work engagement. Further, those with higher sickness presenteeism also had higher HR reactivity (p=0.03). This suggests a potential pathway by which higher work stress might contribute to the risk of future cardiovascular disease.



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The relationship between maternal responsivity, socioeconomic status, and resting autonomic nervous system functioning in Mexican American children

Publication date: Available online 24 February 2017
Source:International Journal of Psychophysiology
Author(s): Megan Johnson, Julianna Deardorff, Elizabeth L. Davis, William Martinez, Brenda Eskenazi, Abbey Alkon
Adversity, such as living in poor socioeconomic conditions during early childhood, can become embedded in children's physiology and deleteriously affect their health later in life. On the other hand, maternal responsivity may have adaptive effects on physiology during early childhood development. The current study tested both the additive and interactive effects of socioeconomic status (SES) and maternal responsivity measured at 1year of age on resting autonomic nervous system (ANS) function and trajectory during the first 5years of life. Participants came from a birth cohort comprised of Mexican-origin families living in California. Children's resting ANS functioning (respiratory sinus arrhythmia; RSA; pre-ejection period; PEP; and heart rate; HR) was collected at 1, 3.5, and 5years of age (N=336) and modeled across time using Hierarchical Linear Modeling. Consistent with hypotheses, results showed that low SES predicted flatter trajectories of resting HR and PEP over early childhood (i.e., patterns of consistently higher heart rate; shorter PEP), whereas children who experienced positive maternal responsivity had steeper trajectories in RSA and PEP over time (i.e., increasing parasympathetic activation; decreasing sympathetic activation). The interaction between SES and maternal responsivity significantly predicted RSA intercept at age 5, such that among children living in low SES environments, high maternal responsivity mitigated the negative effect of poverty and predicted higher resting RSA at 5years of age. Results are consistent with the early life programming theory that suggests that environmental influences become biologically embedded in the physiology of children living in socially disadvantaged contexts, and identify increased maternal responsivity as a developmental mechanism that could offset the deleterious effects of low SES.



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Imaging prevalence of nasal septal perforation in an urban population

Publication date: May–June 2017
Source:Clinical Imaging, Volume 43
Author(s): Menachem Gold, Issac Boyack, Nicholas Caputo, Aaron Pearlman
ObjectiveTo determine the prevalence of nasal septal perforation (NSP) on CT imaging in an urban hospital setting.MethodsFacial bone CT scans from 3708 consecutive patients were reviewed for the presence of NSP. Size of the perforation was measured in two dimensions. Medical records were reviewed for possible risk factors.ResultsThe prevalence of NSP was 2.05%. The most common risk factor was a history of drug abuse. Cocaine was the most prevalent drug used.ConclusionThe prevalence of NSP was more than double of that previously published, likely related to intranasal drug use in our urban population.



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Channel of viral DNA packaging motor for real time kinetic analysis of peptide oxidation states

Publication date: May 2017
Source:Biomaterials, Volume 126
Author(s): Shaoying Wang, Zhi Zhou, Zhengyi Zhao, Hui Zhang, Farzin Haque, Peixuan Guo
Nanopore technology has become a powerful tool in single molecule sensing, and protein nanopores appear to be more advantageous than synthetic counterparts with regards to channel amenability, structure homogeneity, and production reproducibility. However, the diameter of most of the well-studied protein nanopores is too small to allow the passage of protein or peptides that are typically in multiple nanometers scale. The portal channel from bacteriophage SPP1 has a large channel size that allows the translocation of peptides with higher ordered structures. Utilizing single channel conductance assay and optical single molecule imaging, we observed translocation of peptides and quantitatively analyzed the dynamics of peptide oligomeric states in real-time at single molecule level. The oxidative and the reduced states of peptides were clearly differentiated based on their characteristic electronic signatures. A similar Gibbs free energy (ΔG⁰) was obtained when different concentrations of substrates were applied, suggesting that the use of SPP1 nanopore for real-time quantification of peptide oligomeric states is feasible. With the intrinsic nature of size and conjugation amenability, the SPP1 nanopore has the potential for development into a tool for the quantification of peptide and protein structures in real time.



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Pathology-targeted cell delivery via injectable micro-scaffold capsule mediated by endogenous TGase

Publication date: May 2017
Source:Biomaterials, Volume 126
Author(s): Chunxiao Qi, Yaqian Li, Patrick Badger, Hongsheng Yu, Zhifeng You, Xiaojun Yan, Wei Liu, Yan Shi, Tie Xia, Jiahong Dong, Chenyu Huang, Yanan Du
Targeted cell delivery to lesion sites via minimally invasive approach remains an unmet need in regenerative medicine to endow satisfactory therapeutic efficacy and minimized side-effects. Here, we rationally designed a pathology-targeted cell delivery strategy leveraging injectable micro-scaffolds as cell-loading capsule and endogenous tissue transglutaminase (TGase) at lesion site as adhesive. Up-regulated TGase post-liver injury catalyzed chemical bonding between the glutamine and lysine residues on liver surface and micro-scaffolds both ex vivo and in vivo, facilitating sufficient adhesion on the pathological liver. Upon intraperitoneal injection, Mesenchymal Stem Cell-loaded capsules, exhibiting cell protection from shear-induced damage and post-transplantation anoikis, adhered to the CCl4-treated liver with a hundred-fold improvement in targeting efficiency (70.72%) compared to free-cell injection, which dramatically improved mice survival (33.3% vs. 0% for free-cell therapy) even with low-dosage treatment. This unique and widely-applicable cell delivery mechanism and strategy hold great promise for transforming cell therapy for refractory diseases.



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Weekly cisplatin (30–40 mg/m2) as radiosensitizer: Is it high or moderate emetic agent?

A Karpe, VM Patil, A Joshi, V Noronha, S Gupta, A Ramaswamy, A Sahu, V Doshi, T Gupta, S Rath, S Banavali, K Prabhash

Indian Journal of Cancer 2016 53(3):454-456

PURPOSE: The American Society of Clinical Oncology (ASCO) guideline recommends a high antiemetic prophylaxis for any dose of cisplatin. This hypothesis was tested by us in this analysis of solid tumor patients who received weekly cisplatin as a radiosensitizer in a dose range of 30–40 mg/m2. METHODS: This was a retrospective analysis of 181 solid tumor patients who received weekly cisplatin (in the dose range of 30–40 mg/m2) as a radiosensitizer between July 2015 and August 2015. The antiemetic prophylaxis schedule provided was classified as optimal (if a high antiemetic prophylaxis was provided) or suboptimal (if a nonhigh antiemetic prophylaxis was provided). The incidence of acute, delayed and breakthrough vomiting after chemotherapy was noted. SPSS version 20 was used for analysis. Fisher's exact test was used to determine the association between antiemetic schedule (suboptimal vs. optimal) and postchemotherapy emesis. RESULTS: In the present study, of 181 patients, only 25 patients (13.8%) received optimal antiemetic prophylaxis while the remaining 156 (86.2%) received suboptimal prophylaxis. In the cohort of patients with suboptimal prophylaxis, dexamethasone was omitted in all patients (100%) while NK receptor antagonist was omitted in 76 patients (48.7%). The rate of vomiting was lower in patients receiving optimal prophylaxis as compared to that in patients receiving suboptimal prophylaxis (12% vs. 39.75%; P - 0.005). CONCLUSION: Omission of dexamethasone followed by aprepitant was the main reason for suboptimal prophylaxis. High antiemetic prophylaxis in accordance with ASCO guidelines overall decreased the risk of emesis in patients receiving CTRT with weekly cisplatin in the dose range of 30–40 mg/m2.

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Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?

J Bajpai, A Ramaswamy, S Gupta, J Ghosh, S Gulia

Indian Journal of Cancer 2016 53(3):464-467

BACKGROUND: Drugs targeting mammalian target of rapamycin signaling pathway have been recently approved for treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). However, there is lack of real world data from India on the use of this therapeutic strategy. MATERIALS AND METHODS: A retrospective analysis of MBC patients who had recurrence or progression while receiving aromatase inhibitors (AI's) and further treated with everolimus and either tamoxifen/AI/fulvestrant between March 2012 and June 2014, was undertaken. RESULTS: There were 41 patients with median age 55 years, 73% with visceral metastasis, and 73% with ≥2 sites of metastases. Thirty (73%) patients had received 3 prior lines of therapy including AI (100%), tamoxifen (94%), fulvestrant (39%), and chemotherapy (100%) while the remaining had received <3 lines of prior therapy. The commonest Grade 3/4 adverse events were stomatitis (19%), hyperglycemia (new/worsening, 17%), fatigue (14.5%), nonneutropenic infections (14%), anemia (12%) and pneumonitis (7%). Everolimus dose reductions were required in 31% patients. There were 30% partial responses, 38% prolonged disease stabilizations and 32% disease progression as best responses to everolimus. The median progression-free survival was 22 weeks (5 months). CONCLUSIONS: Everolimus based treatment has meaningful activity in heavily pretreated patients with HR-positive MBC but is associated with considerable toxicity and requirement for dose adjustment.

