Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study

Background BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. Methods We analyzed data of 313 patients in the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, with an observation period of 3.3 years (range, 1 – 5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. Results Presumptive BKPyVAN (defined as sustained (>3 weeks) high-level BK viremia >104 copies/mL) within 5 years posttransplant occurred in 49/311 (15.8%) of patients, and biopsy-proven BKPyVAN in 14/313 (4.5%). BKPyV viremia was observed in 115/311 patients (36.7%), of whom 11 of 115 (9.6%) developed viremia late, ie, after the second year posttransplant. In 6/48 patients (12.5%) with high-level viremia and in 3/14 (21.4%) with BKPyVAN this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated with a higher net state of immunosuppression (OR 1.3, p

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Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial

Background Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation. Methods We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n=4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n=6) or BM (n=3) to evaluate islet transplant function and survival Results We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable post transplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except one lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immuno-monitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity. Conclusion BM is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes Correspondence to: Lorenzo Piemonti, Diabetes Research Institute, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan. Fax: 39 02 26432871. Tel: 39 02 26432706. E-mail: piemonti.lorenzo@hsr.it Trial registration. ClinicalTrials.gov NCT01345227 and NCT01722682 Authorship page P.M. and A.S. managed patients. M.P. and C.D performed the histopathological analysis of the bone marrow. R.N., R.M. and A.M. performed islet isolations. V.S. and S.P performed the molecular analysis of the bone marrow biopsy samples. M.S. reviewed and edited the manuscript and contributed to the discussion. J.P., C.M. and F.C. developed the intrabone marrow islet infusion method and performed the transplantations. P.M., S.B., B.R, A.N. and M.C. performed the cellular and humoral immunomonitoring. L.P. conceived the intrabone marrow strategy, developed the concept, designed the experiments, wrote the manuscript, promoted the study, and researched data. L.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Funding This study was supported by the Italian Minister of Health (Ricerca Finalizzata RF-2009-1469691) and by the European Commission (FP7 241883 and H2020 681070). P.M. is supported by a Career Development Award (5-CDA-2015-85-A-N) from JDRF. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Migrating From Universal to Personalized Prevention: Predicting the Risk of Cytomegalovirus Infection after Organ Transplantation

No abstract available

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Outcomes in Third and Fourth Kidney Transplants Based on the Type of Donor

Background An increasing number of patients are requiring multiple retransplants. We assessed outcomes of third and fourth kidney transplants, to aid decision-making on the most suitable donor type. Methods Data were collected retrospectively for 2561 transplants, including 69 third and 8 fourth, performed from 2000-2017. Demographics and outcomes for the combined third/fourth group were compared to first and second transplants. Within the third/fourth kidney transplant group, comparisons were made between deceased-donors (n=39), live-donor-HLA-compatible (n=23) and -incompatible (n=13) transplants, as well as between standard (n=25) and extended-criteria (n=14) deceased-donor transplants. Results Patient survival did not differ significantly by transplant number (p=0.532), whilst death-censored graft survival declined progressively, from 89% at 5 years in first, 85% in second and 74% in the third/fourth transplant group (p

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Obesity and Metabolic Syndrome in Kidney Transplantation: The Role of Dietary Fructose and Systemic Endotoxemia

Background The concepts that obesity is merely a consequence of overeating, and that metabolic health then reflects obesity, may be insufficient and potentially flawed. The role of fructose intake and metabolic endotoxemia have gained attention recently, but data in kidney transplantation are lacking. This study evaluated the risk factors for metabolic syndrome (MS), its components, and other associated markers in kidney transplant recipients (KTRs), focussing particularly on fructose intake and systemic endotoxemia. Methods This cross-sectional observational study enrolled 128 KTRs>1-year posttransplantation. Clinical, biochemical, anthropometric, and questionnaire assessments were undertaken. Results Obesity (body mass index≥30kg/m2) and MS (International Diabetes Federation Definition) were found in 36.7% and 50% of KTRs respectively. Both increased fructose intake (p=0.01) and endotoxin level (p=0.02) were independently associated with MS; and higher fructose intake was independently associated with obesity (p0.6), as well as relationships between increased fructose intake, inflammation and blood glucose (r>0.6). Conclusions Dietary modifications through decreasing fructose intake and addressing systemic endotoxemia are plausible targets for improving metabolic health of KTRs. Corresponding Author: Dr Richard Borrows, Department of Nephrology & Kidney Transplantation, Area 5, Level 7, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK. Tel: +44 (0) 121 371 6099, Fax: +44 (0) 121 371 5858. Email: Richard.Borrows@uhb.nhs.uk Author Contributions Winnie Chan and Richard Borrows designed the research. Winnie Chan, Byron Smith, Mark Stegall, and Richard Borrows wrote the manuscript. Winnie Chan and Richard Borrows conducted the research. Winnie Chan, Byron Smith, and Richard Borrows analysed the data and performed the statistical analysis. Richard Borrows had primary responsibility for the final content. Disclosure: The authors declare no conflict of interest. Funding Winnie Chan received a research grant from the British Renal Society and was awarded a PhD research training fellowship from the National Health Service West Midlands Strategic Healthy Authority. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Fosfomycin-Trometamol for Urinary Tract Infections in Kidney Transplant Recipients

Background The treatment of urinary tract infections (UTI's) in kidney transplant recipients (KTRs) with oral antibiotics is complicated by increasing resistance to trimethoprim-sulfamethoxazole, amoxicillin/clavulanic acid and ciprofloxacin. Fosfomycin-trometamol (FT) could be an alternative, but evidence on clinical effectiveness is scarce. We evaluated the use, effectiveness and safety of FT for UTI in KTRs. Methods Data were retrospectively collected in 2 Dutch transplant hospitals from adult KTRs that were treated with FT as initial treatment for lower-UTI or asymptomatic bacteriuria or as stepdown treatment for upper-UTI after initial intravenous antibiotics. Exclusion criteria were in vitro resistance to FT or concomitant antibiotic treatment. Endpoints were clinical cure within 14 days and severe clinical failure, microbiological cure, relapse, recurrence, and acquired resistance within 90 days postend of treatment. Results 53 episodes in 40 KTRs were included (ASB n=15; lower-UTI n=33; upper-UTI n=5). FT was used for a median short duration in a heterogeneous gift interval. FT resulted in microbiological cure in 25, 28 and 100% of ASB, lower-UTI and upper-UTI with initial positive culture and follow-up culture performed, respectively. Clinical cure rates were 67% for lower-UTI and 80% for upper-UTI. Relapses or recurrences occurred in 31% and 24% of symptomatic UTI episodes, without severe clinical failure. Acquired resistance to fosfomycin was observed in 6 episodes. Conclusions FT has a reasonable effectiveness as last-resort oral treatment for lower-UTI and stepdown treatment for upper-UTI in KTRs. Randomized controlled trials with optimal dosage regimens are warranted. Use of FT is not recommended for ASB. Authorship: TD, HW, SM, JS and MB participated in the research design. TD and JS participated in the collection of the data. TD and HW participated in the data analysis. All authors participated in the writing of the paper. Disclosure: The authors declare no conflicts of interest. Funding: No funding was received for this work. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Serum Factor V is a Continuous Biomarker of Graft Dysfunction and a Predictor of Graft Loss After Liver Transplantation

Background: Factor V has never been compared to a validated early allograft dysfunction (EAD) definition. We aimed to assess Factor V as a biomarker of EAD and a predictor of graft loss after liver transplantation (LT). Methods: We retrospectively assessed the serum Factor V levels on postoperative day 1 after LT. Patients were divided according to their Factor V levels into the ≤36.1U/mL and >36.1U/mL groups. The primary outcome was graft loss within 1, 3, and 6 months. The secondary outcome was EAD, as defined by Olthoff et al Predictors of outcomes were identified by multivariable logistic regression. Results: 227 patients were included in the study: 74 with Factor V ≤36.1U/mL and 153 with Factor V >36.1U/mL. EAD was diagnosed in 41/74 (55.4%) patients with Factor V ≤36.1U/mL and in 20/153 (13.1%) patients with Factor V >36.1U/mL (p36.1U/mL (p=0.001). Factor V was a continuous predictor for 3- and 6-month graft loss [(OR=0.96 (95%CI 0.94–0.99) and OR=0.97 (95% CI 0.94–0.99) per U/mL], whereas EAD was not significant when adjusted for Factor V. Conclusion: Factor V is an early marker for EAD and is a continuous predictor of short-term graft loss after LT. Corresponding Author: Dr. Cleber Rosito Pinto Kruel, Assistant Professor, Liver Transplant Program, Hospital de Clinical de Porto Alegre, 2350 Ramiro Barcelos Street, office 745, Porto Alegre, Brazil, Phone: +55 51 3359 8232. E-mail: crkruel@hcpa.edu.br Authorship: AG has contributed to the study's concept, design, data collection, data analysis, interpretation, and manuscript writing. CP and JEP have contributed to the data collection and approved the manuscript's final version. MFC, ANB, AA, TJMG, IL, ADC, and MRAS have all contributed to the data interpretation and critical appraisal, and they also approved the manuscript's final version. GS and CRPK have contributed to the study's concept, design, data interpretation, and manuscript writing. All authors have approved the manuscript's final version. Category of manuscript: Original investigation Financial Support: None Conflict of Interest: None Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Temporal Changes in the Impact of HLA Mismatching Among Pediatric Kidney Transplant Recipients

