tbuckley/cabot-search huggingface dataset:
Synergy of Tumor Microenvironment Remodeling and Autophagy Inhibition to Sensitize Radiation for Bladder Cancer Treatment
Authors: Tingsheng Lin, Qing Zhang, Ahu Yuan, Baojun Wang, Feifei Zhang, Yuanzhen Ding, Wenmin Cao, Wei Chen, Hongqian Guo
Journal: Theranostics (2020)

Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation.The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME.To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO2) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy.Methods: By taking advantage of the strong affinity between negatively charged MnO2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO2-CQ NPs).Results: HSA-MnO2-CQ NPs NPs efficiently generated O2 and increased pH in vitro after reaction with H + /H2O2 and then released the encapsulated CQ in a H + /H2O2 concentration-dependent manner.The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux.In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues.The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors.Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization.Conclusions: HSA-MnO2-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.
Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials
Authors: R Storb, HJ Deeg, L Fisher, F Appelbaum, CD Buckner, W Bensinger, R Clift, K Doney, C Irle, R McGuffin
Journal: Blood (1988)
Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors
Authors: Roberta Sanfilippo, Chiara Fabbroni, Giovanni Fucà, Elena Fumagalli, Carlo Morosi, Marta Sbaraglia, Alessandro Gronchi, Paola Collini, Angelo P. Dei Tos, Paolo G. Casali
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors. Experimental Design: Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan–Meier method. Results: A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%. Conclusions: In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.
SABRTooth: a randomised controlled feasibility study of stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I nonsmall cell lung cancer considered to be at higher risk of complications from surgical resection
Authors: Kevin N. Franks, Lucy McParland, Joanne Webster, David R. Baldwin, David Sebag-Montefiore, Matthew Evison, Richard Booton, Corinne Faivre-Finn, Babu Naidu, Jonathan Ferguson, Clive Peedell, Matthew E.J. Callister, Martyn Kennedy, Jenny Hewison, Janine Bestall, Walter M. Gregory, Peter Hall, Fiona Collinson, Catherine Olivier, Rachel Naylor, Sue Bell, Peter Allen, Andrew Sloss, Michael Snee
Journal: European Respiratory Journal (2020)

Stereotactic ablative radiotherapy (SABR) is a well-established treatment for medically inoperable peripheral stage I nonsmall cell lung cancer (NSCLC). Previous nonrandomised evidence supports SABR as an alternative to surgery, but high-quality randomised controlled trial (RCT) evidence is lacking. The SABRTooth study aimed to establish whether a UK phase III RCT was feasible.
Publisher Correction: Tumor-necrosis factor impairs CD4+ T cell–mediated immunological control in chronic viral infection
Authors: Marc Beyer, Zeinab Abdullah, Jens M. Chemnitz, Daniela Maisel, Jil Sander, Clara Lehmann, Yasser Thabet, Prashant V. Shinde, Lisa Schmidleithner, Maren Köhne, Jonel Trebicka, Robert Schierwagen, Andrea Hofmann, Alexey Popov, Karl S. Lang, Annette Oxenius, Thorsten Buch, Christian Kurts, Mathias Heikenwalder, Gerd Fätkenheuer, Philipp A. Lang, Pia Hartmann, Percy A. Knolle, Joachim L. Schultze
Journal: Nature Immunology (2020)
Coming Off Prescribed Psychotropic Medications: Insights from Their Use as Recreational Drugs
Authors: Fabrizio Schifano
Journal: Psychotherapy and Psychosomatics (2020)

© 2020 S. Karger AG, Basel. This is the peer-reviewed but unedited manuscript version of the following article: Schifano F: Coming Off Prescribed Psychotropic Medications: Insights from Their Use as Recreational Drugs. Psychother Psychosom 2020;89:274-282. DOI: 10.1159/000361001. The final, published version is available at https://doi.org/10.1159/000507897.
Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II, and Pol III
Authors: Yongpeng Jiang, Jie Huang, Kehuan Lun, Boyuan Li, Haonan Zheng, Yuanjun Li, Rong Zhou, Wenjia Duan, Chenlu Wang, Yuanqing Feng, Hong Yao, Cheng Li, Xiong Ji
Journal: Genome biology (2020)

The relationship between transcription and the 3D chromatin structure is debated. Multiple studies have shown that transcription affects global Cohesin binding and 3D genome structures. However, several other studies have indicated that inhibited transcription does not alter chromatin conformations.
Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma
Authors: Xiaoting Liang, Xin Wang, Yaohui He, Yuanzhong Wu, Li Zhong, Wen Liu, Dan Liao, Tiebang Kang
Journal: Theranostics (2020)