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Efficacy and safety of sorafenib in advanced renal cell cancer and validation of Heng criteria

A Joshi, A Ramaswamy, V Noronha, VM Patil, A Chandrasekharan, A Goel, A Sahu, N Sable, A Agrawal, S Menon, K Prabhash

Indian Journal of Cancer 2016 53(3):423-428

INTRODUCTION: Sorafenib is an established upfront treatment option for metastatic RCC (mRCC). There is no published literature regarding its performance in Indian Patients. We present an analysis of Sorafenib use in our institute and attempt to validate the Heng criteria as a prognostic score in these patients. MATERIALS AND METHODS: Patients who received Sorafenib as first line treatment for advanced RCC from June 2012 to December 2015 were prognosticated by Heng criteria and retrospectively analysed for baseline demographics, toxicity, response and outcomes. RESULTS: 82 patients (65 males, 17 females) with a median age of 57 years were included for final analysis. Median ECOG PS was 1, 95.2 % of the patients had Stage IV disease and clear cell was the predominant histology (79.4%). 23.2%, 42.7% and 34.1% of patients were classified as low, intermediate and high risk by Heng's criteria, respectively. Dose reduction was required in 24.4% of patients, while 14.6% required permanent cessation of Sorafenib due to intolerable or recurrent side effects. Common adverse events included HFS (68.2%), mucositis (35.3%), fatigue (35.3%), rash (32.9%) and hypertension (25.6%). Response rate observed was 18.2%, while clinical benefit rate was 57.2% in the 57 patients where response was evaluable. Median progression free survival was 7.75 months (5.45-10.05) and median overall survival (OS) was 12.18 months (9.61 – 14.76). Median OS was 19.6, 16.1 and 10.3 months respectively for low, intermediate and high risk patients by Heng criteria and the criteria was statistically discriminatory for the 3 groups for OS (p=0.045, chi-square test). CONCLUSION: Sorafenib is a viable upfront treatment option for metastatic RCC in Indian patients with acceptable PFS, although a high incidence of HFS, mucositis and rash is observed. The Heng score has discriminatory value in mRCC with Sorafenib and can be considered for routine use in the clinic.

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Applicability of a single 5 color cytoplasmic markers tube as primary panel for immunophenotyping of acute leukemia: A Gujarat Cancer and Research Institute experience

BP Parikh, SP Patel, BN Raiya, HH Vora, DH Jetly

Indian Journal of Cancer 2016 53(3):349-352

INTRODUCTION: Flow cytometry is highly sensitive for detection and quantitative analysis of surface and intracellular antigens in malignant hemopoietic cells. Immunophenotyping is a routine practice for classification and lineage assignment of acute leukemia. In the present study, our aim is to identify the role of a single 5 color, CD45, myeloperoxidase (MPO), cCD79a, cCD3, and Tdt, cytoplasmic markers combination as a primary tube. We compared with final diagnosis on the basis of morphology, cytochemistry, and primary and secondary panels of immunophenotyping and also with other study. MATERIALS AND METHODS: We have included 455 new cases of acute leukemias with applied primary and secondary panels of markers for immunophenotyping. We analyzed sensitivity and specificity of different subsets with combination of positive and negative markers. RESULTS: MPO was positive in 61.4% of acute myeloid leukemia (AML) cases. All 184 (100%) cases of the AML were negative for cCD3 and cCD79a co-expression. cCD79a expression was highly sensitive as 98.5% B-acute lymphoblastic leukemia (B-ALL) expressed it. cCD3 expression was detected in 100% cases of T-ALL, and its co-expression was not seen in B-ALL and AML. CONCLUSION: Our study indicates that there was very good correlation of 5-color cytoplasmic tube-based diagnosis versus final diagnosis based on morphology, cytochemistry, and flow cytometry. We can use this 5-color cytoplasmic tube method to make immunophenotyping cost-effective.

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Does magnetic resonance imaging accurately predict residual disease after unplanned excision of soft-tissue sarcomas?

S Patkar, A Gulia, S Juvekar, B Rekhi, A Puri

Indian Journal of Cancer 2016 53(3):408-411

BACKGROUND: Often, it is difficult to assess the presence of residual disease after an unplanned excision in soft-tissue sarcomas. Inadequate excision leads to disease recurrence and inferior oncological outcomes while unnecessary excision may lead to additional surgical procedures with inherent morbidity and increased cost of treatment. There is a paucity of literature comparing the preoperative imaging findings with the final histopathology report to accurately assess the presence of residual disease. MATERIALS AND METHODS: The clinical details of 55 patients who had oncological scar excision after unplanned prior excision were retrieved. Histopathological evaluation of scar was compared with presurgery magnetic resonance imaging (MRI) for the presence of residual disease. Sensitivity, specificity, and positive and negative predictive value (NPV) of MRI for detection of residual disease were calculated. RESULTS: On MRI, residual disease was seen in 28 cases, no disease in 24 cases whereas findings of three patients were indeterminate. On final histopathology, residual disease was present in 30 (55%) patients whereas no residual tumor was seen in 25 (45%) patients. Two patients in whom MRI suggested the presence of residual disease had no tumor on final histopathology. No evidence of residual disease was reported in MRI of 24 patients. Of these, twenty patients were confirmed to have no tumor on final histopathology, whereas four patients had a residual tumor. Sensitivity: 86.66%, specificity: 90.90%, positive predictive value (PPV): 92.85%, NPV: 83.33%. CONCLUSION: MRI can aid in preoperative planning by identifying the site and extent of the previous surgery. It has a high PPV (92%) for detection of residual disease. However, a negative scan (NPV 83%) does not reliably exclude the presence of residual disease.

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Epidemiological and survival analysis of triple-negative breast cancer cases in a retrospective multicenter study

R Sarin, L Khandrika, RNM Hanitha, A Avula, M Batra, S Kaul, H Raj, S Shivkumar, S Gupta, E Khan, TPS Bhandari, SVSS Prasad, VA Reddy, G Swarnalata, M Bakre, S Chatterjee, J Jain

Indian Journal of Cancer 2016 53(3):353-359

INTRODUCTION: This is a retrospective study with data collected from breast cancer cases from five major Apollo Hospitals across India, as part of a biobanking process. One aspect of our study focused specifically on data from triple-negative breast cancer (TNBC) cases. The aim of this study was to analyze epidemiology, treatment options, and survival of the patients with TNBC. Our goal was to draw conclusions on the preponderance of the disease and also to understand the outcomes using the existing therapy options. MATERIALS AND METHODS: Data were collected after due ethical clearances and were coded with regard to patient identifiers to protect patient privacy. Data were not only from the various departments of the respective hospitals and the treating physicians but also from the follow-up made by hospital staff and social workers. RESULTS: About 20% of all cases of breast cancer comprised TNBC. Although the disease is generally thought to be an early onset disease, there was no major difference in the median age of diagnosis of TNBC compared to other breast cancer cases. More than 85% of the TNBC cases were of early stage disease with <4% of the cases of metastatic cancer. Data on follow-up were somewhat sporadic as a good number of cases were lost to follow-up, but from the available data, recurrence rate was about 11%. Death, when it occurred, was mostly in the early periods of treatment with 35% of the events occurring before 3 years. The overall survival rates beyond 3 years were more than 86%. CONCLUSIONS: Data and sample collection are an ongoing process, so we expect this data set to be enriched with more cases and longer duration of follow-up in a year. Preliminary analysis sheds light on the potential of such a collection both for understanding the epidemiology of the disease and also for conducting future studies with an eye toward improving treatment outcomes.

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Cancer and cure: A critical analysis

PS Roy, BJ Saikia

Indian Journal of Cancer 2016 53(3):441-442

Cancer is one of the most dreaded diseases of the 20th century and spreading further with continuance and increasing incidence in the 21st century. The situation is so alarming that every fourth person is having a lifetime risk of cancer. India registers more than 11 lakh new cases of cancer every year, whereas, this figure is above 14 million worldwide. Is cancer curable? The short answer to this question is "Yes." In fact, all cancers are curable if they are caught early enough. Cancer cells continue to grow unless one of four things occur: (1) The cancerous mass is removed surgically; (2) using chemotherapy or another type of cancer-specific medication, such as hormonal therapy; (3) using radiation therapy; or (4) the cancer cells shrink and disappear on their own.

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The male breast cancer: Epidemiological data from the North of Peru

G Flores-Trujillo, E Serrano-LaBarrera

Indian Journal of Cancer 2016 53(3):359-359



http://ift.tt/2lR15x0

Utility of driver mutation

V Sharma, VM Patil, V Noronha, A Joshi, K Prabhash

Indian Journal of Cancer 2016 53(3):365-365



http://ift.tt/2lCaWUQ

Prevalence of depression and anxiety disorder in cancer patients: An institutional experience

A Shankar, C Dracham, S Ghoshal, S Grover

Indian Journal of Cancer 2016 53(3):432-434

AIM: This study aimed to screen the patients with various malignancies for the presence of depressive disorders and anxiety disorder using standardized rating scales. MATERIALS AND METHODS: Five hundred and thirty-four (n = 534) patients attending the radiotherapy outpatient services completed the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 (GAD-7) Questionnaire. RESULTS: About half (n = 248; 46.4%) of the patients had psychiatric morbidity either in the form of depressive disorder or in the form of GAD. Higher stage of malignancy (from early, advanced to metastasis) was associated with higher prevalence of depressive disorder and GAD. The presence of psychiatric morbidity, especially anxiety disorder, was associated with being from low socioeconomic status. CONCLUSION: The present study suggests that psychiatric morbidity in the form of depressive and anxiety disorders is very common among patients with malignancies. Accordingly, there is a need for close liaison between oncologists and mental health professionals to improve the outcome of patients with various malignancies.