Background Allocation for pediatric deceased-donor kidney transplantation (pDDKT) in the United States now deemphasizes HLA matching to improve equality in access to transplantation, but other national systems still consider HLA matching due to concerns about graft survival. We hypothesized that the impact of HLA mismatching has decreased over time due to advances including improved immunosuppression. Methods Using SRTR data, we analyzed whether the association between the number of HLA mismatches and outcomes of first-time pDDKTs changed between 2 eras: 1995-2004 (N=2854) and 2005-2014 (N=4643). Results Between eras, the median number of mismatches increased from 4 to 5 (p

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CMV-specific Cell-Mediated Immunity at 3-month Prophylaxis Withdrawal Discriminates D+/R+ Kidney Transplants at risk of Late-onset CMV Infection Regardless the Type of Induction Therapy

Background Whether CMV-specific cell-mediated immunity (CMI) at prophylaxis cessation predicts D+/R+ kidney transplants (KTR) at risk of late-onset CMV infection after receiving distinct induction therapies is still not well characterized. Methods We prospectively assessed CMV-specific CMI predicting late-onset CMV infection at prophylaxis withdrawal and at earlier time-points, in 96 consecutive D+/R+ patients receiving either antiinterleukin 2-receptor antibody (anti-IL2RA; n=50) or rabbit antithymoglobulin (rATG; n=46). CMV-specific CMI was evaluated against CMV antigens (IE-1, pp65) using an IFN-γ ELISpot assay. Results 14/96(14.6%) patients developed late-onset CMV infection and 2/96(2.1%) displayed disease. At 3 months, CMV-specific CMI frequencies were significantly lower in patients developing late-onset CMV infection (p

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Factors Associated With Mortality and Response to Extracorporeal Photopheresis in Lung Allograft Recipients With Bronchiolitis Obliterans Syndrome

Background This study was designed to identify factors associated with clinical response to extracorporeal photopheresis (ECP) and mortality after ECP in lung allograft recipients with bronchiolitis obliterans (BOS). Methods FEV1 values obtained 6 months before (baseline) and 6 months after initiation of ECP were used to plot the linear relationship between FEV1 vs time before and after ECP. Response to ECP was assigned when a positive integer was derived after subtracting the baseline rate of decline from the rate of decline 6 months after ECP. Uni- and multivariate logistic regression analyses were used to identify demographic, treatment related factors or spirometric parameters and that may be associated with response to ECP or mortality at either 6 or 16 months after initiation of ECP. Results FEV1 just prior to ECP was associated with mortality (p=0.007) at 16 months after ECP initiation. An FEV1 ≤ 1.50L had a sensitivity of 87% and a specificity of 60% to identify patients who died within 16 months after ECP initiation. Patients whose FEV1 decline exceeded > 40 mL/month were 12 times more likely to have a response to ECP (p=0.0001). Patients whose decline in FEV1 before ECP was statistically significant (p40 mL/month) and statistical significance of the relationship between FEV1 vs time prior to ECP initiation. Therefore, earlier BOS detection and more timely implementation of ECP (ie, when FEV1 values > 1.5L) should be considered especially in patients with a more aggressive rate of decline of lung function. Correspondence: George Despotis, MD, Washington University School of Medicine, Department of Pathology & Immunology, Division of Laboratory & Genomic Medicine,425 S. Euclid Avenue, Campus Box 8118, Saint Louis, MO 63110. Email gjdespotis@wustl.edu Authorship Hope E. Karnes, MD, PhD: Participated in research design, performance of the research, writing of the paper, data analysis Emily I. Schindler, MD, PhD: Participated in research design, performance of the research, writing of the paper, data analysis Matt Morrell, MD: Participated in research design, performance of the research, writing of the paper, data analysis Ramsey R Hachem MD: Participated in research design, performance of the research, writing of the paper, data analysis Keith Berman, MPH, MPA: Participated in writing of the paper, data analysis Suresh Vedantham, MD: Participated in writing of the paper, data analysis Jeff Atkinson, MD: Participated in writing of the paper, data analysis Edward Spitznagel, PhD: Participated performance of the research, in writing of the paper, data analysis George Despotis, MD: Participated in research design, performance of the research, writing of the paper, data analysis Disclosure: Relationships with entities related to the topic are listed below: Hope E. Karnes, MD, PhD - None Emily I. Schindler, MD, PhD - None Matt Morrell, MD –Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 Ramsey Hachem, MD – Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2, Served on advisory board for Theravance, Served on advisory board for Vectura, Serving on advisory board for Breath Keith Berman MPH, MBA: Consultant to Therakos and Barnes-Jewish Hospital Suresh Vedantham, MD – Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 Jeff Atkinson, MD - None Ed Spitznagel, PhD – Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 George Despotis, MD – Principle Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 Funding: No funding for the current work. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The Effect of Histidine-Tryptophan-Ketoglutarate Solution (HTK) and University of Wisconsin Solution (UW): an Analysis of the Eurotransplant Registry

Background Both UW and HTK are currently used in the Eurotransplant region for preservation of liver allografts. Previous studies on their effect have led to a lot of discussion. This study aims to compare the effect of HTK and UW on graft survival. Methods First liver transplantations in recipients ≥18 years from 1.1.2007 until 31.12.2016 were included. Graft survival was compared for livers preserved with HTK and UW at 30 days, 1, 3 and 5-years. Multivariable analysis of risk factors was performed and outcome was adjusted for important confounders. Results Of all 10,628 first liver transplantations, 8,176 (77%) and 2,452 (23%) were performed with livers preserved with HTK and UW, respectively. Kaplan-Meier curves showed significant differences in graft survival between HTK and UW at 30 days (89% vs 93%, p=

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Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer

Abstract

Fulvestrant is recommended for patients with hormone receptor-positive (HR+) advanced breast cancer (ABC) who progress after aromatase inhibitor therapy. As most patients in this setting have already developed mechanisms of resistance to endocrine therapy, targeting biological pathways associated with endocrine resistance in combination with fulvestrant may improve outcomes. Therefore, evidence supporting a combinatorial treatment approach in the second-line setting was investigated based on a search of PubMed and ClinicalTrials.gov. Twenty-eight studies of targeted therapies plus fulvestrant as second-line treatment for HR+ ABC were identified, including three and six key randomized trials exploring cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors plus fulvestrant respectively. Additional combinations with fulvestrant included inhibitors of epidermal growth factor receptors, androgen receptor, and the bromodomain and extra-terminal family of proteins. Across the studies reviewed with available data, the addition of targeted therapies to fulvestrant resulted in clinically meaningful improvements in progression-free survival compared with fulvestrant alone. While some challenging toxicities were observed, most adverse events could be effectively managed. Selection of second-line targeted therapy for use with fulvestrant should consider prior treatment as well as the mutation status of the tumor. In conclusion, available data indicate that fulvestrant combined with agents targeting mechanisms of endocrine resistance is a promising approach. The ongoing trials identified in this review will help further inform the selection of combination treatments with fulvestrant for HR+ ABC.

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Acute Coronary Syndrome Management in Cancer Patients

Abstract

Purpose of Review

Coronary artery disease and cancer often co-exist. Patients with cancer have been excluded by most major cardiology trials and registries and their management remains largely empiric. Cancer patients experience an approximately 10-times increased mortality compared to the general population. Conservative therapy of ACS in cancer therapy results in 1-year mortality of 74%. This review article aims to describe the mechanisms of acute coronary syndromes in cancer patients, their clinical presentation, and their management.

Recent Findings

Newer studies have shed light on the mechanisms of ACS in cancer patients, which are different and related to the type of malignancy and its associated therapy. Medication-specific coronary effects (vasospasm, endothelial dysfunction, spontaneous thrombosis, accelerated atherosclerosis), radiation vasculitis, cancer cell coronary embolism, and coronary compression from thoracic malignancies are unique ACS mechanisms in cancer patients.

Summary

Close collaboration between oncologists and cardiologists for thoughtful patient selection and decision making strategies is necessary to provide optimal medical care.

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Toward a Risk-Tailored Therapeutic Policy in Mantle Cell Lymphoma

Abstract

Purpose of Review

Mantle cell lymphoma (MCL) prognosis is strictly related to the characteristics of the disease, which can range from very indolent cases to highly aggressive and refractory ones. Here we will review the current knowledge on MCL biomarkers.

