Purpose:Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. Patients and Methods:Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s)...
Fri Sep 13, 2019 10:05
Purpose:Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy. Experimental Design: Isogenic ARID1A–/– and wild-type cell lines were used for assessing DNA damage response, DNA compactness,...
Fri Sep 13, 2019 10:05
Purpose:Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC. Patients and Methods:Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400–800 mg and trametinib 1–2 mg daily. Efficacy in the expansion cohort...
Fri Sep 13, 2019 10:05
Purpose:Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized. Experimental Design: We performed integrated whole-exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)]. Results:CRT was not associated with increased...
Fri Sep 13, 2019 10:05
Purpose:Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule...
Fri Sep 13, 2019 10:05
Purpose:The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results:Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset...
Fri Sep 13, 2019 10:05
Purpose:STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFβ family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455). Patients and Methods:Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation...
Fri Sep 13, 2019 10:05
Purpose:Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of...
Fri Sep 13, 2019 10:05
Both immune checkpoint inhibitors (ICI) and antiangiogenesis agents have changed the landscape of cancer treatment in the modern era. While antiangiogenesis agents have demonstrated activities in tumors with high vascularization, including renal cell carcinoma and colorectal cancer, the effect of ICIs has been seen mainly in immunologically recognized tumors, with highly immune-infiltrative lymphocytes. The main challenge in the drug development of ICIs is moving their activities to noninflamed tumors...
Fri Sep 13, 2019 10:05
Purpose:TP53 mutations are highly prevalent in head and neck squamous cell carcinoma (HNSCC) and associated with increased resistance to conventional treatment primarily consisting of chemotherapy and radiation. Restoration of wild-type p53 function in TP53-mutant cancer cells represents an attractive therapeutic approach and has been explored in recent years. In this study, the efficacy of a putative p53 reactivator called COTI-2 was evaluated in HNSCC cell lines with different TP53 status. Experimental...
Fri Sep 13, 2019 10:05
Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibody–drug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the toxicity...
Fri Sep 13, 2019 10:05
Purpose:CD19 chimeric antigen receptor (CAR)-T therapy has shown impactful results in treatment of B-cell malignancies. However, immune recognition of the murine scFv may render subsequent infusion(s) ineffective. Also, nonselective expansion of both CAR-transduced and nontransduced T cells during the production stage affects the yield and purity of final products. Here, we aim to develop a humanized selective (hs) CD19 CAR to solve the above problems. Experimental Design: A CD19 hsCAR was designed,...
Fri Sep 13, 2019 10:05
The MERIT study was a single-arm, phase II clinical trial of nivolumab for the second- or third-line treatment of patients with malignant pleural mesothelioma in Japan. MERIT confirmed that PD-1 inhibition has activity in mesothelioma and led to the regulatory approval of nivolumab for the treatment of mesothelioma in Japan. See related article by Okada et al., p. 5485
Fri Sep 13, 2019 10:05
Purpose:Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that is broadly chemoresistant, due in part to biophysical properties of tumor stroma, which serves as a barrier to drug delivery for most classical chemotherapeutic drugs. The goal of this work is to evaluate the preclinical efficacy and mechanisms of PTC596, a novel agent with potent anticancer properties in vitro and desirable pharmacologic properties in vivo. Experimental Design: We assessed the pharmacology, mechanism, and preclinical...
Fri Sep 13, 2019 10:05
No immunotherapy strategy is yet offering consistent results against pancreatic ductal adenocarcinoma. A randomized clinical trial testing repeated immunization with a Listeria monocytogenes–based vaccine encoding for mesothelin in combination with a GM-CSF–transfected allogeneic pancreatic cell vaccine reports no survival benefit for the vaccinated patients. See related article by Le et al., p. 5493
Fri Sep 13, 2019 10:05
Purpose:To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence. Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver...
Fri Sep 13, 2019 10:05
Adult granulosa cell tumor (AGCT) is a rare malignancy characterized by FOXL2 (C134W) mutation, an inherent component of the TGFβ pathway. Activin A, a TGFβ superfamily member, is a driver of this activity and is a potential target in AGCT. See related article by Tao et al., p. 5458
Fri Sep 13, 2019 10:05
Purpose:Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. Experimental Design:...