http://ift.tt/2lQYdjK

Incidence and pattern of bone metastases at presentation in Indian carcinoma breast patients

SM Doddala, A Suryadevara, SK Chinta, AL Madisetty

Indian Journal of Cancer 2016 53(3):360-362

BACKGROUND: Breast cancer (BC) is the most common female cancer and frequently metastases to the bones. Breast cancer among Indian women occurs a decade earlier and more aggressive than the western population. Screening guidelines are based on western studies. The aim of our study is to assess the role of Technitium99m bone scan (TBS) in screening Indian EBC patients at presentation. We also looked at the pattern of BM in all stages of BC. METHODS: Patients with BC who had TBS at presentation from January 2012 to September 2015 were included in the study. RESULTS: Bone metastases were seen in 23.42% (241/1029). Of these, 10.06% (31/308) EBC, 25.60% (169/660) locally advanced BC (LABC) and 63.93% (39/61) of metastatic BC (MBC) patients had BM. Most common sites of BM were spine and pelvis. In long bone and sternum, proximal part was commonly involved. CONCLUSION: The incidence of BM in Indian BC patients at presentation is higher than western population. The incidence of BM per stage is similar to west. So TBS should be done in LABC and symptomatic EBC. There is high incidence of BM to spine and pelvis. In pelvis, SI joints and ilium and in long bones and sternum, proximal parts were commonly involved.

http://ift.tt/2lCfSJj

Pattern of care in operable endometrial cancer treated at a rural-based tertiary care cancer center

SB Dessai, D Adrash, M Geetha, S Arvind, J Bipin, S Nayanar, K Sachin, MS Biji, S Balasubramanian

Indian Journal of Cancer 2016 53(3):416-419

PURPOSE: An audit was planned to study the demographics, staging, treatment details, and outcomes of operable endometrial cancers. METHODOLOGY: All operable endometrial cancers treated between January 2009 and October 2014 were included in the study. The details regarding demographics, staging, surgical procedure, pathological staging, adjuvant treatment, and outcomes were extracted from the case records. Descriptive statistics was performed. The time-to-event analysis was done by Kaplan–Meier method. Univariate and multivariate analyses were done for disease-free survival (DFS) and overall survival (OS). RESULTS: There were 55 patients with a median age of 59 years (35–73 years). The Eastern Cooperative Oncology Group performance status was 1 in 52 patients (94.5%) and 2 in 3 patients (5.5%). Forty-nine patients (89.1%) had disease restricted to endometrium while 6 patients (10.9%) had cervical involvement. The surgery done was Type I hysterectomy in 49 patients (89.1%), Type II in 5 patients (9.1%), and Type III in 1 patient (1.8%). Pelvic lymph node dissection was done in all patients while para-aortic (infrahilar) dissection was done in 48 patients (87.3%). The pathological stages were Stage IA in 19 patients, Stage IB in 15 patients, Stage II in 4 patients, Stage IIIA in 3 patients, Stage IIIB in 2 patients, Stage IIIC1 in 5 patients, Stage IIIC2 in 4 patients, and Stage IV in 3 patients. Grade 1 tumors were seen in 23 patients, Grade 2 in 13 patients, and Grade 3 in 19 patients. The histology was endometrioid in 44 patients, serous in 6 patients, clear cell in 3 patients, and others in 2 patients. Adjuvant treatment was received by 40 patients. With a median follow-up of 2.5 years, the 3-year DFS and OS were 78% and 82%, respectively. Age >59 years, Stage III or greater, and Grade 3 tumors were independent prognostic factors adversely affecting both DFS and OS. CONCLUSION: The outcomes in our study are comparable to that seen in Western literature. Elderly status, higher stage, and a poorly differentiated tumor are associated with poor outcomes.

http://ift.tt/2lCnlIr

The pattern of invasive lobular carcinoma in the patients diagnosed with breast cancer from Balochistan

AH Baloch, AN Khosa, N Bangulzai, H Sadia, M Ahmed, F Khan, M Jan, M Tareen, MH Kakar, J Shuja, HK Naseeb, J Ahmad

Indian Journal of Cancer 2016 53(3):363-365

Introduction: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer accounting for 5%–15% of all the breast cancer cases. The present study was performed on 171 breast cancer patients from Balochistan registered in CENAR (Center for Nuclear Medicine and Radiotherapy), Quetta. Materials and Methods: Written consent was obtained from the patients. The history of the disease was taken from the patients, and the patients' enrollment files were retrieved. Results: Of the 171 patients, 5 (2.96%) were diagnosed with ILC with tumor Grade II, and stage of the cancer reported was Grade III in all the 5 patients affected with ILC. Conclusion: ILC is the second most common type of breast cancer diagnosed with comparatively lower grade but almost reported infiltrating.

http://ift.tt/2lR1AHA

Epidemiology and resistance pattern of bacterial isolates among cancer patients in a Tertiary Care Oncology Centre in North India

U Batra, P Goyal, P Jain, A Upadhyay, N Sachdeva, M Agarwal, D Bhurani, V Talwar, SK Gupta, DC Doval

Indian Journal of Cancer 2016 53(3):448-451

OBJECTIVES: To examine the epidemiology of microbiologically documented bacterial infection and the resistance pattern, among cancer patients undergoing treatment at RGCIRC, Delhi. DESIGN AND SETTING: Retrospective observational study in which culture reports obtained over 1 year in 2013, were analyzed. RESULTS: 13329 cultures were obtained over 1 year in 2013 and were analyzed. 23.6 % samples showed positive culture with majority being gram negative isolates (67.9 %). E. coli was the commonest gram negative isolate (49.4%) followed by klebsella (29.7%) and Staph. aureus was the commonest gram positive isolate. There was high incidence of ESBL in blood and urine (87.2% & 88.5%) and BLBLI were also high (78% & 83.9%). Carbapenem resistance was comparatively low (10%) and colistin sensitivity was quiet high (> 95%). CONCLUSIONS: Prevalence of MRSA and VRE in our institute is very less, whereas prevalence of ESBLs and BLBLI isolates amongst gram negative infections is around 80%. Gram negative isolates had poor sensitivity to cephalosporins and fluoroquinolones.

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Alteration in steroid hormone and Her-2/neu receptor status following neoadjuvant chemotherapy in locally advanced breast cancer: Experience at a tertiary care centre in India

P Ramteke, V Seenu, R Prashad, SD Gupta, V Iyer, SVS Deo, A Gogia, S Mathur

Indian Journal of Cancer 2016 53(3):366-371

CONTEXT: Use of neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC) enables tumor reduction and conservative surgery. It is proposed in some studies that there may be an alteration in the hormonal receptor (HR) status and human epidermal growth factor receptor 2 (Her-2)/neu immune-expression following NACT. AIMS: To study the status of estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu receptor before and after NACT in LABC. MATERIALS AND METHODS: HR and Her-2/neu status were evaluated by immunohistochemistry on 100 core needle biopsy of primary tumors and surgical specimens after receiving NACT (NACT group); fifty patients without NACT served as non-NACT group, and discordance was compared between the two groups. RESULTS: In the NACT group, discordance of 17%, 13%, and 11% was noted in ER, PR, and Her-2/neu status, while in non-NACT group, discordance seen in ER, PR, and Her-2/neu was 8%, 8%, and 4%, respectively. CONCLUSIONS: There was a significant alteration in ER and Her-2/neu status from the core biopsy to the treated resected tumor in the study group. As these changes may impact treatment, HR and Her-2/neu expression reanalysis in final surgical specimens is recommended.

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Sensorineural deafness: An uncommon irreversible adverse effect of bortezomib

Parameswaran Anoop, Channappa N Patil, Vaishnavi S Joshi, Poonam Maurya, Pradeep Hosamani

Indian Journal of Cancer 2016 53(3):459-459



http://ift.tt/2mn2I36

Induction chemotherapy with cisplatin and ifosfamide in locally advanced inoperable squamous cell carcinoma of the head and neck: A single-institution experience

S Zaheer, SA Siddiqui, M Akram, SA Hasan

Indian Journal of Cancer 2016 53(3):372-376

BACKGROUND: Induction chemotherapy (ICT) in patients with head and neck cancer has been studied since a long time. The addition of taxanes to the cisplatin and 5-fluorouracil (5FU) (PF) regimen results in superior antitumor activity. We did this study to see the response and toxicity of ICT with cisplatin and ifosfamide followed by concurrent chemoradiotherapy (CRT) in locally advanced, unresectable squamous cell carcinoma of head and neck (SCCHN). AIMS: The aim of this study was to see the results of ICT using cisplatin and ifosfamide regimen in locally advanced unresectable SCCHN in terms of acute and chronic toxicity and response to treatment. MATERIALS AND METHODS: Patients with Stage III and IV, nonmetastatic SCCHN were enrolled in the study. They were given two cycles of ICT with cisplatin and ifosfamide followed by CRT. RESULTS: After ICT, the overall response rate (ORR) was 75.0% at the primary site and 70.0% at the nodal site. ORR for combined primary and nodal disease was observed to be 67.5%. The complete response (CR) and partial response (PR) for combined primary and nodal site were seen in 4 (10.0%) and 23 (57.5%) patients. Of 32 patients who received CRT after ICT, CR was 53.1% and PR was 31.3%. Mucositis, skin reaction, and pharyngeal and laryngeal toxicities were the most common but tolerable. CONCLUSION: ICT with cisplatin and ifosfamide gives comparable results to the standard paclitaxel, PF regimen. We conclude that this combination regimen for ICT is not only an economical alternative of taxol-based regimen but also well tolerated by the patients.

http://ift.tt/2lC1DnX

Epidermal growth factor receptor expression in gastric tumors and its relationship with the germline polymorphisms − 216 G>T, −191 C>A, (CA) n IVS1, and R521K

JH Torres-Jasso, AR Bustos-Carpinteyro, JR Garcia-Gonzalez, J Peregrina-Sandoval, JA Cruz-Ramos, E Santiago-Luna, JY Sanchez-Lopez

Indian Journal of Cancer 2016 53(3):345-348

BACKGROUND: Gastric cancer (GC) is the third worldwide leading cause of cancer-related death affecting both sexes. The aberrant expression of epidermal growth factor receptor (EGFR) gene has been detected in many human epithelial malignancies and linked to advanced disease, more aggressive phenotype, and poor prognosis. AIMS: To analyze the relation that the expression of EGFR in gastric tumors holds with pathological characteristics and with the germline polymorphisms −216 G>T, −191 C>A, (CA) n IVS1, and R521K. MATERIALS AND METHODS: We studied 22 biopsies from gastric tumors obtained by endoscopy. EGFR expression was determined by relative quantification real-time polymerase chain reaction with the glyceraldehyde-3-phosphate dehydrogenase reference gene (as for messenger RNA [mRNA]) and by immunohistochemistry (IHC) (as for protein). EGFR germline polymorphisms were analyzed by sequencing, GeneScan, and restriction fragment length polymorphisms. RESULTS: EGFR mRNA expression was increased (>2-fold) in 13.6% of GC cases, decreased (<0.5-fold) in 68.2%, and normal in 18.2%; overexpression was related to well-differentiated gastric tumors, whereas underexpression was linked to moderate or poorly differentiated gastric tumors (P < 0.001). EGFR protein expression was high (IHC 2+ and 3+) in 29.4% of gastric tumors and was normal or low (score 0 to 1+) in 70.6% cases. EGFR expression, in both mRNA and protein, was not related to any EGFR polymorphism (P > 0.05). CONCLUSIONS: Most gastric tumors showed low EGFR expression (mRNA and protein), whereas EGFR overexpression was related to well-differentiated gastric tumors. Furthermore, germinal polymorphisms −216, −191, (CA) n IVS1, and R521K were not related to EGFR expression (mRNA or protein).

http://ift.tt/2lC9gL3

Seminoma of solitary testis: A case report

I Rana, A Lukram

Indian Journal of Cancer 2016 53(3):376-376



http://ift.tt/2lQSB9b

A cohort study of vulvar cancer over a period of 10 years and review of literature

N Singh, N Negi, K Srivastava, G Agarwal

Indian Journal of Cancer 2016 53(3):412-415

OBJECTIVE: The objective of this study was to study the risk factors, management protocols, and the outcome of vulvar cancer cases over a period of 10 years in a tertiary care hospital. METHODOLOGY: It is a retrospective cohort study. The hospital records of 41 patients with histologically proven vulvar cancer were studied from the Department of Obstetrics and Gynaecology and the Department of Radiotherapy (RT). The presence of risk factors, stage of disease, treatment modalities used, and disease outcomes in terms of survival were studied. The data collected were analyzed and compared with the published literature. RESULTS: The mean age for the diagnosis of vulvar cancer was 52 years and the peak incidence was seen in the age group of 50–70 years. Incidence was significantly more in multiparous (P = 0.001) and postmenopausal women (P = 0.007). An average of 4.1 cases were seen per year. Nearly, 97.56% of the cases were squamous cell carcinomas. Twenty cases belonged to the early stage of the disease (Stage I and II) whereas 21 cases had advanced disease (Stage III and IV). Nearly, 48.78% of the cases were primarily treated with surgery, 26.83% with RT, 7.3% with chemotherapy, and 17.07% with combined chemoradiation. Seventy-eight percent of the surgically treated cases had a mean survival of 5 years. Mean survival of 1 year was recorded in advanced disease cases. Limitation of the study was poor follow-up after treatment. CONCLUSION: Incidence of vulvar cancer is significantly high in multiparous and postmenopausal women. Conservative surgical treatment is the best option in the early stage of the disease (Stage I and II) and gives high survival rates whereas advanced disease treated with chemoradiation has a poor survival.

http://ift.tt/2lR1y2q

Expression of Vav3 protein and its prognostic value in patients with gastric cancer

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Bibo Tan, Yong Li, Xiaoming Shi, Liqiao Fan, Qun Zhao, Yanli Liu, Ming Tan, Qingwei Liu, Nan Jia
Vav3 is associated with tumor growth, apoptosis, invasion, metastasis and angiogenesis. In this study,we detected the expression of Vav3 in gastric cancer tissues, and explored its role in invasion, metastasis and prognosis of gastric cancer. Vav3, MMP-2, MMP-9, TIMP-1 and TIMP-2 in primary lesion and pericarcinous tissues were tested with Immunohistochemistry and Western blot. Results showed a higher expression of Vav3 in primary lesion than in pericarcinous tissue, and the expression of Vav3 was significantly correlated with MMP-2, MMP-9 and TIMP-1 in gastric cancer tissues. Overexpression of Vav3 was associated with poorer differentiation, advanced clinical stage, more significant infiltration depth, lymphatic metastasis, and perineural invasion. Results of Kaplan-Meier verified that overexpression of Vav3 was related to poorer prognosis and shorter survival time. Moreover, Cox proportional hazard model revealed that overexpression of Vav3 was an independent risk factor of prognosis for patients with gastric cancer. In all, we conclude that overexpression of Vav3 is an independent risk factor for prognosis of gastric cancer, and can be used as prognostic indicator. This may be because that Vav3 could regulate genes which associated with the invasion and metastasis.



http://ift.tt/2mgY4ql

The ERK/MAPK pathway is overexpressed and activated in gallbladder cancer

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Kurt Buchegger, Ramón Silva, Jaime López, Carmen Ili, Juan Carlos Araya, Pamela Leal, Priscilla Brebi, Ismael Riquelme, Juan Carlos Roa
Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. Molecular profiling has revealed that the deregulation in the ERK/MAPK signaling pathway plays a crucial role in many disease and malignancies, including GBC. The aim of this study was to measure the expression of ERK1/2 and p-ERK1/2 in a population with high GBC-related mortality, such as the Chilean population, and characterize the protein expression of this ERK/MAPK pathway in seven GBC cell lines. Immunohistochemistry (IHC) for ERK1/2 and p-ERK1/2 was performed in 123 GBC tissues and 37 chronic cholecystitis (CC) tissues. In addition, protein expression analysis by western blot for ERK1/2, p-ERK1/2, EGFR, ERBB2 and ERBB3 were performed in seven GBC cell lines (GB-d1, G415, NOZ, OCUG-1, TGBC-1, TGBC-2 and TGBC-24). A higher ERK1/2 and p-ERK1/2 expression was found in GBC tissues compared to chronic cholecystitis (CC) tissues (P<0.001). However, neither significant differences in overall survival nor significant associations with any of the clinicopathological features were found by comparing low and high expression of both ERK1/2 and p-ERK1/2. Western blot analysis of seven GBC cell lines showed that, in general, GB-d1, G415 and NOZ cells evidenced a strong expression of ERK1/2, p-ERK1/2, EGFR, ERBB2 and ERBB3. Therefore, ERK1/2 and p-ERK1/2 seem to be important in the development of GBC and GB-d1, G415 and NOZ cell lines may be used as experimental models for further in vitro and in vivo studies that help to decipher the role of MAPK/ERK pathway in gallbladder carcinogenesis.



http://ift.tt/2mv3XfW

Clear Cell Colorectal Carcinoma: time to clarify diagnosis

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Andrea Remo, Federica Grillo, Luca Mastracci, Matteo Fassan, Sokol Sina, Caterina Zanella, Pietro Parcesepe, Emanuele D'Urso, Massimo Pancione, Germana Bortuzzo, Aldo Scarpa, Erminia Manfrin
Primary clear cell colorectal carcinoma (CCC) is a very rare entity accounting for only 35 cases reported in the Literature. CCC is neither classified as a distinct entity nor is it defined as a CRC variant because its ontogeny remains unclear. Most of the reported CCC were found in the distal colon in patients with a mean age of 56 years. Histologically, clear cell change is the main morphologic feature and may present in a "pure" form, composed exclusively of clear cells, or in a "composite" form, admixed with other morphologically different components. It is possible to distinguish two biologically different types of CCC, with different clinical-pathologic features, therapeutic management and diagnostic criteria: a) Intestinal CCC consisting of an aggressive neoplasm, affecting mainly adult men, characterized by an intestinal-type immunoprofile (CK20+, CK7-, CEA+, CDX–2+) and b) Müllerian CCC consisting of an indolent carcinoma of the sigmoid-rectum, affecting young women, characterized by a different (CK7+, CK20-, CEA-, CA125+) immunoprofile. Considerable diagnostic difficulties can arise in distinguishing CCC and primary or secondary clear cell neoplasms, such as metastases from renal carcinoma, lower urinary tract, female genital tract, adrenal gland, mesothelioma, melanoma and primary intestinal PEComa. In this paper we review the Literature with two additional cases in order to define the diagnostic criteria of CCC.



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Prevalence of adeno-associated virus and human papillomavirus DNA in Iranian women with and without cervical cancer

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Nazanin Zahra Shafiei-Jandaghi, Jila Yavarian, Ebrahim Faghihloo, Nastaran Ghavami, Zohreh Yousefi ghalejoogh, Seyed Jalal kiani, Somayeh Shatizadeh Malekshahi, Reza Shahsiah, Eisa Jahanzad, Mostafa Hosseini, Talat Mokhtari Azad
There is plenty of substantial evidence to support anti-tumor activity of viruses. Adeno-associated virus (AAV) may interact with human papillomavirus (HPV) to modify the risk of cervical neoplasia. The seroprevalence of AAV among women with cervical cancer has been reported to be lower than healthy ones. In spite of this finding, detection of AAV DNA in cervical biopsies does not entirely support the inverse association between AAV seropositivity and cervical cancer. This association is still controversial and requires more thorough evaluation in different countries. The aim of this case–control study was to find the prevalence of AAV and HPV DNA sequences in Iranian women with and without cervical cancer to assess the probable association of AAV infection and cervical cancer. In this study, paraffin-embedded tissue samples of 61 cervical cancer cases and 50 healthy controls (HCs) were investigated for AAV and HPV DNA by semi-nested and nested PCRs respectively. AAV DNA was detected in 7 cases (14%) of HCs and 9 specimens (14.8%) of case group. According to the branching in the phylogenetic tree, AAV2 was the only type detected in this study. Moreover, HPV DNA was detected in 8 cases (16%) of HCs and 44 specimens (72.13%) of case group. In conclusion, a low proportion of cervical biopsies from Iranian women contained AAV-2 genome. No significant difference in correlation between HPV and cervical cancer in presence or absence of AAV genome in cervix was found.



http://ift.tt/2mgNiAG

Survivin and gynaecological tumours

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Dušan Braný, Dana Dvorská, Pavol Slávik, Richard Školka, Marián Adamkov
Survivin is the smallest member of the inhibitors of apoptosis (IAP) family. However, participation in inhibition of apoptosis is not the only function of this molecule. Survivin can also affect the proper process of mitosis and even promoting of angiogenesis or DNA repair. High levels of survivin expression are connected with foetal tissues during intrauterine development. In the overwhelming majority of healthy, differentiated adult tissues, amounts of survivin are markedly reduced. On the other hand, survivin is also often abundantly expressed in cases of various types of cancer. Generally, high expression levels of survivin are associated with a poor prognosis, an increased rate of tumour recurrence and high resistance to chemo- as well as radiotherapy, hence survivin can be considered a factor in the initiation and progression of many types of cancer with great significance and potential for cancer therapy. Nonetheless, progress in development of survivin inhibitors or primarily, in survivin-related molecular therapies, is surprisingly not very fast and indeed remains a challenge for the future. The objective of this article is to summarize known facts about survivin, its contribution to inhibition of apoptosis and cell division and its implication in the development of gynaecological tumours. At the end, known survivin inhibitors and their effect on regulation of tumour growth will be referenced.



http://ift.tt/2muW35X

Prognostic factors in MNU and DMBA-induced mammary tumors in female rats

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Antonieta Alvarado, Ana Lopes, Ana I. Faustino-Rocha, António Cabrita, Rita Ferreira, Paula A. Oliveira, Bruno Colaço
Chemically-induced mammary tumors in rats by the carcinogens 1-metil-1-nitrosurea (MNU) and 7,12-dimetilbenz [a] antracen (DMBA) are the most widely used models for studies related with human breast cancer. This study aimed to evaluate the immunoexpression of the prognostic factors estrogen receptor α (ERα), progesterone receptor (PR) and Ki-67, in MNU and DMBA-induced rat mammary tumors, in order to know the model that best suits to woman breast cancer. Twenty-eight MNU-induced and 16 DMBA-induced mammary tumors in virgin female Sprague-Dawley rats were analyzed. The expression of the prognostic markers ERα, PR and Ki-67 proliferation index (Ki-67 PI) was assessed by immunohistochemistry. Mitotic activity index (MAI) was also evaluated. More than one histological pattern was identified in each mammary tumor. Carcinomas constituted the lesions most frequently induced by both carcinogens: 33 MNU-induced carcinomas and 23 DMBA-induced carcinomas. All MNU and DMBA-induced mammary carcinomas were ER⁺/PR⁺, with a higher expression of ERα when compared with PR. Tumors' weight, the expression of ERα, PR, Ki-67 PI and MAI were higher in MNU-induced mammary carcinomas when compared with the DMBA-induced ones. Statistically significant differences between groups were observed for ERα, PR and MAI (p <0.05). The higher KI-67 PI and MAI in MNU-induced mammary carcinomas are suggestive of a higher aggressiveness of these carcinomas when compared with the DMBA-induced ones, and consequently a worse response to the therapy and a worse prognosis. In this way, the use of the rat model of MNU-induced mammary tumors is advised in experimental protocols aiming to study more aggressive mammary tumors within the group of double-positive mammary tumors (ER⁺/PR⁺).



http://ift.tt/2muGBXB

Histologic factors predicting invasion in patients with ductal carcinoma in situ (DCIS) in the preoperative core biopsy

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Areej M. Al Nemer
BackgroundIt is desirable to decrease the underestimation rate of invasion in cases diagnosed as ductal carcinoma in situ (DCIS) in breast core needle biopsy (CNB) in order to determine the appropriate candidates for axillary staging. The objective of this study is to identify the predictors of invasion in histology.Methods and resultsConsecutive 92 CNB's were retrospectively evaluated. The upstaging rate was 47.8% after surgery. Among all the evaluated parameters, high nuclear grade, single architectural pattern, marked periductal lymphocytic infiltration, partial myoepithelial loss and the presence of foci suspicious of microinvasion were the significant predictors of invasion (two tailed p values 0.0327, 0.0003, 0.0346,<0.0001, 0.0025; respectively). Variables that didn't show significant upstaging include: comedo necrosis, microcalcification, periductal fibrosis, various architectural patterns, tumor attenuation, and the immunophenotype. Previous studies were also reviewed.ConclusionsWe identified 5 predictive factors of upstaging. The lack of standardized quantification method may account, at least partially, for the conflicting results in different studies. To overcome this, we suggested a comprehensive reporting template for DCIS identified in CNB.



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Primary central nervous system diffuse large B-cell lymphoma shows an activated B-cell-like phenotype with co-expression of C-MYC, BCL-2, and BCL-6

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Xiaomei Li, Ying Huang, Chengfeng Bi, Ji Yuan, Hong He, Hong Zhang, QiuBo Yu, Kai Fu, Dan Li
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, whose main prognostic factor is closely related to germinal center B-cell-like subtype (GCB- DLBCL) or activated B-cell-like type (non-GCB-DLBCL). The most common type of primary central nervous system lymphoma is diffuse large B-cell type with poor prognosis and the reason is unclear. This study aims to stratify primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) according to the cell-of-origin (COO) and to investigate the multiple proteins expression of C-MYC, BCL-6, BCL-2, TP53, further to elucidate the reason why primary central nervous system diffuse large B-cell lymphoma possesses a poor clinical outcome as well. Nineteen cases of primary central nervous system DLBCL were stratified according to immunostaining algorithms of Hans, Choi and Meyer (Tally) and we investigated the multiple proteins expression of C-MYC, BCL-6, BCL-2, TP53. The Epstein-Barr virus and Borna disease virus infection were also detected. Among nineteen cases, most (15–17 cases) were assigned to the activated B-cell-like subtype, highly expression of C-MYC (15 cases, 78.9%), BCL-2 (10 cases, 52.6%), BCL-6 (15 cases, 78.9%). Unfortunately, two cases were positive for PD-L1 while PD-L2 was not expressed in any case. Two cases infected with BDV but no one infected with EBV. In conclusion, most primary central nervous system DLBCLs show an activated B-cell-like subtype characteristic and have multiple expressions of C-MYC, BCL-2, BCL-6 protein, these features might be significant factor to predict the outcome and guide treatment of PCNS-DLBCLs.



http://ift.tt/2mv6u9L

Erratum to: “Functional MRI of Human Eyeblink Classical Conditioning in Children with Fetal Alcohol Spectrum Disorders”

http://ift.tt/2lPiupE

GRK5 Regulates Social Behavior Via Suppression of mTORC1 Signaling in Medial Prefrontal Cortex

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Impairments in social behaviors are features of a number of psychiatric diseases associated with subtle alterations in the medial prefrontal cortex (mPFC) circuitry. G protein-coupled receptor kinase (GRK) 5 is widely expressing in the cortex, however, its role in regulation of the mPFC activity and the development of social behaviors and psychiatric disorders is unclear. Here, we found that GRK5 dificiency in mice caused social behavior impairments. Further morphological, electrophysiological, and biochemical analyses showed abnormal postsynaptic ultrastructure, impaired excitatory synaptic transmission, the increased association of raptor with mTOR, and overactivated mTORC1-S6K signaling in the mPFC of <span style="font-style:italic;">Grk5</span>^{<span style="font-style:italic;">−/−</span>} mice. Conditional knockdown of GRK5 in the mPFC caused impairments in social interaction and social novelty recognition behaviors; whereas selectively overexpressing GRK5 in the mPFC of <span style="font-style:italic;">Grk5</span>^{<span style="font-style:italic;">−/−</span>} mice rescued the social novelty recognition phenotype. Inhibition of the overactivated mTORC1-S6K signaling pathway by rapamycin or mGluR5 antagonist ameliorated the deficiency of the excitatory synaptic transmission in the mPFC and the social recognition of <span style="font-style:italic;">Grk5</span>^{<span style="font-style:italic;">−/−</span>} mice. These results indicate that GRK5 is critical for maintaining normal mTORC1 signaling and connectivity in mPFC, and normal social behavior.</span>

http://ift.tt/2ljPmDN

Layer-Specific Organization of Local Excitatory and Inhibitory Synaptic Connectivity in the Rat Presubiculum

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The presubiculum is part of the parahippocampal spatial navigation system and contains head direction and grid cells upstream of the medial entorhinal cortex. This position within the parahippocampal cortex renders the presubiculum uniquely suited for analyzing the circuit requirements underlying the emergence of spatially tuned neuronal activity. To identify the local circuit properties, we analyzed the topology of synaptic connections between pyramidal cells and interneurons in all layers of the presubiculum by testing 4250 potential synaptic connections using multiple whole-cell recordings of up to 8 cells simultaneously. Network topology showed layer-specific organization of microcircuits consistent with the prevailing distinction of superficial and deep layers. While connections among pyramidal cells were almost absent in superficial layers, deep layers exhibited an excitatory connectivity of 3.9%. In contrast, synaptic connectivity for inhibition was higher in superficial layers though markedly lower than in other cortical areas. Finally, synaptic amplitudes of both excitatory and inhibitory connections showed log-normal distributions suggesting a nonrandom functional connectivity. In summary, our study provides new insights into the microcircuit organization of the presubiculum by revealing area- and layer-specific connectivity rules and sets new constraints for future models of the parahippocampal navigation system.</span>

http://ift.tt/2lP2K5X

Attenuated Fast Steady-State Visual Evoked Potentials During Human Sleep

<span class="paragraphSection"><div class="boxTitle">Abstract</div>During sleep, external sensory events rarely elicit a behavioral response or affect perception. However, how sensory processing differs between wakefulness and sleep remains unclear. A major difficulty in this field stems from using brief auditory stimuli that often trigger nonspecific high-amplitude "K-complex" responses and complicate interpretation. To overcome this challenge, here we delivered periodic visual flicker stimulation across sleep and wakefulness while recording high-density electroencephalography (EEG) in humans. We found that onset responses can be separated from frequency-specific steady-state visual evoked potentials (SSVEPs) selectively observed over visual cortex. Sustained SSVEPs in response to fast (8/10 Hz) stimulation are substantially stronger in wakefulness than in both nonrapid eye movement (NREM) and REM sleep, whereas SSVEP responses to slow (3/5 Hz) stimulation are stronger in both NREM and REM sleep than in wakefulness. Despite wake-like spontaneous activity, responses in REM sleep were similar to those in NREM sleep and different than wakefulness, in accordance with perceptual disconnection during REM sleep. Finally, analysis of amplitude and phase in single trials revealed that stronger fast SSVEPs in wakefulness are driven by more consistent phase locking and increased induced power. These results suggest that the sleeping brain is unable to effectively synchronize large neuronal populations in response to rapid sensory stimulation.</span>

http://ift.tt/2lk1aG0

Working Memory Modulation of Frontoparietal Network Connectivity in First-Episode Schizophrenia

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Working memory (WM) impairment is regarded as a core aspect of schizophrenia. However, the neural mechanisms behind this cognitive deficit remain unclear. The connectivity of a frontoparietal network is known to be important for subserving WM. Using functional magnetic resonance imaging, the current study investigated whether WM-dependent modulation of effective connectivity in this network is affected in a group of first-episode schizophrenia (FES) patients compared with similarly performing healthy participants during a verbal <span style="font-style:italic;">n</span>-back task. Dynamic causal modeling (DCM) of the coupling between regions (left inferior frontal gyrus (IFG), left inferior parietal lobe (IPL), and primary visual area) identified in a psychophysiological interaction (PPI) analysis was performed to characterize effective connectivity during the <span style="font-style:italic;">n</span>-back task. The PPI analysis revealed that the connectivity between the left IFG and left IPL was modulated by WM and that this modulation was reduced in FES patients. The subsequent DCM analysis confirmed this modulation by WM and found evidence that FES patients had reduced forward connectivity from IPL to IFG. These findings provide evidence for impaired WM modulation of frontoparietal effective connectivity in the early phase of schizophrenia, even with intact WM performance, suggesting a failure of context-sensitive coupling in the schizophrenic brain.</span>

http://ift.tt/2lP1H64

Inter-Regional Variations in Gene Expression and Age-Related Cortical Thinning in the Adolescent Brain

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Age-related decreases in cortical thickness observed during adolescence may be related to fluctuations in sex and stress hormones. We examine this possibility by relating inter-regional variations in age-related cortical thinning (data from the Saguenay Youth Study) to inter-regional variations in expression levels of relevant genes (data from the Allen Human Brain Atlas); we focus on genes coding for glucocorticoid receptor (<span style="font-style:italic;">NR3C1</span>), androgen receptor (<span style="font-style:italic;">AR</span>), progesterone receptor (<span style="font-style:italic;">PGR</span>), and estrogen receptors (<span style="font-style:italic;">ESR1</span> and <span style="font-style:italic;">ESR2</span>). Across 34 cortical regions (Desikan-Killiany parcellation), age-related cortical thinning varied as a function of mRNA expression levels of <span style="font-style:italic;">NR3C1</span> in males (<span style="font-style:italic;">R</span>² = 0.46) and females (<span style="font-style:italic;">R</span>² = 0.30) and <span style="font-style:italic;">AR</span> in males only (<span style="font-style:italic;">R</span>² = 0.25). Cortical thinning did not vary as a function of expression levels of <span style="font-style:italic;">PGR</span>, <span style="font-style:italic;">ESR1</span>, or <span style="font-style:italic;">ESR2</span> in either sex; this might be due to the observed low consistency of expression profiles of these 3 genes across donors. Inter-regional levels of the <span style="font-style:italic;">NR3C1</span> and <span style="font-style:italic;">AR</span> expression interacted with each other vis-à-vis cortical thinning: age-related cortical thinning varied as a function of <span style="font-style:italic;">NR3C1</span> mRNA expression in brain regions with low (males: <span style="font-style:italic;">R</span>² = 0.64; females: <span style="font-style:italic;">R</span>² = 0.58) but not high (males: <span style="font-style:italic;">R</span>² = 0.0045; females: <span style="font-style:italic;">R</span>² = 0.15) levels of <span style="font-style:italic;">AR</span> mRNA expression. These results suggest that glucocorticoid and androgen receptors contribute to cortical maturation during adolescence.</span>

http://ift.tt/2ljUzv6

Histological and immunohistochemical characterization of the Mongolian gerbil’s mammary gland during gestation, lactation and involution

Publication date: Available online 24 February 2017
Source:Acta Histochemica
Author(s): Ellen C.R. Leonel, Luiz R. Falleiros, Silvana G.P. Campos, Sebastião R. Taboga
The morphological description of normal tissues is fundamental for making comparisons and in order to identify injuries and lesions. The aim of this work was to describe the morphological characteristics of the female Mongolian gerbil's (Meriones unguiculatus) normal mammary gland, the average expression of hormone receptors, and the average proliferation rates in the epithelial cells during the periods of lactation, pregnancy and involution. Dams were euthanized on the 14th and 21st gestational days, 7 and 14days after parturition, and 3 and 5days after weaning. The dams' mammary tissues were processed and were submitted to haematoxylin and eosin staining, Periodic Acid Schiff (PAS) staining, and Gomori's Reticulin staining. Additionally, immunohistochemistry was performed for the characterization of myoepithelial cells with α-actin, the proliferation rates with proliferating cell nuclear antigen (PCNA), the estrogen hormonal receptors (ESR1 and ESR2), and progesterone receptor (PR) quantifications. It was observed that the abundant adipose tissues were replaced by glandular epithelia and there was an increase in the epithelial cell's height (from 5.97 to 32.4μm in 14th and 21st gestational days and from 20.64 to 25.4μm in 7th and 14th lactational days, respectively) and the acini diameters (from 24.88 to 69.92μm in 14th and 21st gestational days and from 139.69 to 118.59μm in 7th and 14th lactational days, respectively) with the progression of gestation and lactation. The PAS staining intensity varied throughout the glands and between the stages that were evaluated. The extracellular matrix showed different phenotypes too, with more of a presence of the Type I collagen during the early gestation and involution and with more reticular fibers (Type III collagen) during the late gestation period and lactation. The myoepithelial layers showed alterations in their distribution with thick patterns as verified by the α-actin labeling. The PCNA showed higher rates of the marked cells in 14th and 21st gestational days (40.25 and 60.28%) and in 7th and 14th lactational days (64.08 and 65.08%). The hormone receptor quantifications showed a high variation in the rates: the average PR staining decreased from 14th to 21st gestational days (from 42.3 to 8.54%), from 7th to 14th lactational days (from 59.83 to 23.18%) and from 3rd to 5th days after weaning (from 39.98 to 12.72). There were higher averages of ESR1 staining in gestational days 14 and 21(from 58.06 to 30.02%). ESR2 staining decreased during gestation (25.7 and 12.94% in 14th and 21st gestational days)and involution (from 50.97 to 30.18% in 3rd and 5th days after weaning). The Mongolian gerbils showed similar morphological characteristics when they were compared to mice and rats. However, the higher proliferation rates with a smaller involution period compared to other murine characterized this species as being adequate for mammary pathologies studies.



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New derivatives of quinoline-4-carboxylic acid with antiplasmodial activity

Publication date: Available online 24 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Patrick Hochegger, Johanna Faist, Werner Seebacher, Robert Saf, Pascal Mäser, Marcel Kaiser, Robert Weis
New analogues of the recently published compound DDD107498 were prepared. Their activities were examined in vitro against the chloroquine-sensitive NF54 strain. The most active were also tested against the multiresistant K1 strain of Plasmodium falciparum. A couple of the newly synthesized compounds showed promising antiplasmodial activity and selectivity. A single compound showed adequate reduction of parasitaemia (98.1%) in mice infected with Plasmodium berghei. Survial time was doubled compared to control. The results of the biological tests of the novel compounds were compared with the activities of drugs in use. Structure-activity relationships were discussed.

Graphical abstract

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Development of a novel near-infrared fluorescent theranostic Combretastain A-4 analogue, YK-5-252, to target triple negative breast cancer

Publication date: Available online 24 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yali Kong, Jacqueline Smith, Kongwen Li, Jake Cui, John Han, Shujie Hou, Milton L. Brown
The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.

Graphical abstract

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Synthesis of 4-aminotetrahydropyran scaffolds for drug discovery

Publication date: Available online 22 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Andrew Nortcliffe, Gavin D.S. Milne, Daniel Hamza, Christopher J. Moody
Functionalised tetrahydropyran scaffolds were prepared using a tethered enol-ether Prins cyclisation and elaborated to show their potential use in library synthesis. The key 4-hydroxytetrahydropyran scaffold could be readily manipulated to the 4-azidotetrahydropyran that could be elaborated via copper catalysed azide-alkyne cycloaddition or by reduction to the amine, to provide sp³-rich scaffolds useful for drug discovery.

Graphical abstract

http://ift.tt/2lFdqli

Characterization and geochemistry of technogenic magnetic particles (TMPs) in contaminated industrial soils: Assessing health risk via ingestion

Publication date: 1 June 2017
Source:Geoderma, Volume 295
Author(s): Anna Bourliva, Lambrini Papadopoulou, Elina Aidona, Katerina Giouri, Konstantinos Simeonidis, George Vourlias
The objective of this study was the detailed characterization of "technogenic" magnetic particles (TMPs) separated from contaminated industrial soils. Moreover, non-carcinogenic health risk posed by "technogenic" metals Pb and Zn via the ingestion exposure pathway was carried out. Volume magnetic susceptibility (κ) was measured directly in the field around a chemical industry in Sindos industrial area, Northern Greece. Representative soil samples were collected from the sites where elevated κ values were recorded. Mass specific magnetic susceptibility (χlf) depended on the content of TMPs and ranged from 52.6×10⁻⁸m³kg⁻¹ to 821.2×10⁻⁸m³kg⁻¹ with the maximum values detected in the immediate vicinity of the industrial unit where the most contaminated soils were also identified. Mineralogically the TMPs exhibited a dominant iron spinel phase, while other iron-bearing phases such as hematite and lepidocrocite were detected. Morphologically, Fe-rich spherules and irregular-shaped particles were the most commonly observed particles in TMPs, revealing various Fe contents often associated with elevated heavy metal contents. TMPs exhibited significantly higher concentrations of trace elements compared to non-magnetic fractions (NMFs) indicating that potentially harmful elements (PHEs) are preferentially enriched in the TMPs. Furthermore, for the first time, a health risk assessment study for the incidental soil magnetic fractions (MFs) ingestion of the "technogenic" metals Pb and Zn was carried out based on U.S. Environmental Protection Agency (U.S.E.P.A.) guidelines, incorporating oral bioaccessibility measurements using the BARGE Unified Bioaccessibility Method (UBM). Significant fractions (>50%) of Pb and Zn occur in bioaccessible forms in the TMPs and both children and adults are experiencing potential health risk since determined HQs values were significantly higher than safe level (=1).



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Nature and evolution of fluids associated with specularite-bearing Fe and Au-PGE (Jacutinga) mineralization during the Brasiliano orogeny in the eastern São Francisco Craton, Minas Gerais, Brazil

Publication date: June 2017
Source:Ore Geology Reviews, Volume 86
Author(s): Lucilia Aparecida Ramos de Oliveira, Francisco Javier Rios, Carlos Alberto Rosière, Markus Wälle, Melissa Ortelli, Kalin Kouzmanov
Hydrothermal fluids related to the development of the Araçuaí Orogen during the Brasiliano Cycle have affected Paleoproterozoic banded iron formation-bearing sequences along the eastern border of the São Francisco Craton. Controversy surround the origin of specularite in high-grade schistose iron ore-bodies in the Serpentina Range ("Serpentina-type" ore) versus specularite-rich, S-free Au-PGE quartz veins ("Jacutinga-type") that occur at the eastern border of the Quadrilátero Ferrífero mining district. Chemical and thermobarometric characteristics of fluid inclusions from Serpentina-type quartz-specularite veins show that metamorphic aqueous-saline fluids of low to moderate temperature (i.e. salinity between 6.3 and 13.7wt% NaCleqv and homogenization temperatures from 91° to 228°C) were responsible for silica leaching and Fe enrichment along shear zones in the Statherian Serra da Serpentina Group. These Serpentina-type fluids present a distinct pattern with Na>Ca≫K. The fluids are depleted in Li, Na, Ba, Ca, K, Cu and Mg; and enriched in As and Sr in comparison to the Jacutinga-type fluids. In contrast, other two distinct fluids and chemical processes were involved to precipitate Fe oxides with Au-PGE in Jacutinga-type veins. The first type is an aqueous-carbonic fluid from the Catas Altas and Itabira deposits. These Jacutinga-type fluids present a pattern with Na>K>Ca≫Mg and K>Li>Ba>Sr. The fluids are interpreted to be of Brasiliano age and are typically associated with anatectic pegmatites from Santa Maria de Itabira. The high salinity of these brines (23.2–25.3wt% NaCleqv) from the Itabira ore likely originated from their percolation through evaporitic layers, from salt concentration during deformation, or from fluid/rock interactions. Mixing between high-temperature aqueous-carbonic pegmatite-forming fluids and low-temperature aqueous metamorphic brines could have induced an abrupt change in the physical-chemical conditions of the system, which led to Au and PGE precipitation in the Itabira Jacutinga-type deposit. A second Jacutinga-type fluid is observed at the Gongo Soco and Barão de Cocais deposits. This fluid is interpreted as an aqueous-saline metamorphic fluid with the pattern Na>Ca>K≫Mg, low-to-moderate-salinity (4.3–16.4wt% NaCleqv) and temperatures of 77° to 305°C. It is relatively enriched in B; depleted in Li, Ba, Na, Cu, Zn and K; and follows the trend K>Li>Ba. In both types of fluids responsible for Jacutinga-type mineralization, gold was transported as chlorine complexes under acidic and oxidizing conditions. The metal precipitation may have occurred due to a rapid depressurization during failure of shear zones operating in the upper levels of the crust, or variations in the pH and redox conditions during the interaction with the host dolomitic itabirite.



http://ift.tt/2ljP3Jb

New fluorescent azo-Schiff base Cu(II) and Zn(II) metal chelates; spectral, structural, electrochemical, photoluminescence and computational studies

Publication date: 5 June 2017
Source:Journal of Molecular Structure, Volume 1137
Author(s): Fatih Purtas, Koray Sayin, Gokhan Ceyhan, Muhammet Kose, Mukerrem Kurtoglu
A new Schiff base containing azo chromophore group obtained by condensation of 2-hydroxy-4-[(E)-phenyldiazenyl]benzaldehyde with 3,4-dimethylaniline (HL) are used for the syntheses of new copper(II) and zinc(II) chelates, [Cu(L)2], and [Zn(L)2], and characterized by physico-chemical and spectroscopic methods such as ¹H and ¹³C NMR, IR, UV.–Vis. and elemental analyses. The solid state structure of the ligand was characterized by single crystal X-ray diffraction study. X-ray diffraction data was then used to calculate the harmonic oscillator model of aromaticity (HOMA) indexes for the rings so as to investigate of enol-imine and keto-amine tautomeric forms in the solid state. The phenol ring C10-C15 shows a considerable deviation from the aromaticity with HOMA value of 0.837 suggesting the shift towards the keto-amine tautomeric form in the solid state. The analytical data show that the metal to ligand ratio in the chelates was found to be 1:2. Theoretical calculations of the possible isomers of the ligand and two metal complexes are performed by using B3LYP method. Electrochemical and photoluminescence properties of the synthesized azo-Schiff bases were also investigated.