Recent Findings

Biomarker-informed diagnosis is essential for differentiating MCL from other mature B cell tumors. Diagnosis of MCL relies on the identification of the t(11;14) translocation by FISH or the consequently aberrant expression of cyclin D1 by immunohistochemistry. For the few cases staining negative for cyclin D1, SOX11 may help to define the diagnosis. Prognostic biomarkers have been proposed to stratify MCL patients, including baseline clinical aspects (leukemic non-nodal presentation, in situ presentation, Mantle cell International Prognostic Index—MIPI), pathological aspects (blastoid morphology, Ki-67 proliferation index, SOX11 expression), genetic aspects (immunoglobulin gene mutation status, TP53 deletion or mutation, CDKN2A deletion), and depth of response after treatment (PET imaging, molecular minimal residual disease). Such tools are increasingly used as a guide for therapeutic decisions. Watchful waiting approach is recommended for patients harboring favorable clinico-biological features, such as leukemic non-nodal presentation, low MIPI score, non-blastoid disease, low Ki-67 proliferation rate, mutated immunoglobulin genes, and the lack of SOX11 expression. For patients in need of frontline therapy, the decision of whether to undertake intensive regimens is based upon patient's age and comorbidities. Central nervous system prophylaxis is recommended for cases showing blastoid morphology. The duration of remission is tightly correlated to the depth of response. With the aim of achieving a longer duration of remission and survival, younger patients may pursue more intensive regimens incorporating high-dose cytarabine, followed by myeloablative consolidation chemotherapy, autologous stem cell transplantation, and rituximab maintenance. Older patients could, on the other hand, benefit from lower intensity immunochemotherapy followed or not by a maintenance therapy depending on which frontline regimen is used.

Summary

Despite the identification of several potential useful biomarkers that may inform the treatment decisions and the design of clinical trials, the treatment choice remains nowadays determined by the patient age and fitness rather than by the individual patient characteristics. Tailoring therapy toward a risk-adapted strategy to accommodate the wide spectrum of disease is an urgent challenge, and clinical trials may explore the feasibility of a biomarker-defined therapeutic policy.

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DNA methylation associated with healthy aging of elderly twins

Abstract

Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. One approach to this goal is to find genomic sites or regions where DNA methylation correlates with biological age. Using health data from 134 elderly twins, we calculated a frailty index as a quantitative indicator of biological age, and by applying the Infinium HumanMethylation450K BeadChip technology to their leukocyte DNA samples, we obtained quantitative DNA methylation data on genome-wide CpG sites. We analyzed the health and epigenome data by taking two independent associative approaches: the parametric regression-based approach and a non-parametric machine learning approach followed by GO ontology analysis. Our results indicate that DNA methylation at CpG sites in the promoter region of PCDHGA3 is associated with biological age. PCDHGA3 belongs to clustered protocadherin genes, which are all located in a single locus on chromosome 5 in human. Previous studies of the clustered protocadherin genes showed that (1) DNA methylation is associated with age or age-related phenotypes; (2) DNA methylation can modulate gene expression; (3) dysregulated gene expression is associated with various pathologies; and (4) DNA methylation patterns at this locus are associated with adverse lifetime experiences. All these observations suggest that DNA methylation at the clustered protocadherin genes, including PCDHGA3, is a key mediator of healthy aging.

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Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Research of steroidal compounds as anticancer agents started almost 50 years ago. During the past decades, several innovative new steroids, like cyproterone, finasteride, estramustin, exemestane and fulvestrant have successfully become a part of routine clinical practice. Meanwhile, a vast amount of new information have accumulated about the functions of the endogenous steroid system (including the characterization of enzymes, receptors, transcription pathways, etc.) and about the role of steroids in carcinogenesis. Therefore, it is regularly required to review the latest published results, focusing on a well-defined part within this research field that has definitely developed into a highly diversified speciality by now. Herein, we make an attempt to summarize the most recent results reported about anticancer agents of estrane backbone, focusing on their mechanisms of action and their structure-activity relationships. Due to the vast number and various accessibilities of scientific publications, neither other reviews nor this one can be considered as absolutely exhaustive. In spite of these restrictive factors, the current review makes a good opportunity to define the recent scientific trends in the field of estradiol-related anticancer agents.

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Meet Our Associate Editor

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New Approaches to Cancer Chemoprevention

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Synthesis, Spectral Characterization, Antibacterial and Anticancer Activity of some Titanium Complexes

Abstract: Background: After the discovery of cisplatin, first non platinum anticancer drugs having excellent efficacy were budotitane and TiCl2(cp)2 but action mechanism is not clear. Therefore, we hereby reporting synthesis and biological activities novel titanium complexes to explore their mode of action.

Objectives: Synthesis, spectral characterization, antibacterial and anticancer activity of some titanium complexes. Antibacterial studies on various bacterial strains and anticancer studies on HeLa, C6, CHO cancerous cell lines have been performed. Further, the cell death mechanistic study was done on CHO cell lines.

Method: Titanium complexes with and without labile groups have been synthesized by reacting of TiCl4 with nitrogen containing ligands viz. 1,2-diaminocyclohexane, 1,10-Phenanthroline, adamantylamine, 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine in predetermined molar ratios. Antibacterial and anticancer studies were performed by agar well diffusion method and MTT assay respectively. Cell cycle analysis is done by using flow cytometry.

Results: Complex 2 i.e TiCl2(Phen)2 showed better activity than other complexes as an antibacterial as well as anticancer agent. Phase contrast imaging indicates that observed morphological changes of cells was dose dependent. Cell death mechanistic study have shown the increase in sub G0 phase population as well as formation of blebbing and fragmentation of chromatin material which is an indicative measure of apoptosis.

Conclusion: Complex 2 proved to be more effective bactericide and cytotoxic agent. Cell cycle analysis showed cell arrest in G0 phase. Apoptosis percentage was found to increase in a dose dependent manner. So, prepared titanium complexes can be put to use as an important chemotherapeutic agents.

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Natural Compounds in the Chemoprevention of Malignant Melanoma

Malignant melanoma is a very aggressive form of skin cancer, with increasing rates every year, with an etiology that derives from the transformation and uncontrolled growth of melanocytes. There are several treatment options which can be used as unique treatment or combined, depending upon the stage of melanoma including surgical excision, chemotherapy, immunotherapy, targeted therapy. Plant Kingdom displays an unequalled potential for the synthesis of highly diversified chemical structures. Although natural compounds are synthesized in order to help the plant to interact with the environment, a large number of phytochemicals act as drugs within the human or animal body by activating various biochemical pathways. The study aims to review another approach in the management of this highly aggressive form of skin cancer, namely the effect of natural compounds in the chemoprevention of malignant melanoma.

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Antitumor Potential of Marine Natural Products: A Mechanistic Investigation

Background: Compounds obtained from natural resources have become important candidates in the discovery and development of drugs. Over the past few decades, marine resources have gradually attracted a large amount of attention from researchers, and many compounds with varying structures and activities have been derived from various marine resources. Since the ocean experiences more variable temperatures, lower oxygen levels and less light than the terrestrial environment, marine resources offer a substantial number of organisms that are not available or rarely detected on land.

Description: Researchers expect that they can discover agents from marine organisms that exhibit good activity for diseases. Of the marine compounds acquired, the majority have shown to have good antitumor activity, and range in phases from clinical trials up to being used in the clinic. These natural products operate through different pathways and have unique antitumor effects that include inducing cell apoptosis, inhibiting cell proliferation and influencing cell migration. A variety of drugs have been used for cancer treatment during the last few years, but it has not been possible to greatly extend the survival time of advanced cancer patients. In addition, researchers are actively looking for compounds to overcome problems that include a lack of effective drugs to control the transfer of cancer cells and the development of drug-resistant microbes.

Conclusion: Here, we summarize the marine natural products that have been obtained over the past few years, and analyze their antitumor effects and mechanisms. Our research will provide a significant basis for anticancer drug screening and development.

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Immunopharmacological Activity of Betulin in Inflammation-associated Carcinogenesis

This review highlights the multiple properties of the birch bark-derived pentacyclic triterpene betulin with special focus on its pharmacological activity in cancer and inflammation. While less well characterized compared to its hydrophilic derivative, betulinic acid, it exhibits potent anticancer activity described in many publications. Indeed, underinvestigated are its immunomodulatory functions in inflammatory diseases that appeared to enhance innate immune cell activities in an adjuvant-like fashion towards an interleukin-12 driven antitumor immunity. Herein, we like to emphasize the simultaneous and dual function of betulin on the basis of recent investigations of the tumor microenvironment and enlighten the potential use of betulin in the control of inflammation-associated carcinogenesis.

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α-Aroylketene Dithioacetal Mediated Synthesis of (E)-3-(benzo[d]thiazol-2-ylamino)-2-(1-methyl-1H-indole-3-carbonyl)-3-(methylthio)acrylonitrile Derivatives and their Biological Evaluation

Background: The blending of two pharmacophores would generate novel molecular templates that are likely to exhibit interesting biological properties.

Objective: A facile, efficient and high yielding synthesis of (E)-3-(benzo[d]thiazol-2-ylamino)-2-(1-methyl-1Hindole- 3-carbonyl)-3-(methylthio) acrylonitrile derivatives and evaluation of therapeutic potential.