Background: Rab22a-NeoF1 fusion gene containing the 1-38aa of Rab22a (Rab22a 1-38 ) plays a decisive role in driving tumor metastasis by activating RhoA via binding to SmgGDS607.However, its intercellular regulation remains unknown.Methods: The Lys7 (K7) acetylation of Rab22a-NeoF1 was initially identified by mass spectrum.Co-transfection, immunoprecipitation and Western blotting were used to characterize the acetyltransferases and deacetylases responsible for the K7 acetylation of Rab22a-NeoF1, and to define the interaction of proteins.The specificity of K7 acetylation of Rab22a-NeoF1 was determined by its specific anti-K7ac-Rab22a-NeoF1 antibody and its K7R mutant.RhoA-GTP was measured by RhoA activation assay.The migration and invasion were assessed by Transwell assay without and with Matrigel matrix, respectively.The orthotopic osteosarcoma metastasis model in vivo was used to monitor the lung metastases of U2OS/MTX300-Luc stably expressing Vector, Rab22a-NeoF1 or its K7R mutant with or without C646, a relatively specific inhibitor of p300/CBP.The unpaired Student t test was used for the statistical significance.Results: The K7 of Rab22a-NeoF1 is acetylated by p300/CBP while is de-acetylated by both HDAC6 and SIRT1.The K7R mutant of Rab22a-NeoF1 lacks its binding to SmgGDS607 and subsequently lost its promoting functions, such as activation of RhoA, cell migration, invasion and lung metastasis in osteosarcoma in vitro and in vivo, which are also diminished by p300/CBP inhibitor C646. Conclusion:The promoting function of Rab22a-NeoF1 is dependent on its K7 acetylation in osteosarcoma, and targeting this acetylation (e.g., C646) may benefit cancer patients, in particular osteosarcoma patients, who are positive for the Rab22a 1-38 .
Surgical Treatment for Recurrent Bulbar Urethral Stricture: A Randomised Open-label Superiority Trial of Open Urethroplasty Versus Endoscopic Urethrotomy (the OPEN Trial)
Authors: Beatriz Goulao, Sonya Carnell, Jing Shen, Graeme MacLennan, John Norrie, Jonathan Cook, Elaine McColl, Matt Breckons, Luke Vale, Paul Whybrow, Tim Rapley, Rebecca Forbes, Stephanie Currer, Mark Forrest, Jennifer Wilkinson, Daniela Andrich, Stewart Barclay, Anthony Mundy, James N’Dow, Stephen Payne, Nick Watkin, Robert Pickard
Journal: European Urology (2020)
Distinct Subgroups in Hypertrophic Cardiomyopathy: Baseline Results From HCMR
Authors: S Neubauer, P Kolm, C Ho, M Desai, S Dolman, E Appelbaum, P M Desvigne-nickens, J P Dimarco, M G Friedrich, N Geller, M Jerosch-Herold, Kim D-Y., M S Maron, J Schulz-Menger, S Piechnik, C Zhang, H Watkins, W S Weintraub, C M Kramer
Journal: Circulation (2019)
Should doctors tackling covid-19 be immune from negligence liability claims?
Authors: Christine Tomkins, Craig Purshouse, Rob Heywood, José Miola, Emma Cave, Sarah Devaney
Journal: BMJ (2020)

Litigation related to exceptional circumstances would be a complicated drain on a workforce and system already on its knees after the pandemic, says <b>Christine Tomkins</b>. But <b>Craig Purshouse, Rob Heywood, José Miola, Emma Cave, and Sarah Devaney</b> argue that, despite extraordinary times, immunity from negligence is unnecessary and sends the wrong message about practice standards
Letter to the Editor: Coronavirus Disease 2019–Related Liver Injury and Clinical Outcomes: Does It Really Exist?
Authors: Cyriac Abby Philips, Rizwan Ahamed, Philip Augustine
Journal: Hepatology (2020)

Potential conflict of interest: Dr. Philips advises Cipla. TO THE EDITOR: We read with interest the study by Lei and colleagues on the association between markers of liver injury and mortality in coronavirus disease 2019 (COVID‐19) in China.(1) The authors have painstakingly collated data from a large number of patients with COVID‐19 from multiple centers across Wuhan. They found that an increase in aspartate aminotransferase (AST) and its dynamicity correlated with COVID‐19‐related liver injury and patient outcomes. They concluded that the dynamic patterns of liver injury indicators, represented by AST, correspond with COVID‐19‐related liver injury. A basic understanding of enzymes that form part of the liver test is fundamental to the interpretation of clinical events. Alanine aminotransferase (ALT) produced in the hepatocytes is a very specific marker of liver cell injury, with relatively lower concentrations in other organ tissues. The rise in ALT may occur with the use of specific drugs, such as antibiotics and glucocorticoids. AST, on the other hand, occurs in two isoforms, indistinguishable on standard assays. It is the mitochondrial isoenzyme, which is produced by the hepatocyte, that reacts to membrane damage similar to ALT, whereas the cytosolic isoenzyme is produced by cells of skeletal muscles, cardiac myocytes, and renal tissue. The use of AST in isolation is not recommended as a marker for hepatocellular injury.(2) The conclusion inculpating AST with COVID‐19 liver injury is inaccurate and factually related to the evolving multiorgan dysfunction (MOD). This is underscored by the fact that most patients had already developed cardiac and renal injury before the development of proposed acute liver injury (ALI) at 10‐15 days after admission, further exacerbated by antibiotics and glucocorticoids. AST and ALT levels were significantly high in those with lymphocytopenia, a marker of severe COVID‐19.(3) Scoring systems for MOD were not used by the authors, adding to the confounding. The definition of ALI in the current study is flawed. An important criterion for diagnosing ALI in those without preexisting liver disease is an international normalized ratio >2.(4) The current study does not incorporate appropriate methods to clearly identify synthetic and metabolic hepatocellular dysfunction. The term "COVID‐19‐related liver injury" is perchance misleading, akin to the recently described COVID‐19 involvement of the pancreas.(5)
Response to: ‘Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis’ by Györfi <i>et al</i>
Authors: Milena Gianfrancesco, Kimme L Hyrich, Jinoos Yazdany, Pedro M Machado, Philip C Robinson
Journal: Annals of the Rheumatic Diseases (2020)

We thank Gyorfi et al for their correspondence.1 The case they present demonstrates a potentially important point that was reported in our manuscript2: the effect of systemic glucocorticoids may worsen outcomes in patients with rheumatic disease. However, as has been highlighted recently by the results of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial, systemic glucocorticoids may have a role to play in treating COVID-19.3 Noteworthy, in the RECOVERY trial, dexamethasone (6 mg daily for 10 days) only reduced deaths in the patients that were ventilated (one-third reduction) or receiving oxygen (one-fifth reduction) but no benefit was seen among those patients who did not require respiratory support; moreover, the trial did not study …
How to Safely Reopen Colleges and Universities During COVID-19: Experiences From Taiwan
Authors: Shao-Yi Cheng, C. Jason Wang, April Chiung-Tao Shen, Shan-Chwen Chang
Journal: Annals of Internal Medicine (2020)

Reopening colleges and universities during the coronavirus disease 2019 (COVID-19) pandemic poses a special challenge worldwide. Taiwan is one of the few countries where schools are functioning normally. To secure the safety of students and staff, the Ministry of Education in Taiwan established general guidelines for college campuses. The guidelines delineated creation of a task force at each university; school-based risk screening based on travel history, occupation, contacts, and clusters; measures on self-management of health and quarantine; general hygiene measures (including wearing masks indoors); principles on ventilation and sanitization; regulations on school assemblies; a process for reporting suspected cases; and policies on school closing and make-up classes. It also announced that a class should be suspended if 1 student or staff member in it tested positive and that a school should be closed for 14 days if it had 2 or more confirmed cases. As of 18 June 2020, there have been 7 confirmed cases in 6 Taiwanese universities since the start of the pandemic. One university was temporarily closed, adopted virtual classes, and quickly reopened after 14 days of contact tracing and quarantine of possible contacts. Taiwan's experience suggests that, under certain circumstances, safely reopening colleges and universities this fall may be feasible with a combination of strategies that include containment (access control with contact tracing and quarantine) and mitigation (hygiene, sanitation, ventilation, and social distancing) practices.
After COVID-19, a future for the world's children?
Authors: Helen Clark, Awa Marie Coll-Seck, Anshu Banerjee, Stefan Peterson, Sarah L Dalglish, Shanthi Ameratunga, Dina Balabanova, Zulfiqar A Bhutta, John Borrazzo, Mariam Claeson, Tanya Doherty, Fadi El-Jardali, Asha S George, Angela Gichaga, Lu Gram, David B Hipgrave, Aku Kwamie, Qingyue Meng, Raúl Mercer, Sunita Narain, Jesca Nsungwa-Sabiiti, Adesola O Olumide, David Osrin, Timothy Powell-Jackson, Kumanan Rasanathan, Imran Rasul, Papaarangi Reid, Jennifer Requejo, Sarah S Rohde, Nigel Rollins, Magali Romedenne, Harshpal Singh Sachdev, Rana Saleh, Yusra R Shawar, Jeremy Shiffman, Jonathon Simon, Peter D Sly, Karin Stenberg, Mark Tomlinson, Rajani R Ved, Anthony Costello
Journal: The Lancet (2020)
Sport Physiotherapy Canada issue: change is in the air
Authors: Christopher Napier, Paul Hunter
Journal: British Journal of Sports Medicine (2020)

As the world has come to grip with the enormous upheavals over the last several months, we have all had to adjust to this new way of life (figure 1). For many in the sports medicine community, this has meant abandoning conferences and large sporting events, working from home and perhaps assisting on the front lines of this pandemic. While many of these changes have been abrupt, there have also been predictable changes going on in the background as we progress from one season to the next and from year to year.



Figure 1 
Symbolising 2020 and the COVID-19 pandemic: The Sport Physio Canada @SportPhysioCan issue of BJSM.



Fresh from our 2020 Annual Members Meeting, which was held online from home with record attendance—perhaps there are some upsides to some of these changes—Sport Physiotherapy Canada (SPC) (@sportphysiocan) says goodbye to some of our executive committee as we welcome new members. Notably, Kim Lee-Knight, our Chairperson for the last 2 years, moves on to the position of past-Chair and I (Paul Hunter) have stepped into the role of Chairperson for the next 2 years.

The last 2 years have been filled with many new opportunities and growth. The SPC credentialing syllabus has been completely overhauled …
Immune responses in pancreatic cancer may be restricted by prevalence of activated regulatory T-cells, dysfunctional and senescent T-cells
Authors: S Sivakumar, E Abu-Shah, D J Ahern, E H Arbe-Barnes, N Mangal, S Reddy, A Rendek, A Easton, E Kurz, M Silva, L R Heij, Z Soonawalla, R Bashford-Rogers, M R Middleton, M L Dustin
Journal: Cancer Discovery (2020)
Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition
Authors: Sheng F. Cai, S. Haihua Chu, Aaron D. Goldberg, Salma Parvin, Richard P. Koche, Jacob L. Glass, Eytan M. Stein, Martin S. Tallman, Filiz Sen, Christopher A. Famulare, Monica Cusan, Chun-Hao Huang, Chun-Wei Chen, Lihua Zou, Keith B. Cordner, Nicole L. DelGaudio, Vidushi Durani, Mitali Kini, Madison Rex, Helen S. Tian, Johannes Zuber, Timour Baslan, Scott W. Lowe, Hugh Y. Rienhoff, Anthony Letai, Ross L. Levine, Scott A. Armstrong
Journal: Cancer Discovery (2020)

Abstract The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin–driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1hi acute myeloid leukemia. Significance: We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax. See related commentary by Gu et al., p. 1445. This article is highlighted in the In This Issue feature, p. 1426
Toward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma
Authors: Daisuke Ennishi, Eric D. Hsi, Christian Steidl, David W. Scott
Journal: Cancer Discovery (2020)

Diffuse large B-cell lymphoma (DLBCL) represents a grouping of clinically and biologically heterogeneous tumors. Application of advanced molecular technology has significantly expanded our knowledge of DLBCL pathobiology, allowing identification of subgroups with common, potentially targetable, biological themes. Here, we review the recent molecular analyses that could provide a paradigm shift to a new taxonomy, foundational to the rational transition to precision medicine. We discuss how classification systems may be synthesized into a common taxonomy, drawing strength from the relationships between genetic alterations, gene expression, and tumor microenvironment. Finally, challenges to translating such a taxonomy to the clinic will be outlined.
Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B
Authors: Matteo S. Carlino, Alexander M. Menzies, Victoria Atkinson, Jonathan S. Cebon, Michael B. Jameson, Bernard M. Fitzharris, Catriona M. McNeil, Andrew G. Hill, Antoni Ribas, Michael B. Atkins, John A. Thompson, Wen-Jen Hwu, F. Stephen Hodi, Alexander D. Guminski, Richard Kefford, Haiyan Wu, Nageatte Ibrahim, Blanca Homet Moreno, Georgina V. Long
Journal: Clinical Cancer Research (2020)

Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte-associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma.Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively.Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.
Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society
Authors: Hiroto Hatabu, Gary M Hunninghake, Luca Richeldi, Kevin K Brown, Athol U Wells, Martine Remy-Jardin, Johny Verschakelen, Andrew G Nicholson, Mary B Beasley, David C Christiani, Raúl San José Estépar, Joon Beom Seo, Takeshi Johkoh, Nicola Sverzellati, Christopher J Ryerson, R Graham Barr, Jin Mo Goo, John H M Austin, Charles A Powell, Kyung Soo Lee, Yoshikazu Inoue, David A Lynch
Journal: The Lancet Respiratory Medicine (2020)