Fri Sep 13, 2019 10:05
Fri Sep 13, 2019 10:05
Purpose:DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer. Experimental Design: DNA-PK function was...
Fri Sep 13, 2019 10:05
Abstract Glucosamine (GlcN) is an amine sugar, in which a hydroxyl group of glucose is replaced with an amino group. It is an important part of the polysaccharides chitin and chitosan and is highly hydrophilic. It is also an important compound required for the formation of cartilage cells and represents one of the elementary units of the cartilage matrix and joint fluid. GlcN has been widely used in food, cosmetics, health care, and pharmaceutical industries. This paper fully...
Fri Sep 13, 2019 11:56
Abstract The synthesis of rhamnosylated compounds has gained great importance since these compounds have potential therapeutic applications. The enzymatic approaches for glycosylation of bioactive molecules have been well developed; however, the enzymatic rhamnosylation has been largely hindered by lacking of the glycosyl donor for rhamnosyltransferases. Here, we employed an α-l-rhamnosidase from Alternaria sp. L1 (RhaL1) to perform one-step rhamnosylation of anticancer drugs,...
Fri Sep 13, 2019 11:56
The name of the author “Yamaguchi Tokutaro” is incorrect for the first and last name has been interchanged. The correct presentation is “Tokutaro Yamaguchi”.
Fri Sep 13, 2019 11:56
Abstract Sensitive and rapid methods for determining viral contamination of water are critical, since illness can be caused by low numbers of viruses and bacterial indicators do not adequately predict viral loads. We developed novel rapid assays for detecting the viral water quality indicator human adenovirus (HAdV). A simple 15-min recombinase polymerase amplification step followed by a 5-min lateral flow detection is used. Species-specific assays were developed to discriminate...
Fri Sep 13, 2019 11:56
Abstract Acidithiobacillus thiooxidans (A. thiooxidans) is a widespread, mesophilic, obligately aerobic, extremely acidophilic, rod-shaped, and chemolithoautotrophic gram-negative gammaproteobacterium. It can obtain energy and electrons from the oxidation of reducible sulfur, and it can fix carbon dioxide and assimilate nitrate, nitrite, and ammonium to satisfy carbon and nitrogen requirement. This bacterium exists as different genomovars and its genome size range from 3.02 to...
Fri Sep 13, 2019 11:56
Abstract As a highly valued fungus, Cordyceps militaris has been widely used all over the world. Although the wild resources of C. militaris are limited, the fruiting bodies of C. militaris have been successfully cultivated on a large-scale. However, the high-frequency degeneration of C. militaris during subculture and preservation seriously limits the development of the C. militaris industry. How to solve the degeneration of C. militaris has become an unsolved bottleneck problem...
Fri Sep 13, 2019 11:56
Abstract Chinese hamster ovary (CHO) cells are commonly used for the production of monoclonal antibodies. Omics technologies have been used to elucidate cellular switch points which result in higher monoclonal antibody (mAb) productivity and process yields in CHO and other biopharmaceutical production cell lines such as human or mouse. Currently, investigations of the phosphoproteome in CHO cell lines are rare yet could provide further insights into cellular mechanisms related...
Fri Sep 13, 2019 11:56
Abstract Infant acute lymphoblastic leukemias (ALL) are rare hematological malignancies occurring in children younger than 1 year of age, most frequently associated with KMT2A rearrangements (KMT2A‐r). The smaller subset without KMT2A‐r, which represents 20% of infant ALL cases, is poorly characterized. Here we report two cases of chemotherapy‐sensitive non KMT2A‐r infant ALL. Transcriptome analyses revealed identical ACIN1‐NUTM1 gene fusions in both cases, derived from cryptic chromosomal rearrangements...
Thu Sep 12, 2019 20:10
Abstract Neuroblastoma, the most common extracranial solid tumor of childhood, can present in multiple primary sites, but the extent of genetic heterogeneity among tumor foci, as well as the presence or absence of common oncogenic drivers, remains unknown. Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development....