Graphical abstract

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Synthesis and antimicrobial properties of Zn-mineralized alginate nanocomposites

Publication date: 1 June 2017
Source:Carbohydrate Polymers, Volume 165
Author(s): Ivana Malagurski, Steva Levic, Milena Pantic, Danka Matijasevic, Miodrag Mitric, Vladimir Pavlovic, Suzana Dimitrijevic-Brankovic
New bioactive and antimicrobial biomaterials were produced by alginate-mediated biomineralization with Zn-mineral phase. The synthesis procedure is simple, cost-effective and resulted in two different Zn-mineralized alginate nanocomposites, Zn-carbonate/Zn-alginate and Zn-phosphate/Zn-alginate. The presence of Zn-mineral phase and its type, have significantly affected nanocomposite morphology, stability, total metallic loading and potential to release Zn(II) in physiological environment. Antimicrobial experiments showed that both types of Zn-mineralized nanocomposites exhibit strong antimicrobial effect against Escherichia coli, Staphylococcus aureus and Candida albicans. These results suggest that alginate biomineralization, where minerals are salts of essential metallic ions like Zn(II), represents a good strategy for designing multifunctional biomaterials for potential biomedical applications.



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Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): M.D. Franken, E.M. van Rooijen, A.M. May, H. Koffijberg, H. van Tinteren, L. Mol, A.J. ten Tije, G.J. Creemers, A.M.T. van der Velden, B.C. Tanis, C.A. Uyl-de Groot, C.J.A. Punt, M. Koopman, M.G.H. van Oijen
AimCapecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment.MethodsDecision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters.ResultsCAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated.ConclusionCAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective.



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Efficacy of the combination of ipilimumab and nivolumab following progression on pembrolizumab in advanced melanoma with poor risk features

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Lavinia Spain, Thomas Schmid, Martin Gore, James Larkin




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The role of bevacizumab in solid tumours: A literature based meta-analysis of randomised trials

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Giandomenico Roviello, Thomas Bachelot, Clifford A. Hudis, Giuseppe Curigliano, Andrew R. Reynolds, Roberto Petrioli, Daniele Generali
BackgroundBevacizumab is a humanised monoclonal antibody which blocks the binding of circulating vascular endothelial growth factor to its receptors. To date, the Food and Drug Administration has approved bevacizumab for the treatment of several solid tumours. To assess the impact of bevacizumab-based regimens on outcome in these advanced solid tumour types, we performed a meta-analysis. We included all of the randomised trials (phase II or III) where bevacizumab was tested in the first line setting compared with a control arm, including chemotherapy, placebo or other anti-neoplastic agents.MethodsA literature-based meta-analysis of randomised controlled trials (RCTs) in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines were undertaken. The primary end-point considered was overall survival (OS). The secondary end-points were progression-free survival (PFS) time, response rate and safety. A subgroup analysis was performed to highlight any differences between studies in different tumour types for all end-points.ResultsThe pooled analysis from RCTs on bevacizumab-based regimens revealed significantly increased OS (hazard ratio [HR] for death 0.92, 95% confidence interval [CI]: 0.88–0.95; P < 0.0001), PFS (HR: 0.72, 95% CI: 0.67–0.78; P < 0.00001) and response rate (risk ratio: 1.38, 95% CI: 1.27–1.50; P < 0.00001) compared to control arm in solid tumours overall and in colorectal, lung, ovarian and renal cancer as single indications. However, notably, no effect on survival was seen in breast cancer.ConclusionThis study confirmed that bevacizumab-based regimens result in a significant effect on survival and response in advanced colorectal, lung, ovarian and kidney cancer. In cancers where bevacizumab failed overall as in breast cancer, a dedicated biomarkers analysis is warranted to select the proper subgroup of patient that might have the adequate clinical benefit.



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The role of image-guided therapy in the management of colorectal cancer metastatic disease

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Thierry de Baere, Lambros Tselikas, Steven Yevich, Valérie Boige, Frederic Deschamps, Michel Ducreux, Diane Goere, France Nguyen, David Malka
The European Society for Medical Oncology (ESMO) have stressed that the option for treating oligometastatic disease is a strategy of local ablative therapy, the goal of which is to improve disease control. The spectrum of the local ablative therapy toolbox described by the ESMO includes surgical R0 resection, percutaneous ablation and intra-arterial therapies, the choice of treatment being left to the multidisciplinary team. Interventional therapy involving image-guided treatment offers the possibility of less invasive treatments for colorectal cancer metastases in the liver, lung and bone by preserving from toxicity distant healthy organs or even parts of the diseased organs. Oligometastases can be targeted by image-guided puncture for percutaneous ablation by delivering locally, through inserted probes, heat (radiofrequency, microwaves), extreme cold (cryoablation) or electric pulses (electroporation). Radiofrequency (RFA) is the mainstay of percutaneous ablation and provides local control rates of around 90% when metastases are small (<3 cm), located away from hilum and large vessels, and perfectly visible under imaging guidance. The lung provides a specific environment with excellent visibility of the target tumour, and insulation of the tumour by the healthy lung improves thermal delivery. RFA of colorectal lung metastases provides a 5-year overall survival of 56.0%, with a 91.6% control rate for metastases with a diameter <3 cm. These results are comparable to results of surgical series. Non-resectable, non-ablatable liver metastases can be targeted through their preferential arterial vascularisation with hepatic arterial infusion chemotherapy (HAIC) or selective internal radiation therapy (SIRT) with radioactive microspheres. HAIC with oxaliplatin has demonstrated an impressive response rate when patients who have previously failed intravenous oxaliplatin are rechallenged. The response rate in first-line therapy is around 90%, with conversion to surgery in roughly 40% of patients. SIRT has recently demonstrated a benefit for progression-free survival in the liver when used as first-line treatment in combination with systemic therapy.



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Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Makoto Tahara, Martin Schlumberger, Rossella Elisei, Mouhammed Amir Habra, Naomi Kiyota, Ralf Paschke, Corina E. Dutcus, Taro Hihara, Shannon McGrath, Mark Matijevic, Tadashi Kadowaki, Yasuhiro Funahashi, Steven I. Sherman
BackgroundLenvatinib significantly prolonged progression-free survival (PFS) versus placebo in the phase III Study of (E7080) LEnvatinib in differentiated Cancer of the Thyroid (SELECT) of patients with radioiodine-refractory differentiated thyroid cancer. This exploratory analysis investigated potential predictive biomarkers of lenvatinib efficacy and target engagement.Patients and methodsCirculating cytokine/angiogenic factors (CAFs) in blood samples collected at baseline and throughout treatment were analysed from patients randomised to receive lenvatinib or placebo from August 5, 2011 to October 4, 2012. For CAF biomarker analyses, patients were dichotomised by baseline levels. Tumour tissues were analysed for BRAF and NRAS/KRAS/HRAS mutations.ResultsTumours and CAFs were analysed from 183/392 (47%) and 387/392 (99%) patients, respectively. Lenvatinib PFS benefit was maintained in all assessments. For lenvatinib-treated patients, interaction-term analyses revealed that low baseline Ang2 level was predictive of tumour shrinkage (Pinteraction = 0.016) and PFS (Pinteraction = 0.018). Vascular endothelial growth factor and fibroblast growth factor 23 (FGF23) were significantly upregulated with lenvatinib, and FGF23 upregulation on cycle 1/day 15 was associated with longer PFS. In mutation analyses, no significant differences in clinical outcomes were observed. BRAF^WT may be a negative prognostic factor for PFS in placebo-treated patients with papillary thyroid cancer (P = 0.019).ConclusionThe lenvatinib PFS benefit was maintained regardless of baseline CAF or BRAF/RAS status. Baseline Ang2 was predictive of PFS in a subgroup of lenvatinib-treated patients, indicating that Ang2 may be predictive of lenvatinib sensitivity. BRAF^WT may be a poor prognostic factor in patients with radioiodine-refractory papillary thyroid cancer. Improved PFS associated with upregulated FGF23 suggests that lenvatinib-induced FGF receptor inhibition contributes to lenvatinib efficacy.Trial registration ID of the main study, SELECT: ClinicalTrials.gov: NCT01321554.



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A PET-based nomogram for oropharyngeal cancers

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): J. Castelli, A. Depeursinge, V. Ndoh, J.O. Prior, M. Ozsahin, A. Devillers, H. Bouchaab, E. Chajon, R. de Crevoisier, N. Scher, F. Jegoux, B. Laguerre, B. De Bari, J. Bourhis
PurposeIn the context of locally advanced oropharyngeal cancer (LAOC) treated with definitive radiotherapy (RT) (combined with chemotherapy or cetuximab), the aims of this study were: (1) to identify PET-FDG parameters correlated with overall survival (OS) from a first cohort of patients; then (2) to compute a prognostic score; and (3) finally to validate this scoring system in a second independent cohort of patients.Materials and methodsA total of 76 consecutive patients (training cohort from Rennes) treated with chemoradiotherapy or RT with cetuximab for LAOC were used to build a predictive model of locoregional control (LRC) and OS based on PET-FDG parameters. After internal calibration and validation of this model, a nomogram and a scoring system were developed and tested in a validation cohort of 46 consecutive patients treated with definitive RT for LAOC in Lausanne.ResultsIn multivariate analysis, the metabolic tumour volume (MTV) of the primary tumour and the lymph nodes were independent predictive factors for LRC and OS. Internal calibration showed a very good adjustment between the predicted OS and the observed OS at 24 months. Using the predictive score, two risk groups were identified (median OS 42 versus 14 months, p < 0.001) and confirmed in the validation cohort from Lausanne (median OS not reached versus 26 months, p=0.008).ConclusionsThis is the first report of a PET-based nomogram in oropharyngeal cancer. Interestingly, it appeared stronger than the classical prognostic factors and was validated in independent cohorts markedly diverging in many aspects, which suggest that the observed signal was robust.



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