Method: The synthesis of target molecules has been achieved by reacting 2-aminobenzothiazole and substituted 2-(1-methyl-1H-indole-3-carbonyl)-3,3-bis(methylthio)acrylonitrile in the presence of a catalytic amount of sodium hydride in THF. Structural investigations were carried using 1H NMR, 13C NMR, FT-IR, and HRMS data.

Results: In vitro anti-tumor evaluation of the synthesized compounds against MCF-7 (breast carcinoma) cell line revealed that they possess good anti-tumor activities. Compounds, 4j and 4i demonstrated significant activities against breast carcinoma (GI50 14.3 and 19.5 µM respectively). Most of the synthesized compounds were also found to be excellent NO, H2O2, DPPH, and superoxide radical scavengers. Anti-diabetic and antiinflammatory evaluation also displayed moderate activity.

Conclusion: Among the compounds synthesized some of the compounds possess significant anticancer, antioxidant and anti-inflammatory properties.

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A Review of Electroporation-based Antitumor Skin Therapies and Investigation of Betulinic Acid-loaded Ointment

Background: Electrochemotherapy is a novel treatment for cutaneous and subcutaneous tumors utilizing the combination of electroporation and chemotherapeutic agents. Since tumors have an increasing incidence nowadays as a result of environmental and genetic factors, electrochemotherapy could be a promising treatment for cancer patients.

Objective: The aim of this article is to summarize the novel knowledge about the use of electroporation for antitumor treatments and to present a new application of electrochemotherapy with a well-known plant derived antitumor drug betulinic acid. For the review we have searched the databases of scientific and medical research to collect the available publications about the use of electrochemotherapy in the treatment of various types of cancer.

Method: By the utilization of the available knowledge, we investigated the effect of electroporation on the penetration of a topically applied betulinic acid formulation into the skin by ex vivo Raman spectroscopy on hairless mouse skin.

Results: Raman measurements have demonstrated that the penetration depth of betulinic acid can be remarkably ameliorated by the use of electroporation, so this protocol can be a possibility for the treatment of deeper localized cancer nodules. Furthermore, it proved the influence of various treatment times, since they caused different spatial distributions of the drug in the skin.

Conclusion: The review demonstrates that electrochemotherapy is a promising tool to treat different kinds of tumors with high efficiency and with only a few moderate adverse effects. Moreover, it presents a non-invasive method to enhance the penetration of antitumor agents, which can offer novel prospects for antitumor therapies.

https://ift.tt/2ByMM9l

Ganoderma lucidum Polysaccharides as An Anti-cancer Agent

The mushroom Ganoderma lucidum (G. lucidum) has been used for centuries in Asian countries to treat various diseases and to promote health and longevity. Clinical studies have shown beneficial effects of G. lucidum as an alternative adjuvant therapy in cancer patients without obvious toxicity. G. lucidum polysaccharides (GLP) is the main bioactive component in the water soluble extracts of this mushroom. Evidence from in vitro and in vivo studies has demonstrated that GLP possesses potential anticancer activity through immunomodulatory, anti-proliferative, pro-apoptotic, anti-metastatic and anti-angiogenic effects. Here, we briefly summarize these anticancer effects of GLP and the underlying mechanisms.

https://ift.tt/2o08UjE

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment

Background: Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patient's survival are the new era for the colon cancer drug development.

Objective: The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line.

Method: Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level.

Results: The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50

Conclusion: Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.

https://ift.tt/2we7rd6

Natural Macromolecules with Protective and Antitumor Activity

This review summarizes the literature data regarding plant lectins as novel drug sources in the prevention or treatment of cancer. Moreover, such compounds have been described as natural toxins that possess different biological activities (cytotoxic, antitumor, antimutagenic and anticarcinogenic properties). This activity depends greatly on their structure and affinity. Most of the mushroom heterosides are known as β-glucans with β-(1→3)-glycosidic bonds. It is thought that their conformation, bonds, molecular size can modulate the immune response by triggering different receptors. The mechanism on normal and tumor cells of various plant and mushroom polysaccharides and lectins is briefly presented in this paper.

https://ift.tt/2PvnBYz

Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity

Background: 4-Substitutedaminoquinazoline scaffolds were reported to possess potent cytotoxic and EGFR inhibitory activity such as gefitinib (Iressa), erlotinib (Tarceva) and tandutinib.

Objective: Synthesis of novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives as bioisosters of 4-substitutedaminoquinazoline derivatives with potential cytotoxic and EGFR inhibitory activity.

Methods: Novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives 4a-i and 5a-c were synthesized via reacting corresponding 4-chlorothieno[2,3-d]pyrimidine derivatives 3a-c with N-methylpiperazine, morpholine, N-phenylpiperazine or 1,3-propanediamine. Six compounds (2a, 4d, 4e, 5a-c) were selected by the National Cancer Institute (USA) for evaluating their cytotoxic activity using 60 different human tumor cell lines using a single dose (10-5 Molar). The rest of the synthesized compounds (2b, 2c, 3a-c, 4a-c and 4f-i) were subjected to screening against T47D breast cancer cell line using a single dose (10-5 Molar) at Pharmacology lab., Cancer biology lab., Egyptian National Institute. Moreover, compounds 2a and 4b-e were subjected to further evaluation by IC50 determination. Finally, the inhibition of epidermal growth factor receptor (EGFR) was then investigated for the most active compounds 2a and 4d.

Results: Compounds 2a and 4b-e showed significant cytotoxic activity. Compound 2a was more potent than doxorubicin against lung cancer cell line A549 with IC50 = 13.40 μM and comparable activity against MCF7. Compound 4d exhibited more potent activity than Doxorubicin against prostate PC3 (IC50 = 14.13 µM) while showed comparable activity against MCF7 and T47D.

Conclusion: 4-Substitutedaminothieno[2,3-d]pyrimidine is a promising backbone for the design and synthesis of potent cytotoxic leads.

https://ift.tt/2wllZYk

Modulation of Cancer Metabolism by Phytochemicals - A Brief Overview

Despite tremendous research efforts for effective therapies, cancer remains the plague of the century and its burden is expected to increase worldwide in the near future. Metabolic reprogramming is a firmly established hallmark of all cancers, regardless of their cellular or tissue origin, being a prerequisite for both tumor growth and invasion. Functional dependence of tumors on glycolysis and glutaminolysis and the crucial contribution of mitochondria to the tumor bioenergetic versatility are well recognized features and established therapeutic targets. The complex landscape of tumor metabolism in the context of the dynamic, bidirectional crosstalk with its stromal environment is a rapidly evolving field that increasingly supports the view of cancer both as metabolic disease and a disease of impaired cellular 'communication'. Many of the approved anticancer drugs are derived from natural sources and the search of novel drug candidates is still a priority view the rapid development of chemoresistance. Phytochemicals are biologically active plant compounds with preventive and/or curative anticancer properties able to potentiate the effects of standard therapies while decreasing their toxicity via multitarget modulatory effects. The present mini-review will briefly summarize the hallmarks of metabolic reprogramming in tumor cells and the phytochemicals that have been reported to modulate the dysregulated metabolism of tumor and its environment, with special emphasis on triterpenes.

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ERRATUM

https://ift.tt/2BFFHDY

Learning curve for single‐incision laparoscopic totally extraperitoneal inguinal hernia repair

Asian Journal of Endoscopic Surgery, EarlyView.


https://ift.tt/2MBK9Iv

Safety of laparoscopic colorectal surgery in patients with ventriculoperitoneal shunt

Asian Journal of Endoscopic Surgery, EarlyView.


https://ift.tt/2Lc0eje

Optimal introduction of laparoscopic liver resection for Child–Pugh B

Asian Journal of Endoscopic Surgery, EarlyView.


https://ift.tt/2Ppsfat

Laparoscopic high anterior resection for triple colorectal cancers with persistent ascending and descending mesocolons: A case report

Asian Journal of Endoscopic Surgery, EarlyView.


https://ift.tt/2Bv2FO4

One Group's Historical Reflections on DNA Vaccine Development

Human Gene Therapy, Ahead of Print.


https://ift.tt/2N84KkD

Genetic Architecture of Soybean Yield and Agronomic Traits

Soybean is the world's leading source of vegetable protein and demand for its seed continues to grow. Breeders have successfully increased soybean yield, but the genetic architecture of yield and key agronomic traits is poorly understood. We developed a 40-mating soybean nested association mapping (NAM) population of 5,600 inbred lines that were characterized by single nucleotide polymorphism (SNP) markers and for six agronomic traits in field trials in 22 environments. Analysis of the yield, agronomic, and SNP data revealed 23 significant marker-trait associations for yield, 19 for maturity, 15 for plant height, 17 for plant lodging, and 29 for seed mass. A higher frequency of estimated positive yield alleles was evident from elite founder parents than from exotic founders, although unique desirable yield alleles from the exotic group were identified, demonstrating the value of expanding the genetic base of US soybean breeding.

https://ift.tt/2OWdhHU

Imputation-Aware Tag SNP Selection To Improve Power for Large-Scale, Multi-ethnic Association Studies

The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. These strategies have benefited from improvements in imputation methods and association tests, however little attention has been paid to ways in which array design can increase rare variant association power. Therefore, we developed a novel framework to select tag SNPs using the reference panel of 26 populations from Phase 3 of the 1000 Genomes Project. We evaluate tag SNP performance via mean imputed r² at untyped sites using leave-one-out internal validation and standard imputation methods, rather than pairwise linkage disequilibrium. Moving beyond pairwise metrics allows us to account for haplotype diversity across the genome for improve imputation accuracy and demonstrates population-specific biases from pairwise estimates. We also examine array design strategies that contrast multi-ethnic cohorts versus single populations, and show a boost in performance for the former can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Using our framework, we demonstrate increased imputation accuracy for rare variants (frequency<1%) by 0.5-3.1% for an array of one million sites and 0.7-7.1% for an array of 500,000 sites, depending on the population. Finally, we show how recent explosive growth in non-African populations means tag SNPs capture on average 30% fewer other variants than in African populations. The unified framework presented here will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.

https://ift.tt/2Prxne7

First-In-Human Phase I Trial of a Tumor-Targeted Cytokine (NHS-IL12) in Subjects with Metastatic Solid Tumors

Purpose: The NHS-IL12 immunocytokine is composed of two IL-12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL-12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors. Experimental Design: Subjects (n=59) were treated subcutaneously with NHS-IL12 in a single ascending dose cohort followed by a multiple ascending dose cohort (n=37 with every 4-week dosing). Results: The most frequently observed treatment-related adverse events (TRAEs) included decreased circulating lymphocytes, increased liver transaminases and flu-like symptoms. Of the grade ≥ 3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 µg/kg. A time-dependent rise in IFN- and an associated rise in IL-10 were observed post-NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on TCR sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed post-treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range 6-30+ months). Conclusions: NHS-IL12 was well tolerated up to a dose of 16.8 µg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.

https://ift.tt/2LeNPeg

Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Experimental Design: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analyses was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Results: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N=7), BRCA2 (N=5), PALB2 (N=3), MSH2 (N=1) and FANCF (N=1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent (14 vs. 5 months; HR 0.58 [0.29-1.14], log-rank p=0.08). Multivariate logistic (OR 1.47 [1.04-2.06], p = 0.04) and Cox regression (HR 0.37 [0.15-0.94], p = 0.04) showed presence of DDR gene mutations was associated with improved OS. Conclusion: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

https://ift.tt/2PtkOib

RAB37 hypermethylation regulates metastasis and resistance to docetaxel-based induction chemotherapy in nasopharyngeal carcinoma

Purpose: Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis. Experimental Design: Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published GEO dataset. The regulatory and functional role of RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity. Results: We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 co-localized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, RAB37 hypermethylation was correlated with poor clinical outcomes in NPC patients. We developed a prognostic model based on RAB37 methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients. Conclusions: This study show that RAB37 hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.

https://ift.tt/2Bwphhu

SLC46A3 as a potential predictive biomarker for antibody-drug conjugates bearing non-cleavable linked maytansinoid and pyrrolobenzodiazepine warheads

Purpose: Antibody-drug conjugates (ADCs) utilizing non-cleavable linker-drugs have been approved for clinical use, and several are in development targeting solid and hematological malignancies including multiple myeloma (MM). Currently there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance. Experimental Design: The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the non-cleavable linker pyrrolobenzodiazepine payload SG3376 in vitro. The functional relevance of SLC46A3, a lysosomal transporter of non-cleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EphA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft and in-vitro models of acquired T-DM1 resistance and MM bone marrow samples by RT-PCR. Results: Loss of SLC46A3 expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of SLC46A3, suggesting that expression of SLC46A3 may be more predictive of activity than target antigen levels alone. Interrogation of primary MM samples indicated a range of SLC46A3 expression, including samples with undetectable levels like MM cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs. Conclusion: Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.

https://ift.tt/2nVEgYz

Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T-cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma

Purpose: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study we investigated the impact of nivolumab therapy on peripheral blood Tregs and its relation to patient outcomes. Experimental Design: Peripheral blood Tregs and conventional CD4+ T-cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions. Results: Tregs from non-relapse patients had increased expression of proliferation associated genes . An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg suppressive function. PD-1 blockade also led to IL-10 production by T-cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL-10 production in vitro. Conclusions: These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.

https://ift.tt/2BwpeCk

Abemaciclib is Active in Preclinical Models of Ewing's Sarcoma via Multi-pronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling

Purpose: Ewing's sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study we evaluated abemaciclib, a small molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. Experimental Design: Using western blot, high content imaging, flow cytometry, ELISA, RNAseq, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived and patient-derived xenograft (CDX and PDX, respectively) mouse models of ES as either a monotherapy or in combination with chemotherapy. Results: Abemaciclib induced quiescence in ES cell lines via a G1 cell cycle block, characterized by decreased proliferation and reduction of Ki67 and FOXM1 expression and RB phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. Conclusions: Collectively, our data demonstrate that the anti-tumor effects of abemaciclib in preclinical ES models are multifaceted and include cell cycle inhibition, DNA demethylation, and immunogenic changes.

https://ift.tt/2PsiBUc

Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma

Purpose: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). Experimental Design: Adults meeting eligibility criteria were enrolled in this prospective, single arm, open-label multi-institution phase II trial with median overall survival (mOS) compared to a historical control as the primary objective. A safety run-in component of RT+TMZ+iniparib (n=5) was followed by an efficacy study (n=76) with the recommended phase II doses of iniparib (8.0 mg/kg IV twice/week with RT + daily TMZ followed by 8.6 mg/kg IV twice/week with 5/28 day TMZ). Results: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥80% in 87% of participants. The mOS was 22 months (95%CI: 17-24) and the hazard rate was 0.44 (95%CI: 0.35-0.55) per-person year of follow-up. The 2 and 3 year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AE) occurred in 27% of patients; nine patients had AEs requiring drug discontinuation including: infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. Conclusions: Iniparib is well tolerated with RT and TMZ in patients with newly diagnosed GBM at up to 17.2mg/kg weekly. The primary objective of improved mOS compared with historical a control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

https://ift.tt/2Lf4fDB

Plan to Relax Coal-Fired Power Plant Rules Could Up Mortality

TUESDAY, Aug. 21, 2018 -- The Trump administration's plan to relax pollution rules for coal-fired power plants will increase carbon emissions and cause up to 1,400 premature deaths a year, according to details released Tuesday. The new plan issued...

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Doctors Often Not Discussing Risk Factors With Patients

TUESDAY, Aug. 21, 2018 -- Patients report that doctors are routinely not discussing known risk factors for common causes of death, according to a survey conducted by ImagineMD. ImagineMD conducted a survey of 3,000 patients to examine whether...

https://ift.tt/2wmrSoq

Patient Education Urged to Prevent Opioid OD After Sobriety

TUESDAY, Aug. 21, 2018 -- The American Medical Association (AMA) encourages patient education to raise awareness of the risks associated with opioid use after a prolonged period of sobriety, according to a report in the organization's AMA Wire. The...

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USPSTF Updates Guidance for Cervical Cancer Screening

TUESDAY, Aug. 21, 2018 -- The U.S. Preventive Services Task Force (USPSTF) has updated the recommendations for screening for cervical cancer; the final recommendation statement has been published in the Aug. 21 issue of the Journal of the American...

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FDA Extends EpiPen Expiration Dates to Tackle Shortage

TUESDAY, Aug. 21, 2018 -- The expiration dates of certain batches of EpiPens have been extended by the U.S. Food and Drug Administration in an effort to reduce shortages of the life-saving devices. The FDA said that it has extended by four months...

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Enhancement of the Medial Olivocochlear System Prevents Hidden Hearing Loss

Cochlear synaptopathy produced by exposure to noise levels that cause only transient auditory threshold elevations is a condition that affects many people and is believed to contribute to poor speech discrimination in noisy environments. These functional deficits in hearing, without changes in sensitivity, have been called hidden hearing loss (HHL). It has been proposed that activity of the medial olivocochlear (MOC) system can ameliorate acoustic trauma effects. Here we explore the role of the MOC system in HHL by comparing the performance of two different mouse models: an α9 nicotinic receptor subunit knock-out (KO; Chrna9 KO), which lacks cholinergic transmission between efferent neurons and hair cells; and a gain-of-function knock-in (KI; Chrna9L9'T KI) carrying an α9 point mutation that leads to enhanced cholinergic activity. Animals of either sex were exposed to sound pressure levels that in wild-type produced transient cochlear threshold shifts and a decrease in neural response amplitudes, together with the loss of ribbon synapses, which is indicative of cochlear synaptopathy. Moreover, a reduction in the number of efferent contacts to outer hair cells was observed. In Chrna9 KO ears, noise exposure produced permanent auditory threshold elevations together with cochlear synaptopathy. In contrast, the Chrna9L9'T KI was completely resistant to the same acoustic exposure protocol. These results show a positive correlation between the degree of HHL prevention and the level of cholinergic activity. Notably, enhancement of the MOC feedback promoted new afferent synapse formation, suggesting that it can trigger cellular and molecular mechanisms to protect and/or repair the inner ear sensory epithelium.

SIGNIFICANCE STATEMENT Noise overexposure is a major cause of a variety of perceptual disabilities, including speech-in-noise difficulties, tinnitus, and hyperacusis. Here we show that exposure to noise levels that do not cause permanent threshold elevations or hair cell death can produce a loss of cochlear nerve synapses to inner hair cells as well as degeneration of medial olivocochlear (MOC) terminals contacting the outer hair cells. Enhancement of the MOC reflex can prevent both types of neuropathy, highlighting the potential use of drugs that increase α9α10 nicotinic cholinergic receptor activity as a pharmacotherapeutic strategy to avoid hidden hearing loss.

https://ift.tt/2w4zCMh

Amplification and Suppression of Distinct Brainwide Activity Patterns by Catecholamines

The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects of catecholaminergic modulation on network dynamics are homogeneous across the brain. However, the brain is equipped with a variety of catecholamine receptors with distinct functional effects and heterogeneous density across brain regions. Consequently, catecholaminergic effects on brainwide network dynamics might be more spatially specific than assumed. We tested this idea through the analysis of fMRI measurements performed in humans (19 females, 5 males) at "rest" under pharmacological (atomoxetine-induced) elevation of catecholamine levels. We used a linear decomposition technique to identify spatial patterns of correlated fMRI signal fluctuations that were either increased or decreased by atomoxetine. This yielded two distinct spatial patterns, each expressing reliable and specific drug effects. The spatial structure of both fluctuation patterns resembled the spatial distribution of the expression of catecholamine receptor genes: α₁ norepinephrine receptors (for the fluctuation pattern: placebo > atomoxetine), D₂-like dopamine receptors (pattern: atomoxetine > placebo), and β norepinephrine receptors (for both patterns, with correlations of opposite sign). We conclude that catecholaminergic effects on the forebrain are spatially more structured than traditionally assumed and at least in part explained by the heterogeneous distribution of various catecholamine receptors. Our findings link catecholaminergic effects on large-scale brain networks to low-level characteristics of the underlying neurotransmitter systems. They also provide key constraints for the development of realistic models of neuromodulatory effects on large-scale brain network dynamics.

SIGNIFICANCE STATEMENT The catecholamines norepinephrine and dopamine are an important class of modulatory neurotransmitters. Because of the widespread and diffuse release of these neuromodulators, it has commonly been assumed that their effects on neural interactions are homogeneous across the brain. Here, we present results from the human brain that challenge this view. We pharmacologically increased catecholamine levels and imaged the effects on the spontaneous covariations between brainwide fMRI signals at "rest." We identified two distinct spatial patterns of covariations: one that was amplified and another that was suppressed by catecholamines. Each pattern was associated with the heterogeneous spatial distribution of the expression of distinct catecholamine receptor genes. Our results provide novel insights into the catecholaminergic modulation of large-scale human brain dynamics.

https://ift.tt/2N33O0K

Neural Firing Patterns Are More Schematic and Less Sensitive to Changes in Background Visual Scenes in the Subiculum than in the Hippocampus

Literature suggests that the hippocampus is central to processing visual scenes to remember contextual information, but the roles of its downstream structure, subiculum, remain unknown. Here, single units were recorded simultaneously in the dorsal CA1 and subiculum while male rats made spatial choices using visual scenes as cues in a T-maze. The firing fields of subicular neurons were schematically organized following the task structure, largely divided into pre-choice and post-choice epochs, whereas those of CA1 cells were more punctate and bound to specific locations. When the rats were tested with highly familiar scenes, neurons in the CA1 and subiculum were indistinguishable in coding the task-related information (e.g., scene, choice) through rate remapping. However, when the familiar scenes were blurred parametrically, the neurons in the CA1 responded sensitively to the novelty in task demand and changed its representations parametrically following the physical changes of the stimuli, whereas these functional characteristics were absent in the subiculum. These results suggest that the unique function of the hippocampus is to acquire contextual representations in association with discrete positions in space, especially when facing new and ambiguous scenes, whereas the subiculum may translate the position-bound visual contextual information of the hippocampus into schematic codes once learning is established.

SIGNIFICANCE STATEMENT Although the potential functional significance has been recognized for decades for the subiculum, its exact roles in a goal-directed memory task still remain elusive. In the current study, we present experimental evidence that may indicate that the neural population in the subiculum could translate the location-bound spatial representations of the hippocampus into more schematic representations of task demands. Our findings also imply that the visual scene-based codes conveyed by the hippocampus and subiculum may be identical in a well learned task, whereas the hippocampus may be more specialized in representing altered visual scenes than the subiculum.

https://ift.tt/2vZPQ9q

“Recurrent multiple cerebral infarctions related to the progression of adenomyosis: a case report”

Benign gynecologic tumor, such as uterine adenomyosis, has been suggested to develop hypercoagulability. Although some cases of cerebral infarction associated with adenomyosis have been reported, the mechanism...

https://ift.tt/2Ps5bYk

A retrospective case series of segmental zoster paresis of limbs: clinical, electrophysiological and imaging characteristics

Segmental zoster paresis (SZP) of limbs, characterized by focal weakness of extremity, is recognized as a rare complication of herpes zoster (HZ). The following study analyzes the clinical characteristics and ...

https://ift.tt/2wmq9zs

Reversible reddish skin color change in a patient with compressive radial neuropathy

The motor and sensory symptoms caused by compressive radial neuropathy are well-known, but the involvement of the autonomic nervous system or the dermatologic symptoms are less well known. We report an unusual...

https://ift.tt/2nZguLo

Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. Among pyrophosphates generated by IP6Ks, diphosphoinositol pentakisphosphate (IP7), and bis-diphosphoinositol tetrakisphosphate have been extensively characterized. IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. We report that IP6K2 binds protein 4.1.N with high affinity and specificity. Nuclear translocation of 4.1N, which is required for its principal functions, is dependent on IP6K2. Both of these proteins are highly expressed in granule cells of the cerebellum where their interaction regulates Purkinje cell morphology and cerebellar synapses. The deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. Moreover, the disruption of IP6K2–4.1N interactions impairs cell viability. Thus, IP6K2 and its interaction with 4.1N appear to be major determinants of cerebellar disposition and psychomotor behavior.

SIGNIFICANCE STATEMENT Inositol phosphates are produced by a family of inositol hexakisphosphate kinases (IP6Ks)—IP6K1, IP6K2, and IP6K3. Of these, the physiological roles of IP6K2 in the brain have been least characterized. In the present study, we report that IP6K2 binds selectively to the neuronal protein 4.1N. Both of these proteins are highly expressed in granule cells of the cerebellum. Using IP6K2 knock-out (KO) mice, we establish that IP6K2–4.1N interactions in granule cells regulate Purkinje cell morphology, the viability of cerebellar neurons, and psychomotor behavior.

https://ift.tt/2N8agDV

Long-Term Depression Induced by Optogenetically Driven Nociceptive Inputs to Trigeminal Nucleus Caudalis or Headache Triggers

The peripheral trigeminovascular pathway mediates orofacial and craniofacial pain and projects centrally to the brainstem trigeminal nucleus caudalis (TNc). Sensitization of this pathway is involved in many pain conditions, but little is known about synaptic plasticity at its first central synapse. We have taken advantage of optogenetics to investigate plasticity selectively evoked at synapses of nociceptive primary afferents onto TNc neurons. Based on immunolabeling in the trigeminal ganglia, TRPV1-lineage neurons comprise primarily peptidergic and nonpeptidergic nociceptors. Optical stimulation of channelrhodopsin-expressing axons in the TRPV1/ChR2 mouse in TNc slices thus allowed us to activate a nociceptor-enriched subset of primary afferents. We recorded from lamina I/II neurons in acutely prepared transverse TNc slices, and alternately stimulated two independent afferent pathways, one with light-activated nociceptive afferents and the other with electrically-activated inputs. Low-frequency optical stimulation induced robust long-term depression (LTD) of optically-evoked EPSCs, but not of electrically-evoked EPSCs in the same neurons. Blocking NMDA receptors or nitric oxide synthase strongly attenuated LTD, whereas a cannabinoid receptor 1 antagonist had no effect. The neuropeptide PACAP-38 or the nitric oxide donors nitroglycerin or sodium nitroprusside are pharmacologic triggers of human headache. Bath application of any of these three compounds also persistently depressed optically-evoked EPSCs. Together, our data show that LTD of nociceptive afferent synapses on trigeminal nucleus neurons is elicited when the afferents are activated at frequencies consistent with the development of central sensitization of the trigeminovascular pathway.

SIGNIFICANCE STATEMENT Animal models suggest that sensitization of trigeminovascular afferents plays a major role in craniofacial pain syndromes including primary headaches and trigeminal neuralgia, yet little is known about synaptic transmission and plasticity in the brainstem trigeminal nucleus caudalis (TNc). Here we used optogenetics to selectively drive a nociceptor-enriched population of trigeminal afferents while recording from superficial laminae neurons in the TNc. Low-frequency optical stimulation evoked robust long-term depression at TRPV1/ChR2 synapses. Moreover, application of three different headache trigger drugs also depressed TRPV1/ChR2 synapses. Synaptic depression at these primary afferent synapses may represent a newly identified mechanism contributing to central sensitization during headache.

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Reiter’s syndrome following intravesical Bacillus Calmette-Guerin therapy for bladder carcinoma: a report of five cases

Abstract

Reiter's syndrome is known to be a rare severe adverse of Bacillus Calmette-Guerin (BCG) therapy. We report five cases of patients with Reiter's syndrome following intravesical BCG therapy for bladder carcinoma, and review the clinical characteristics, treatments, and outcomes of these patients. Each patient developed polyarthritis after urinary tract symptoms, and developed conjunctivitis anywhere from the third to the eighth BCG induction cycle. One case presented a slight elevation of inflammatory responses in blood analysis, and the other four cases had a higher level of white blood cell (WBC) counts and C-reactive protein (CRP) values. WBC counts at the diagnosis of Reiter's syndrome had a positive correlation with the time from initial treatment to cure of the disease. In all cases, BCG therapy was discontinued, and non-steroidal anti-inflammatory drugs (NSAIDs), oral steroids, and anti-tuberculosis drugs were administered. Anti-rheumatic drugs were not used in these cases. Improvement of symptoms was reported from 1 to 13 months after initial treatment. No patients had recurrence of Reiter's syndrome, whereas 2 patients had alternative treatment 2 and 18 months later, respectively, because of cancer recurrence. For cases with conjunctivitis and joint pain occurring during intravesical BCG therapy, early clinical interventions such as NSAIDs, steroids, and anti-tuberculosis drugs should be introduced, especially in cases with a high level of inflammatory changes in blood analysis.

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Webinar: How can prehospital providers can quickly identify and treat sepsis?

Learn how you can quickly assess and treat patients with sepsis as an EMS provider.

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Force-Clamp Rheometry for Characterizing Protein-based Hydrogels

A new force-clamp rheometry technique is used to investigate the mechanical properties of low-volume protein-based hydrogel samples tethered between a voice-coil motor and a force sensor. An analog proportional-integral-derivative (PID) system allows for the 'clamping' of the force experienced to the desired protocol.

https://ift.tt/2MEcs90

Microparticle Manipulation by Standing Surface Acoustic Waves with Dual-frequency Excitations

A protocol for manipulating the microparticles in a microfluidic channel with a dual-frequency excitation is presented.

https://ift.tt/2NbcGBK

A Novel Saturation Mutagenesis Approach: Single Step Characterization of Regulatory Protein Binding Sites in RNA Using Phosphorothioates

Proteins that bind specific RNA sequences play critical roles in gene expression. Detailed characterization of these binding sites is crucial for our understanding of gene regulation. Here, a single-step approach for saturation mutagenesis of protein-binding sites in RNA is described. This approach is relevant for all protein-binding sites in RNA.

https://ift.tt/2MEgUEQ

Three-Dimensional Ultrasonic Needle Tip Tracking with a Fiber-Optic Ultrasound Receiver

Accurate and efficient visualization of invasive medical devices is extremely important in many ultrasound-guided minimally invasive procedures. Here, a method for localizing the spatial position of a needle tip relative to the ultrasound imaging probe is presented.

https://ift.tt/2N6IRCc

APTA Physical Therapy Outcomes Registry: How it Works

APTA's Physical Therapy Outcomes Registry is a platform that allows all physical therapists and practices to leverage EHR data to improve patient outcomes. APTA has partnered with FIGmd, a leading IT company that specializes in EHR-integrated registries, to power the Physical Therapy Outcomes Registry. To learn more or request a demo, visit www.ptoutcomes.com

https://www.youtube.com/watch?v=G5alOCwohLo

Tox and Hound – Dialyze This

by Diane Calello   Dialyze This – Extracorporeal Removal Techniques for the Poisoned Patient Case A 26-year-old woman presents with palpitations after intentionally ingesting 180 tablets (36 g) of caffeine in a suicide attempt. Her triage vitals are notable for a HR of 160 bpm, and BP of 92/60 mmHg. During your initial evaluation, she […]

EMCrit Project by Tox & Hound.

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Pennsylvania Case Could Affect Evidence for Malpractice Defense

TUESDAY, Aug. 21, 2018 -- The Pennsylvania Supreme Court has agreed to hear a case that could affect what evidence physicians may present in defense during medical malpractice suits, according to an article published in the American Medical...

https://ift.tt/2OXSQub

Young, Growing Athletes at High Risk for ACL Injuries

TUESDAY, Aug. 21, 2018 -- Young, growing athletes are at high risk for anterior cruciate ligament (ACL) injuries, according to a report published by Penn State Health News. Most tears of the ACL are non-contact injuries. Primary causes during sports...

https://ift.tt/2MsQHcQ

Hypnosis Doesn't Cut Post-Op Pain in Breast Cancer Surgery

TUESDAY, Aug. 21, 2018 -- Hypnosis before general anesthesia does not reduce postoperative breast pain among patients undergoing minor breast cancer surgery, according to a study published online Aug. 17 in JAMA Network Open. Jibba Amraoui, M.D.,...

https://ift.tt/2vZndJk

Large Number of Presumed Sudden Cardiac Deaths Are Not

TUESDAY, Aug. 21, 2018 -- A large percentage of deaths attributed to cardiac arrest are neither sudden nor unexpected, according to a study published recently in Circulation. Zian H. Tseng, M.D., from the University of California in San Francisco,...

https://ift.tt/2OUB6je

Side Effects of Biologics for Rheumatic Dz May Up Anxiety

TUESDAY, Aug. 21, 2018 -- Potential side effects of biological agents may increase anxiety in patients with rheumatic disease, according to research published in the June issue of the International Journal of Rheumatic Diseases. Yavuz Pehlivan,...

https://ift.tt/2MtTin9

Sentinel Lymph Node Mapping Most Cost-Effective for Uterine CA

TUESDAY, Aug. 21, 2018 -- Sentinel lymph node mapping has the lowest costs and highest quality-adjusted survival compared to both routine and selective lymphadenectomy for managing low-risk endometrial carcinoma, according to a study published in...

https://ift.tt/2OXSHH9

Amount of Physical Exercise Affects Mental Health Burden

TUESDAY, Aug. 21, 2018 -- Physical exercise is associated with self-reported mental health burden in the past month, according to a study published online Aug. 8 in The Lancet Psychiatry. Sammi R. Chekroud, from the University of Oxford in the...

https://ift.tt/2ORw7zQ

Preventable Adverse Drug Events Usually of Minor Severity in Kids

TUESDAY, Aug. 21, 2018 -- The incidence of preventable adverse drug events (pADEs) is zero to 17 per 1,000 patient-days in general pediatric wards and zero to 29 in intensive care units, with most pADEs of minor severity, according to a review...

https://ift.tt/2w2g6zV

WPSI Recommends Annual Urinary Incontinence Screening

TUESDAY, Aug. 21, 2018 -- The Women's Preventive Services Initiative (WPSI) recommends annual urinary incontinence screening for women and referral for further evaluation and treatment if indicated, according to a clinical guideline published online...

https://ift.tt/2OSnLI8

Interim Guidance Provided for Men With Possible Zika Infection

TUESDAY, Aug. 21, 2018 -- Interim guidance recommends that men with possible Zika virus infection wait three months before trying to conceive or engaging in unprotected sex, according to research published in the Aug. 10 issue of the U.S. Centers...

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Correlation of plasma erlotinib trough concentration with skin rash in Chinese NSCLC patients harboring exon 19 deletion mutation

Abstract

Purpose

Erlotinib is an essential drug for non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations. The relationship between the pharmacokinetics and skin rash and diarrhea of erlotinib in Chinese patients with EGFR mutated NSCLC is unknown. In this study, we evaluated the variability in erlotinib trough concentration and its relationship with the severity of skin rash and diarrhea in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R.

Patients and methods

EGFR mutation-positive Chinese patients (n = 52) treated with erlotinib were included in our study; the steady-state trough concentrations were assessed; and the occurrence and severity of skin rash and diarrhea after the onset of treatment with erlotinib were recorded. The patients were divided into two groups by mutation type (exon 19 deletions or exon 21 L858R point mutations). Occurrence and severity of skin rash and diarrhea was analyzed in both groups.

Results

The overall mean (± SD) steady-state trough concentration for erlotinib was 1380 ± 663 ng/mL, and there was no significant difference of erlotinib concentrations between the two mutation groups. Occurrence and severity of skin rash was significantly associated with trough concentration in patients with exon 19 deletions but not exon 21 L858R point mutations. Significant association of erlotinib concentrations with diarrhea was found neither in the exon 19 deletions group nor in the exon 21 L858R point mutation group.

Conclusions

The occurrence and severity of skin rash correlated with increase in erlotinib trough concentrations only in Chinese patients with exon 19 deletion; the erlotinib trough concentrations were not associated with diarrhea.

https://ift.tt/2N4tPNf

A continuous-time multistate Markov model to describe the occurrence and severity of diarrhea events in metastatic breast cancer patients treated with lumretuzumab in combination with pertuzumab and paclitaxel

Abstract

Purpose

To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancer patients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches.

Methods

The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events.

Results

The model was able to capture the time course of different severities of diarrhea reasonably well. The effect of lumretuzumab and pertuzumab was well described by an E_max function indicating an increased rate of transition from moderate to mild or more severe diarrhea with higher doses. The concentration needed to trigger or worsen diarrhea episodes was estimated to be 120-fold lower in combination therapy compared to monotherapy, suggesting strong synergy between the two monoclonal antibodies. The prophylactic effect of loperamide in a subset of patients was also well captured by the model with a clear tendency to reduce the occurrence of diarrhea events.

Conclusions

This work shows that PK-toxicity modeling provides insight into how the severity of key adverse events evolves over time and highlights the potential use to support decision making in drug development.

https://ift.tt/2LbAIKN

A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies

Abstract

Purpose

To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.

Methods

Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine C_max, and AUC. Patients remained on study until progressive disease or unacceptable AEs.

Results

In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.

Conclusions

For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.

https://ift.tt/2MEmAyt

A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

Abstract

Purpose

Belinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide.

Methods

The PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelosuppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data.

Results

Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle.

Conclusions

This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.

https://ift.tt/2Ps4RJd

A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer

Abstract

Purpose

The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer.

Methods

Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model.

Results

Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1.

Conclusions

Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.

https://ift.tt/2OXQfQX

Natural low- and high-density lipoproteins as mighty bio-nanocarriers for anticancer drug delivery

Abstract

Lipoproteins (LPs) are a set of naturally occurring bio-nanoparticles consisting of Apo-LPs, phospholipids, a highly hydrophobic core of cholesteryl esters and triglycerides that participate mainly in the targeted transport of cholesteryl esters and other hydrophobic molecules through the bloodstream. They also are able to recognize specific receptors on normal and abnormal cells. Therefore, LPs represent a relevant tool for targeted delivery of cancer diagnostics and therapeutics due to their native biocompatibility, biodegradability, nano-scale size and receptor-mediated uptake. The circulating LPs are categorized into five classes, each with its own characteristic protein and lipid composition. Low-density LPs (LDL) and high-density LPs (HDL) are two major subclasses of LPs which were extensively subjected to attractive and versatile vehicles for targeted delivery of anticancer drugs. This study focus to highlight the potential applications of LDL and HDL bio-nanocarriers in the field of specific target drug delivery to cancer cells.

https://ift.tt/2MpsNiK

Genetic polymorphisms in cyclin H gene are associated with oxaliplatin-induced acute peripheral neuropathy in South Indian digestive tract cancer patients

Abstract

Purpose

Digestive tract cancer patients treated with oxaliplatin are often associated with the development of peripheral neuropathy. The aim of the present study is to identify the influence of single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, cell cycle control, detoxification or excretion pathways with the development of oxaliplatin-induced acute peripheral neuropathy (acute OXAIPN) and its severity among digestive tract cancer patients treated with oxaliplatin-based chemotherapy.

Patients and methods

A total of 228 digestive tract cancer patients undergoing with the oxaliplatin-based chemotherapy between November 2014 and December 2016 were included in the current study. Genomic DNA was extracted from peripheral blood by standard phenol–chloroform method. Genotyping of five SNPs in four genes [GSTP₁ (rs1965), ABCG2 (rs3114018), CCNH (rs2230641, rs3093816), AGXT (rs4426527)] was carried out by Real-Time TaqMan SNP genotyping assay.

Results

We found that the two genetic variants rs2230641 and rs3093816 in cyclin H (CCNH) gene were significantly associated with both the incidence and severity of acute OXAIPN. For CCNH-rs2230641 (AA vs AG+GG; dominant model) Incidence: OR 2.62, 95% CI 1.44–4.75, p = 0.001, severity; OR 4.64, 95% CI 1.58–13.62, p = 0.002. For CCNH-rs3093816 (AA vs AG+GG; dominant model); incidence: OR 3.43, 95% CI 1.57–7.50, p = 0.001; severity: OR 2.36, 95% CI 1.05–5.30, p = 0.033.

Conclusions

The results of the present study found significant association between CCNH polymorphisms and acute OXAIPN development. However, further studies are warranted from independent groups to validate our study results.

https://ift.tt/2ORhEnx

Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer

Abstract

Purpose

Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer.

Methods

MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model.

Results

The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone.

Conclusions

The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.

https://ift.tt/2MnPy6q

The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment

Abstract

Background

The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Elucidation of the LNM associated genomic alteration and underlying molecular mechanisms may provide clinical therapeutic strategies for ESCC treatment.

Methods

Joint analysis of ESCC sequencing data were conducted to comprehensively survey SCNAs and identify driver genes which significantly associated with LNM. The roles of miR-548k in lymphangiogensis and lymphatic metastasis were validated both in vitro and in vivo. ESCC tissue and blood samples were analyzed for association between miR-548k expression and patient clinicopathological features and prognosis and diagnosis.

Results

In the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions. Clinical implication analysis revealed a panel of genes associated with LNM with the most frequently amplified gene being MIR548K harbored in the 11q13.3 amplicon. Overexpression of miR-548k remarkably promotes lymphangiogenesis and lymphatic metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-548k modulating the tumor microenvironment by promoting VEGFC secretion and stimulating lymphangiogenesis through ADAMTS1/VEGFC/VEGFR3 pathways, while promoting metastasis by regulating KLF10/EGFR axis. Importantly, we found that serum miR-548k and VEGFC of early stage ESCC patients were significantly higher than that in healthy donators, suggesting a promising application of miR-548k and VEGFC as biomarkers in early diagnosis of ESCC.

Conclusions

Our study comprehensively characterized SCNAs in ESCC and highlighted the crucial role of miR-548k in promoting lymphatic metastasis, which might be employed as a new diagnostic and prognostic marker for ESCC.

https://ift.tt/2MAEJ0n

SABCS 2017: lifestyle factors, hormone receptor-positive advanced disease, liquid biopsies, and prognosis

Summary

This article reviews the clinically most relevant presentations at the San Antonio Breast Cancer Symposium (SABCS) 2017 on the topics lifestyle factors, hormone receptor-positive advanced disease, liquid biopsies, and prognosis.

In a retrospective analysis of the Women's Health Initiative Observational Study, a reduction in the body mass index (BMI) of at least 5% within 3 years significantly reduced the risk of breast cancer compared to women with a stable weight (HR 0.77; 95% CI 0.78–0.98). In the MONALEESA-7 trial investigating ribociclib or placebo in combination with endocrine therapy as first-line treatment in pre- and perimenopausal women with hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer, a significantly longer progression-free survival was shown for patients treated with ribociclib compared to the placebo group (23.8 vs. 13.0 months; HR 0.55; 95% CI 0.43–0.72; P < 0.001). In a pooled toxicity and efficacy analysis of elderly women treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in combination with an aromatase inhibitor in first-line, toxicities of higher grade were more common in elderly compared to younger patients, despite comparable efficacy. And the Clinical Treatment Score post-5 years (CTS5), accurately estimated the risk of late recurrence after 5 years of adjuvant endocrine treatment using routinely available clinical parameters.

https://ift.tt/2OSpDRm

The effects of instrumental action on perceptual hand maps

Abstract

Perceiving the external spatial location of body parts using position sense requires that immediate proprioceptive afferent signals be integrated with information about body size and shape. Longo and Haggard (Proc Natl Acad Sci 107:11727–11732, 2010) developed a method to measure perceptual hand maps reflecting this metric information about body size and shape. In this paradigm, participants indicate the perceived location of landmarks on their occluded hand by pointing with a long baton held in their other hand. By comparing the relative location of judgments of different hand landmarks, perceptual hand maps can be constructed and compared to actual hand structure. The maps show large and highly stereotyped distortions. Here, I investigated the potential effect of biases related to active motor control of the hand doing the pointing in these distortions. Participants localized the fingertip and knuckle of each finger on their occluded left hand either by actively pointing with a baton held in their right hand (pointing condition) or by giving verbal commands to an experimenter on how to move the baton (verbal condition). Similar distortions were clearly apparent in both conditions, suggesting that they are not an artifact of motor control biases related to the pointing hand.

https://ift.tt/2PtfSKf