Thu Sep 12, 2019 20:13
Abstract MicroRNAs (miRNAs) play important roles in prostate cancer development. However, it remains unclear how individual miRNAs contribute to the initiation and progression of prostate cancer. Here we show that a basal layer‐enriched miRNA is required for prostate tumorigenesis. We identify miR‐205 as the most highly expressed miRNA and enriched in the basal cells of the prostate. Although miR‐205 is not required for normal prostate development and homeostasis, genetic deletion of miR‐205 in...
Thu Sep 12, 2019 13:17
Abstract Ovarian cancer is the most lethal gynecologic malignancy due to the lack of symptoms until advanced stages, and new diagnosis and treatment strategy is in urgent need. In this study, we found higher expression of miR‐19a‐3p in ovarian cancer tissues compared with that in the adjacent normal tissues. By chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) analysis, we showed that nuclear factor‐kappaB (NF‐κB) binds to the promoter of miR‐19a‐3p, leading to...
Thu Sep 12, 2019 16:14
Abstract As mouse double minute 4 (MDM4) and HPV16 E6 oncoproteins play important roles in inhibition of p53 activity, a functional polymorphism (rs4245739) in the 3′ untranslated regions of MDM4 targeted by microRNA‐191 may alter its expression level or functional efficiency, thus affecting tumor status and survival in human papillomavirus (HPV)‐positive squamous cell carcinoma of oropharynx (SCCOP). A total of 564 incident SCCOP patients with definitive radiotherapy were included for determination...
Thu Sep 12, 2019 16:14
Abstract Fatigue arises during everyday activities, diminishes movement performance, and increases injury risk. Physical (PE) and cognitive exertion (CE) can induce similar feelings of fatigue, but it is not clear whether these also similarly affect movement performance. Therefore, this study examined the influence of PE and CE on anticipatory postural adjustments (APAs) of trunk muscles, which are feedforward mechanisms that contribute to motor control and controlled movement....
Fri Sep 13, 2019 03:00
Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. Objective: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. Methods: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system...
Fri Sep 13, 2019 11:54
Reed beds represent an important habitat for the survival of birds by providing favorable foraging and reproduction conditions. Reed management, as a traditional agricultural activity, primarily includes water level control and vegetation removal by cutting. Red-crowned crane (Grus japonensis) is one of the most endangered cranes, and their population continues to decline due to habitat loss caused by artificial activities. A lack of research relating to how reed management affects crane habitat...
Fri Sep 13, 2019 03:00
Over half of all extant stony corals (Cnidaria: Anthozoa: Scleractinia) harbour endosymbiotic dinoflagellates of the family Symbiodiniaceae, forming the foundational species of modern shallow reefs. However, whether these associations are conserved on the coral phylogeny remains unknown. Here we aim to characterise Symbiodiniaceae communities in eight closely-related species in the genera Merulina, Goniastrea and Scapophyllia, and determine if the variation in endosymbiont community structure can...
Fri Sep 13, 2019 03:00
Chromatin contacts between regulatory elements are of crucial importance for the interpretation of transcriptional regulation and the understanding of disease mechanisms. However, existing computational methods mainly focus on the prediction of interactions between enhancers and promoters, leaving enhancer-enhancer (E-E) interactions not well explored. In this work, we develop a novel deep learning approach, named Enhancer-enhancer contacts prediction (EnContact), to predict E-E contacts using genomic...
Fri Sep 13, 2019 03:00
Allopolyploidy is an evolutionary and mechanisticaly intriguing process involving the reconciliation of two or more sets of diverged genomes and regulatory interactions, resulting in new phenotypes. In this study, we explored the small RNA changes of eight F2 synthetic B. napus using small RNA sequencing. We found that a part of miRNAs and siRNAs were non-additively expressed in the synthesized B. napus allotetraploid. Differentially expressed miRNAs and siRNAs differed among eight F2 individuals,...
Fri Sep 13, 2019 03:00
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου