tbuckley/cabot-search huggingface dataset:
Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer
Authors: Ming Zhao, Stephen Scott, Kurt W. Evans, Erkan Yuca, Turcin Saridogan, Xiaofeng Zheng, Heping Wang, Anil Korkut, Christian X. Cruz Pico, Mehmet Demirhan, Bryce Kirby, Scott Kopetz, Irmina Diala, Alshad S. Lalani, Sarina Piha-Paul, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA approved for HER2-overexpressing/amplified (HER2+) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2+ cancers in vitro and in vivo. Experimental Design: Cell viability, colony formation assays, and Western blotting were used to determine the effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDX): two breast, two colorectal, and one esophageal cancer (with HER2 mutations). Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through reverse phase protein arrays and network-level adaptive responses were assessed through Target Score algorithm. Results: In HER2+ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors everolimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Kα inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2+ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1/4) and 60% (3/5) of models, respectively, while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR, and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib. Conclusions: Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR, and MEK inhibitors for the treatment of HER2+ cancer.
Risk-Based Selection of Individuals for Oral Cancer Screening
Authors: Li C. Cheung, Kunnambath Ramadas, Richard Muwonge, Hormuzd A. Katki, Gigi Thomas, Barry I. Graubard, Partha Basu, Rengaswamy Sankaranarayanan, Thara Somanathan, Anil K. Chaturvedi
Journal: Journal of Clinical Oncology (2021)

PURPOSE: We evaluated proof of principle for resource-efficient, risk-based screening through reanalysis of the Kerala Oral Cancer Screening Trial. METHODS: The cluster-randomized trial included three triennial rounds of visual inspection (seven clusters, n = 96,516) versus standard of care (six clusters, n = 95,354) and up to 9 years of follow-up. We developed a Cox regression–based risk prediction model for oral cancer incidence. Using this risk prediction model to adjust for the oral cancer risk imbalance between arms, through intention-to-treat (ITT) analyses that accounted for cluster randomization, we calculated the relative (hazard ratios [HRs]) and absolute (rate differences [RDs]) screening efficacy on oral cancer mortality and compared screening efficiency across risk thresholds. RESULTS: Oral cancer mortality was reduced by 27% in the screening versus control arms (HR = 0.73; 95% CI, 0.54 to 0.98), including a 29% reduction in ever-tobacco and/or ever-alcohol users (HR = 0.71; 95% CI, 0.51 to 0.99). This relative efficacy was similar across oral cancer risk quartiles ( P interaction = .59); consequently, the absolute efficacy increased with increasing model-predicted risk—overall trial: RD in the lowest risk quartile (Q1) = 0.5/100,000 versus 13.4/100,000 in the highest quartile (Q4), P trend = .059 and ever-tobacco and/or ever-alcohol users: Q1 RD = 1.0/100,000 versus Q4 = 22.5/100,000; P trend = .026. In a population akin to the Kerala trial, screening of 100% of individuals would provide 27.1% oral cancer mortality reduction at number needed to screen (NNS) = 2,043. Restriction of screening to ever-tobacco and/or ever-alcohol users with no additional risk stratification would substantially enhance efficiency (43.4% screened for 23.3% oral cancer mortality reduction at NNS = 1,029), whereas risk prediction model–based screening of 50% of ever-tobacco and/or ever-alcohol users at highest risk would further enhance efficiency with little loss in program sensitivity (21.7% screened for 19.7% oral cancer mortality reduction at NNS = 610). CONCLUSION: In the Kerala trial, the efficacy of oral cancer screening was greatest in individuals at highest oral cancer risk. These results provide proof of principle that risk-based oral cancer screening could substantially enhance the efficiency of screening programs.
Proteasome inhibitor MG-132 induces p27Kip1 expression through SKP2 degradation in diffuse large B cell lymphoma
Authors: Shahab Uddin, Azhar Hussain, Maqbool Ahmed, Asma Khan, Prashant Bavi, Khawla Al-Kuraya
Journal: Cancer Research (2008)

3331  Diffuse Large B-cell lymphoma (DLBCL) is considered to be the most common type of lymphoma in adults, accounting for 30-40 percent of cases of non-Hodgkin’s lymphoma. Although patients with DLBCLs are potentially curable with combination chemotherapy, the disease proves fatal in approximately 50 % of patients. The cause of most DLBCLs remains unknown, however several studies suggest that dysregulated survival/apoptosis or defective repair pathways have been implicated. Recently proteasome pathway has implicated in its role in a variety of cancers. S-phase kinase associated protein (SKP2), a member of F-box family, is the substrate-recognition sub-unit of the SKP2 ubiquitin ligase complex. SKP2 has been shown to degrade the cyclin-dependent kinase (CDK) inhibitor p27KIP1and positive regulator of cell cycle. Several studies implicated that SKP2 play role in oncogenesis of a variety of tumor including lymphomas. We vestigated the role of SKP2 and its ubiquitin-proteasome pathway in DLBL using a panel of cell lines and clinical samples. MG132, a reversible and specific inhibitor of ubiquitin-proteasome pathway that acts through blocking ubiquitin-mediated proteolysis via binding to 20S and 26S proteasomes. Our study showed that treatment of DLBCL cell lines (SUDHL4, SUDHL5, SUDHL8 and OCILY19) with MG132 suppressed growth and induced apoptosis. Treatment of DLBCL cells with MG132 caused downregulation of SKP2, accumulation and stabilization of p27KIP1 leading to the apoptosis. Further downstream, MG132 induced activation of caspase-8 and cleavage of Bid subsequently leading to loss of mitochondrial membrane potential and release of cytochrome c from mitochondria into cytosol, resulting in activation of caspase-3 and cleavage of PARP. zVAD-fmk, a universal inhibitor of caspases prevented caspase-3 activation and abrogated apoptosis induced by MG132 treatment. Finally, using immunohistochemistry, SKP2 was detected in 94 (32.9%) of 286 DLBCL tumors. Furthermore, patients with high SKP2 expression were associated with high expression of Ki67, a proliferative marker. Altogether, these results suggest that SKP2 and ubiquitin-proteasome pathway may be a potential target for therapeutic intervention in diffuse large B-cell lymphoma.
MicroPhenoDB Associates Metagenomic Data with Pathogenic Microbes, Microbial Core Genes, and Human Disease Phenotypes
Authors: Guocai Yao, Wenliang Zhang, Minglei Yang, Huan Yang, Jianbo Wang, Haiyue Zhang, Lai Wei, Zhi Xie, Weizhong Li
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Microbes play important roles in human health and disease. The interaction between microbes and hosts is a reciprocal relationship, which remains largely under-explored. Current computational resources lack manually and consistently curated data to connect metagenomic data to pathogenic microbes, microbial core genes, and disease phenotypes. We developed the MicroPhenoDB database by manually curating and consistently integrating microbe-disease association data. MicroPhenoDB provides 5677 non-redundant associations between 1781 microbes and 542 human disease phenotypes across more than 22 human body sites. MicroPhenoDB also provides 696,934 relationships between 27,277 unique clade-specific core genes and 685 microbes. Disease phenotypes are classified and described using the Experimental Factor Ontology (EFO). A refined score model was developed to prioritize the associations based on evidential metrics. The sequence search option in MicroPhenoDB enables rapid identification of existing pathogenic microbes in samples without running the usual metagenomic data processing and assembly. MicroPhenoDB offers data browsing, searching, and visualization through user-friendly web interfaces and web service application programming interfaces. MicroPhenoDB is the first database platform to detail the relationships between pathogenic microbes, core genes, and disease phenotypes. It will accelerate metagenomic data analysis and assist studies in decoding microbes related to human diseases. MicroPhenoDB is available through http://www.liwzlab.cn/microphenodb and http://lilab2.sysu.edu.cn/microphenodb.
Abstract 13405: Genetic Deletion of Stimulator of Interferon Genes Attenuates Atherogenesis in Apolipoprotein E-deficient Mice
Authors: Phuong T Pham, Daiju Fukuda, Masataka Sata
Journal: Circulation (2020)

Introduction: Recent studies show the contribution of innate immunity system to the pathogenesis of inflammatory diseases, including atherosclerosis. Stimulation of interferon genes (STING), originally known as a cytosolic DNA sensor, recognizes cytosolic DNA fragments, activating innate immunity. Here, we investigated whether STING contributes to the development of vascular inflammation and atherogenesis in apolipoprotein E-deficient (Apoe –/– ) mice. Methods and Results: The expression of STING increased in the atherosclerotic aorta in both gene and protein expression levels. STING-deficient Apoe –/– (STING –/– Apoe –/– ) mice reduced atherosclerotic lesions in the aortic arch ( P &lt;0.05), along with the reduction of lipid and macrophage accumulation in atherosclerotic plaques ( P &lt;0.05, respectively), and inflammatory molecule expression in the aorta compared with those in Apoe –/– mice after 20 weeks on a western-type diet. Also, pharmacologic blockade of STING in Apoe –/– mice for 12 weeks treatment attenuated atherogenesis in the aortic arch ( P &lt;0.05), reduced the accumulation of lipid in atherosclerotic plaques ( P &lt;0.05) with no alteration of metabolic parameters. Restoration of STING in bone marrow in STING –/– Apoe –/– mice promoted atherogenesis ( P &lt;0.05), lipid deposition ( P &lt;0.05), and vascular inflammation. cGAMP, a specific STING agonist, or mitochondrial DNA extracted from macrophages promoted expression of inflammatory molecules more effectively in Apoe -/- macrophages than in STING –/– Apoe –/– macrophages, while C-176, a specific STING inhibitor, attenuated these inflammatory responses. The results of western blotting showed the involvement of NF-κB and IRF-3 signaling in STING-associated vascular inflammation and macrophage activation. Furthermore, in humans, STING expression was confirmed in atherosclerotic lesions in the carotid artery. Conclusion: STING signaling activates macrophages, promotes vascular inflammation and atherosclerosis in Apoe -/- mice. Our results suggest that STING may serve as a potential therapeutic target for atherosclerosis.
Vitamin D—Liver Disease Association: Biological Basis and Mechanisms of Action
Authors: Christos Triantos, Ioanna Aggeletopoulou, Konstantinos Thomopoulos, Athanasia Mouzaki
Journal: Hepatology (2021)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Poorer Clinical Outcomes for Black Patients with AML: A Wake-Up Call for Better Data and Greater Understanding of Cancer Outcomes in All Ethnic Groups
Authors: Paresh Vyas
Journal: Cancer Discovery (2021)

In this issue of Cancer Discovery, Bhatnagar and colleagues show that Black patients in the United States with acute myeloid leukemia have a shorter survival compared with white patients. This is an important paper as it addresses an under researched issue: the complex interaction of race, tumor genetics, socioeconomic factors, and access to treatment in defining treatment outcomes for a devastating cancer.See related article by Bhatnagar et al., p. 626.
A child with multiple hypopigmented lesions
Authors: Ruojun Wang, Zhimiao Lin
Journal: BMJ (2021)

A 3 year old girl presented with multiple hypopigmented body lesions that had been present since birth. On examination, about 20 pale macules and patches were visible on her trunk and neck. The lesions showed limited vascularisation after rubbing, which is a characteristic feature of naevus anaemicus (fig 1). She also had about 30 café au lait macules (CALMs)—well demarcated, brown macules on the trunk and neck (0.2 cm to 1 cm in diameter) (fig 1). The patient was otherwise healthy. Fig 1 Multiple naevus anaemicus and café au lait macules on back of a 3 year old girl Molecular testing of the NF1 gene showed a heterozygous nonsense variation of c.4537C>T (p.R1513*).
Out‐of‐the‐Box Nanocapsules Packed with On‐Demand Hydrophobic Anticancer Drugs for Lung Targeting, Esterase Triggering, and Synergy Therapy
Authors: Di Zhao, Kai Jiang, Yuqi Wang, Jin Cheng, Fangli Mo, Tao Luo, Yuanyuan Guo, Chuan Zhang, Jie Song
Journal: Advanced Healthcare Materials (2021)

Abstract Most anticancer drugs, particularly paclitaxel (PTX), are suffering the challenges of cancer chemotherapy due to their poor water‐solubility, high toxicity under effective therapeutic dosages, and multi‐drug resistance. Currently, nanoscale drug delivery systems (DDSs) represent an efficient platform to overcome the above challenges. However, those DDSs generally need a careful design of conjugation, complexation, or co‐self‐assembly. Herein, a facile out‐of‐the‐box nanocapsule is developed not only to be easily packed with on‐demand hydrophobic anticancer drugs (up to 76% of loading efficiency for PTX), but also to be loaded with other concomitant drugs for synergy therapy (Itraconazole (ITA) here as P‐glycoprotein inhibitor for drug resistance and antiangiogenic agent for combination therapy with PTX). Three kinds of biocompatible poly(ethylene glycol) dimethacrylates (PEGDM) derivatives usually as cross‐linking agents are selected and successfully constructed adequate nanocapsules with single monomer as shell materials. More importantly, as‐prepared nanocapsules have abilities of esterase triggering and lung targeting. Both in vitro and in vivo studies showed that the drug‐loaded nanocapsules can effectively inhibit tumor growth and vascular proliferation in PTX‐resistant tumor models without apparent systemic toxicity. The above results demonstrate that the nanocapsule system provides an effective and universal strategy for lung targeting, esterase triggering, and synergy therapy.
The aryl hydrocarbon receptor and the gut–brain axis
Authors: Andreia Barroso, João Vitor Mahler, Pedro Henrique Fonseca-Castro, Francisco J. Quintana
Journal: Cellular and Molecular Immunology (2021)

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified as the receptor for dioxin. Almost half a century after its discovery, AHR is now recognized as a receptor for multiple physiological ligands, with important roles in health and disease. In this review, we discuss the role of AHR in the gut–brain axis and its potential value as a therapeutic target for immune-mediated diseases.
MO01.21 Phase 2 GEOMETRY Mono-1 Study: Capmatinib in Patients with METex14-mutated Advanced Non-Small Cell Lung Cancer who Received Prior Immunotherapy
Authors: R.S. Heist, J. Vansteenkiste, E. Smit, H. Groen, E. Garon, T. Hida, M. Nishio, K. Kokowski, C. Grohe, N. Reguart, A. Mansfield, A. Robeva, S. Ghebremariam, M. Waldron-Lynch, M. Akimov, N. Nwana, M. Giovannini, J. Wolf
Journal: Journal of Thoracic Oncology (2021)
Effect of non-uniform cyst distribution in lymphangioleiomyomatosis on pulmonary function: a cross-sectional study
Authors: Amir M. Hasani, Brianna Matthew, Mahshid Goljamali, Yun-Ching Chen, Mario Stylianou, Mehdi Pirooznia, Angelo Taveira-DaSilva, Marcus Y. Chen, Han Wen, Joel Moss
Journal: European Respiratory Journal (2021)

<b>Cysts in LAM patients tend to be more concentrated in the middle half of the lungs. FEV<sub>1</sub> but not <i>D</i><sub>LCO</sub> is influenced by cyst distribution.</b>https://bit.ly/3p8z9CF
Location is everything when it comes to megakaryocyte function
Authors: Eric Boilard, Kellie R. Machlus
Journal: Journal of Clinical Investigation (2021)

Megakaryocytes (MKs) give rise to platelets, which are blood cells that are essential to prevent hemorrhage. Although the majority of MKs localize to the bone marrow, there is a distinct population of lung-residing MKs (MKL). In this issue of the JCI, Pariser et al. examined gene expression patterns of MKs collected from murine and nonhuman primate bone marrow or lung. This Commentary explores the premise that environmental factors from the lung determine the genetic and phenotypic similarity of MKL to lung dendritic cells, distinguishing MKL from bone marrow MKs. Indeed, while MKL retain the ability to make platelets, they also process and present antigens that activate CD4+ lymphocytes. These data suggest that MKL may play an important role in immune processes beyond platelet production.
Offline: The cosmopolitan state
Authors: Richard Horton
Journal: The Lancet (2021)

Britain feels broken. Broken by COVID-19. Broken by Brexit. Broken by the lies that have been dripped into British political debates these past 5 years. Those scientists and doctors who voted to remain in the European Union—perhaps based on a belief in the public value of research and clinical networks that have been painstakingly built over half a century between the UK and its European neighbours—were accused of Project Fear. But now that the UK has finally left the EU, with the thinnest of thin deals, one can look back and say that the arguments to leave were themselves based on nothing but fear—fear of European expansion, fear of the costs of EU membership, fear of immigration, fear of the Euro, and fear of the European Court of Justice.
COVID-19 Trends Among Persons Aged 0–24 Years — United States, March 1–December 12, 2020
Authors: Eva Leidman, Lindsey M. Duca, John D. Omura, Krista Proia, James W. Stephens, Erin K. Sauber-Schatz
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Coronavirus disease 2019 (COVID-19) case and electronic laboratory data reported to CDC were analyzed to describe demographic characteristics, underlying health conditions, and clinical outcomes, as well as trends in laboratory-confirmed COVID-19 incidence and testing volume among U.S. children, adolescents, and young adults (persons aged 0-24 years).This analysis provides a critical update and expansion of previously published data, to include trends after fall school reopenings, and adds preschool-aged children (0-4 years) and college-aged young adults (18-24 years) (1).Among children, adolescents, and young adults, weekly incidence (cases per 100,000 persons) increased with age and was highest during the final week of the review period (the week of December 6) among all age groups.Time trends in weekly reported incidence for children and adolescents aged 0-17 years tracked consistently with trends observed among adults since June, with both incidence and positive test results tending to increase since September after summer declines.Reported incidence and positive test results among children aged 0-10 years were consistently lower than those in older age groups.To reduce community transmission, which will support schools in operating more safely for in-person learning, communities and schools should fully implement and strictly adhere to recommended mitigation strategies, especially universal and proper masking, to reduce COVID-19 incidence.Children, adolescents, and young adults were stratified into five age groups: 0-4, 5-10, 11-13, 14-17, and 18-24 years to align with educational groupings (i.e., pre-, elementary, middle, and high schools, and institutions of higher education), and trends in these groups were compared with those in adults aged ≥25 years.Confirmed COVID-19 cases, defined as positive real-time reverse transcription-polymerase chain reaction (RT-PCR) test results for SARS-CoV-2, the virus that causes COVID-19, were identified from individual-level case reports submitted by state and territorial health departments during March 1-December 12, 2020.*COVID-19 case data for all confirmed cases were analyzed to * CDC official counts of COVID-19 cases and deaths, released daily at https:// www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html, are aggregate counts from reporting jurisdictions.Individual-level case report data were available for approximately 75% of the aggregate number of confirmed cases.Cases reported without sex or age data and in persons repatriated to the United States from Wuhan, China, or the Diamond Princess cruise ship were excluded from this analysis.
Negligible risk of zoonotic anisakid nematodes in farmed fish from European mariculture, 2016 to 2018
Authors: Maria Letizia Fioravanti, Andrea Gustinelli, George Rigos, Kurt Buchmann, Monica Caffara, Santiago Pascual, Miguel Ángel Pardo
Journal: Eurosurveillance (2021)

Background The increasing demand for raw or undercooked fish products, supplied by both aquaculture and fisheries, raises concerns about the transmission risk to humans of zoonotic fish parasites. This has led to the current European Union (EU) Regulation No 1276/2011 amending Annex III of Regulation (EC) No 853/2004 and mandating a freezing treatment of such products. Zoonotic parasites, particularly anisakid larvae, have been well documented in wild fish. Data on their presence in European aquaculture products, however, are still scarce, except for Atlantic salmon ( Salmo salar ), where the zoonotic risk was assessed as negligible, exempting it from freezing treatment. Aim To evaluate the zoonotic Anisakidae parasite risk in European farmed marine fish other than Atlantic salmon. Methods From 2016 to 2018 an observational parasitological survey was undertaken on 6,549 farmed fish including 2,753 gilthead seabream ( Sparus aurata ), 2,761 European seabass ( Dicentrarchus labrax ) and 1,035 turbot ( Scophthalmus maximus ) from 14 farms in Italy, Spain and Greece. Furthermore, 200 rainbow trout ( Oncorhynchus mykiss ) sea-caged in Denmark, as well as 352 seabream and 290 seabass imported in Italy and Spain from other countries were examined. Fish were subjected to visual inspection and candling. Fresh visceral organs/fillet samples were artificially digested or UV pressed and visually examined for zoonotic anisakid larvae. Results No zoonotic parasites were found in any of the fish investigated. Conclusions The risk linked to zoonotic Anisakidae in the examined fish species from European mariculture appears negligible. This study laid the groundwork for considerations to amend the current EU regulation.
Abstract 11757: Low Venous Capacitance and High Venous Return Resistance in the Fontan Circulation: Potential for New Therapies
Authors: Hirofumi Saiki, Mitsuru Seki, Clara Kurishima, Satoshi Masutani, Hideaki Senzaki
Journal: Circulation (2011)

Background: Preservation of preload reserve is extremely important in patients with Fontan circulation in whom the pulmonary ventricle is lacking. We hypothesized that venous capacitance (Cv) is re...