tbuckley/cabot-search huggingface dataset:
Elucidating mechanisms of antitumor immunity mediated by live oncolytic vaccinia and heat-inactivated vaccinia
Authors: Weiyi Wang, Shuaitong Liu, Peihong Dai, Ning Yang, Yi Wang, Rachel A Giese, Taha Merghoub, Jedd Wolchok, Liang Deng
Journal: Journal for ImmunoTherapy of Cancer (2021)

Viral-based immunotherapy can overcome resistance to immune checkpoint blockade (ICB) and fill the unmet needs of many patients with cancer. Oncolytic viruses (OVs) are defined as engineered or naturally occurring viruses that selectively replicate in and kill cancer cells. OVs also induce antitumor immunity. The purpose of this study was to compare the antitumor effects of live oncolytic vaccinia viruses versus the inactivated versions and elucidate their underlying immunological mechanisms.We engineered a replication-competent, oncolytic vaccinia virus (OV-GM) by inserting a murine GM-CSF gene into the thymidine kinase locus of a mutant vaccinia E3L∆83N, which lacks the Z-DNA-binding domain of vaccinia virulence factor E3. We compared the antitumor effects of intratumoral (IT) delivery of live OV-GM versus heat-inactivated OV-GM (heat-iOV-GM) in a murine B16-F10 melanoma bilateral implantation model. We also generated vvDD, a well-studied oncolytic vaccinia virus, and compared the antitumor effects of live vvDD vs heat-inactivated vvDD (heat-ivvDD) in a murine A20 B-cell lymphoma bilateral tumor implantation model.Heat-iOV-GM infection of dendritic cells (DCs) and tumor cells in vitro induced type I interferon and proinflammatory cytokines and chemokines, whereas live OV-GM did not. IT live OV-GM was less effective in generating systemic antitumor immunity compared with heat-iOV-GM. Similar to heat-iOV-GM, the antitumor effects of live OV-GM also require Batf3-dependent CD103+ dendritic cells. When combined with systemic delivery of ICB, IT heat-iOV-GM was more effective in eradicating tumors, compared with live OV-GM. IT heat-ivvDD was also more effective in treating murine A20 B-cell lymphoma, compared with live vvDD.Tumor lysis induced by the replication of oncolytic vaccinia virus has a limited effect on the generation of systemic antitumor immunity. The activation of Batf3-dependent CD103+ DCs is critical for antitumor effects induced by both live OV-GM and heat-iOV-GM, with the latter being more potent than live OV-GM in inducing innate and adaptive immunity in both locally injected and distant, non-injected tumors. We propose that evaluations of both innate and adaptive immunity, induced by IT oncolytic viral immunotherapy at injected and non-injected tumors, should be included as potential biomarkers for host responses to viral therapy.
Abstract 11486: Impact of Right Ventricular Dyssynchrony on Left Ventricular Performance in Patients with Pulmonary Hypertension
Authors: Marlieke L Haeck, Ulas Höke, Nina Ajmone Marsan, Eduard R Holman, Ron Wolterbeek, Jeroen J Bax, Martin J Schalij, Hubert W Vliegen, Victoria Delgado
Journal: Circulation (2012)

Background: Pulmonary hypertension has been associated with right ventricular (RV) dyssynchrony, which may induce left ventricular (LV) dysfunction and dyssynchrony through ventriculo-ventricular i...
Abstract SP021: Understanding current platforms
Authors: M Burkard
Journal: Cancer Research (2021)

Abstract Next-generation sequencing (NGS) of breast cancer is becoming increasingly integrated into clinical practice. The fast pace of advances coupled with the dizzying array of technologies and platforms challenges the oncologist to select the right test for each patient. The choice could depend on a host of factors including the accessibility of clinical trials, clinical scenario and sample type, and the interest in turning up improbable but profoundly useful findings. Here, I will review the various types of clinical NGS platforms—including tumor and circulating-tumor DNA—particularly highlighting the unique features of commercial platforms that are widely available. Performance characteristics differ by technology: amplification technologies can detect mutations with smaller specimens, whereas capture-based NGS platforms may perform better for detecting novel genomic alterations. Assays integrating RNA-based analysis may enhance detection of rare but impactful gene fusions, such as of FGFR1-3 and NTRK1-3. Some potentially actionable genomic alterations only emerge after therapy, and are detected only with repeat tumor biopsy or cell-free DNA. Some assays include parallel germline testing which can clearly distinguish inherited from somatic (tumor-specific) findings, but may offer logistical challenges. An ever expanding set of ‘genomic phenotypes’ may be captured in these updated assays, with their limitations, including tumor mutational burden, microsatellite instability and homologous recombination. Newer platforms are now including exome and whole-genome sequencing, which may require more tissue and offer research insights, but currently add little to directing clinical care. New technologies, such as long-read and single-cell platforms of the future, may elucidate genomic features that are undetectable with current bulk short-read platforms, and will enable new genomic biomarkers. Despite the differences in genomics platforms, practical matters such as reimbursement, ease of use, and turn-around-time will likely govern platform selection for most oncologists in the near future. Citation Format: M Burkard. Understanding current platforms [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP021.
Abstract SP114: Body Image and Sexual Health
Authors: A Partridge
Journal: Cancer Research (2021)

Abstract Attention to body image and sexual health after breast cancer are important components of treatment decisions, support through treatment and survivorship care. A high proportion of breast cancer survivors report dissatisfaction with their physical appearance. Body image issues are particularly common among women who undergo mastectomy with or without reconstructive surgery and those who experience weight gain, hair loss from chemotherapy, and other psychosocial issues. Scalp cooling, proactive counseling about potential effects of treatment on weight and physical activity, and psychosocial support through treatment may help to prevent some of these negative effects. Weight loss and subsequent weight maintenance are notoriously difficult to achieve through diet alone, and exercise plays an important role in energy balance through and after treatment. Sexual health is frequently a concern for breast cancer survivors as well, with up to 40% of women reporting issues with sexual interest and 60% with physical sexual function. Issues may arise in the short term following both surgery and chemotherapy, due to factors including lower perceived attractiveness and vaginal dryness. Endocrine therapy with tamoxifen, aromatase inhibitors, and treatment-related amenorrhea or ovarian suppression treatment in premenopausal women are associated with sexual dysfunction. However, a multi-prong approach has been shown to improve such problems. Providers should actively monitor for and manage the consequences of diagnosis and treatment on body image and sexual health in survivors, using psychosocial, behavioral, and pharmacologic tools as needed. Citation Format: A Partridge. Body Image and Sexual Health [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP114.
Abstract PD10-01: Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017
Authors: Allison W Kurian, Monica Morrow, Steven Katz
Journal: Cancer Research (2021)

Abstract Background: Genetic testing is increasingly important for breast and ovarian cancer risk reduction and treatment. However, little is known about trends and disparities in receipt of testing in the community and test results after diagnosis. Methods: We linked records of all women with breast cancer or ovarian cancer diagnosed from 2013-2017 in Georgia and California and reported to Surveillance, Epidemiology and End Results (SEER) registries to genetic testing results from four laboratories that did most clinical testing in the studied regions (Ambry Genetics, GeneDx, Invitae, Myriad Genetics). We combined test results performed by all laboratories over 2012-2019 with SEER data. We measured use of any test, median number of genes tested, rates of variants of uncertain significance (VUS) and pathogenic variants (PVs). Results: A total of 25.2% of 187,535 breast cancer patients, and 34.3% of 14,689 ovarian cancer patients, had genetic testing. Testing increased annually by 2% while the median number of genes tested increased annually by 28%. Among tested patients diagnosed with breast cancer in 2017, 5.2% had BRCA1/2 PVs while 4.9% had PVs in genes associated with a recognized cancer syndrome (APC, CDH1, MLH1, MSH2, MSH6, NF1, PMS2, PTEN, RET and TP53) or with emerging evidence for an increased risk of breast cancer and/or ovarian cancer (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C and RAD51D). Among tested patients diagnosed with ovarian cancer in 2017, 11.0% had BRCA1/2 PVs while 2.3% had PVs in a syndromic gene (APC, MLH1, MSH2, MSH6, NF1, PMS2, and TP53) or an emerging breast/ovarian cancer gene (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C and RAD51D). PVs in other tested genes were rare (generally &amp;lt;1%). VUS rates increased from patients diagnosed in 2013 (11.2% breast, 11.2% ovarian) to 2017 (26.4% breast, 26.8% ovarian) and were higher in racial/ethnic minorities (47.8% Asian, 46.0% Black, 40% Hispanic versus 24.6% non-Hispanic Whites diagnosed with ovarian cancer in 2017; p&amp;lt;.001). Conclusions: A substantial gap persists in testing ovarian cancer patients (34.5% versus nearly 100% recommended) while testing more genes was associated with a substantial racial/ethnic gap in VUS. Most clinically relevant PVs occurred in the 17 genes (ovarian cancer patients) to 20 genes (breast cancer patients) reported above; testing only these genes may optimize the clinically salient PV-to-VUS ratio, particularly for racial/ethnic minorities. Citation Format: Allison W Kurian, Monica Morrow, Steven Katz. Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-01.
Patient Preferences for Hepatocellular Carcinoma Surveillance Parameters
Authors: Sean A. Woolen, Amit G. Singal, Matthew S. Davenport, Jonathan P. Troost, Shokoufeh Khalatbari, Sukul Mittal, Sehar Siddiqui, Austin Fobar, Jason Morris, Mobolaji Odewole, Elliot B. Tapper, Anjana Pillai, Neehar D. Parikh
Journal: Clinical Gastroenterology and Hepatology (2021)
Sixty seconds on . . . hotel quarantine
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Is this a new covid themed hotel?You could put it like that.From 15 February UK residents returning to England having visited a country on a "red list" in the previous 10 days will be required to quarantine in a hotel for 10 days, to try to prevent new chains of transmission.Many countries have already rolled out similar policies, including China, Australia, Hong Kong, India, New Zealand, the Philippines, Qatar, Taiwan, Singapore, and Thailand, though most of them took this action during the first covid-19 peak in early 2020. Plenty of room?That's what the government is saying.It has struck deals with 16 hotels so far, providing 4963 rooms, with a further 58 000 rooms on standby. What's the cost?The charge for a single adult is £1750 (€2000; $2420) for 10 days and 11 nights, £650 for an additional adult, and £32 for a child.They will get three meals a day, fruit, tea and coffee, soft drinks, and water, and two covid-19 tests. And access to the spa?Uhm, no.Most people won't be allowed out of their rooms.Only in exceptional circumstances will people be allowed outside to exercise and then will be escorted and required to wear a face covering.Families with children and people with specific medical needs will be prioritised.Let's hope the wifi is good. Which countries are on the "red list"?Brazil, South Africa, United Arab Emirates, Uruguay, Venezuela, and Zimbabwe are among the countries on the list.Non-UK residents and citizens from those destinations are currently banned from entering the UK. 1
Association of Opioid Use Disorder Treatment With Alcohol-Related Acute Events
Authors: Kevin Y. Xu, Ned Presnall, Carrie M. Mintz, Jacob T. Borodovsky, Nisha R. Bhat, Laura J. Bierut, Richard A. Grucza
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Persons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied and undertreated. It is unknown whether the use of medications to treat OUD is associated with reduced risk of alcohol-related morbidity. <h3>Objective</h3> To determine whether the use of OUD medications is associated with decreased risk for alcohol-related falls, injuries, and poisonings in persons with OUD with and without co-occurring AUD. <h3>Design, Setting, and Participants</h3> This recurrent-event, case-control, cohort study used prescription claims from IBM MarketScan insurance databases from January 1, 2006, to December 31, 2016. The sample included persons aged 12 to 64 years in the US with an OUD diagnosis and taking OUD medication who had at least 1 alcohol-related admission. The unit of observation was person-day. Data analysis was performed from June 26 through September 28, 2020. <h3>Exposures</h3> Days of active OUD medication prescriptions, with either agonist (ie, buprenorphine or methadone) or antagonist (ie, oral or extended-release naltrexone) treatments compared with days without OUD prescriptions. <h3>Main Outcomes and Measures</h3> The primary outcome was admission for any acute alcohol-related event defined by<i>International Classification of Diseases, Ninth Revision</i>and<i>International Statistical Classification of Diseases and Related Health Problems, Tenth Revision</i>codes. Conditional logistic regression was used to compare OUD medication use between days with and without an alcohol-related event. Stratified analyses were conducted between patients with OUD with and without a recent AUD diagnostic code. <h3>Results</h3> There were 8 424 214 person-days of observation time among 13 335 participants who received OUD medications and experienced an alcohol-related admission (mean [SD] age, 33.1 [13.1] years; 5884 female participants [44.1%]). Agonist treatments (buprenorphine and methadone) were associated with reductions in the odds of any alcohol-related acute event compared with nontreatment days, with a 43% reduction for buprenorphine (odds ratio [OR], 0.57; 95% CI, 0.52-0.61) and a 66% reduction for methadone (OR, 0.34; 95% CI, 0.26-0.45). The antagonist treatment naltrexone was associated with reductions in alcohol-related acute events compared with nonmedication days, with a 37% reduction for extended-release naltrexone (OR, 0.63; 95% CI, 0.52-0.76) and a 16% reduction for oral naltrexone (OR, 0.84; 95% CI, 0.76-0.93). Naltrexone use was more prevalent among patients with OUD with recent AUD claims than their peers without AUD claims. <h3>Conclusions and Relevance</h3> These findings suggest that OUD medication is associated with fewer admissions for alcohol-related acute events in patients with OUD with co-occurring AUD.
Isolated Unilateral Orbital Metastasis From Ewing Sarcoma Detected on FDG PET/CT Scan
Authors: Rinky Agarwal, Abhishek Khare, Nitin Gupta
Journal: Clinical Nuclear Medicine (2021)

Ewing sarcoma is the second most common primary malignant bone tumor that usually affects diaphysis of long bones during the second decade of life. Isolated unilateral orbital metastasis from this tumor presenting as proptosis is extremely rare. Here we report a case of 11-year-old boy where whole-body FDG PET/CT scan detected primary an Ewing sarcoma site in the left femur and isolated orbital metastasis in the left eye. Follow-up PET/CT scan after 6 cycles of chemotherapy showed resolution of the previously seen lesions.
Abstract PD15-07: Myc regulates alternative splicing through a network of RNA binding proteins in breast cancer
Authors: Laura Urbanski, Brittany Angarola, Mattia Brugiolo, Marina Yurieva, Sunghee Park, Olga Anczukow
Journal: Cancer Research (2021)

Abstract The oncogenic transcription factor MYC is one of the most frequently altered genes in cancer and is highly dysregulated in aggressive tumor types, including triple negative breast cancer (TNBC). Although direct targeting of MYC or its regulators in human tumors has proved difficult, the undisputed clinical relevance of this transcription factor warrants continued study for therapeutic targeting of MYC-driven processes in tumors. Recently, we and others have shown the tumorigenic capacity of MYC is critically dependent on the RNA splicing machinery and on several splicing factor RNA-binding proteins (RBPs). Dysregulation of alternative mRNA splicing, a key step in gene expression regulation, is a hallmark of cancer, and can lead to the expression of isoforms driving tumor initiation, progression or drug resistance. Understanding which component(s) of the RNA machinery are regulated by MYC, and the functions of MYC-induced spliced isoforms, may reveal new targets that circumvent prior failures of directly targeting MYC. Here, we examine MYC-induced changes in gene expression and alternative splicing through RNA-sequencing of breast cell lines and tumors. Using a mammary epithelial cell line with an inducible MYC system, we identified over 4,000 MYC-induced alternative splicing events as well as 378 MYC-induced RBPs. Co-expression network analysis of these RBPs in TCGA breast tumor RNA-seq data uncovered 8 RBP modules, four of which are highly correlated with MYC activity and highly expressed in TNBC. One of these modules is preserved across almost all other TCGA tumor types and remains highly correlated with MYC activity, suggesting a pan-cancer role of this co-expression module. We are now defining the functional role of these RBP modules in MYC-driven tumorigenesis in breast cancer models, as well as identifying their downstream oncogenic splicing targets. Our research project will define the role and regulation of alternative splicing in breast cancer, and more specifically in aggressive tumor types such as TNBC. Our findings will provide mechanistic insight into the role of MYC-driven splicing in tumor maintenance and will uncover novel therapeutic targets for MYC-active tumors. Citation Format: Laura Urbanski, Brittany Angarola, Mattia Brugiolo, Marina Yurieva, Sunghee Park, Olga Anczukow. Myc regulates alternative splicing through a network of RNA binding proteins in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-07.
Recent Evolutionary History of Tigers Highlights Contrasting Roles of Genetic Drift and Selection
Authors: Ellie E Armstrong, Anubhab Khan, Ryan W Taylor, Alexandre Gouy, Gili Greenbaum, Alexandre Thiéry, Jonathan T Kang, Sergio A Redondo, Stefan Prost, Gregory Barsh, Christopher Kaelin, Sameer Phalke, Anup Chugani, Martin Gilbert, Dale Miquelle, Arun Zachariah, Udayan Borthakur, Anuradha Reddy, Edward Louis, Oliver A Ryder, Yadvendradev V Jhala, Dmitri Petrov, Laurent Excoffier, Elizabeth Hadly, Uma Ramakrishnan
Journal: Molecular Biology and Evolution (2021)

Abstract Species conservation can be improved by knowledge of evolutionary and genetic history. Tigers are among the most charismatic of endangered species and garner significant conservation attention. However, their evolutionary history and genomic variation remain poorly known, especially for Indian tigers. With 70% of the world’s wild tigers living in India, such knowledge is critical. We re-sequenced 65 individual tiger genomes representing most extant subspecies with a specific focus on tigers from India. As suggested by earlier studies, we found strong genetic differentiation between the putative tiger subspecies. Despite high total genomic diversity in India, individual tigers host longer runs of homozygosity, potentially suggesting recent inbreeding or founding events, possibly due to small and fragmented protected areas. We suggest the impacts of ongoing connectivity loss on inbreeding and persistence of Indian tigers be closely monitored. Surprisingly, demographic models suggest recent divergence (within the last 20,000 years) between subspecies and strong population bottlenecks. Amur tiger genomes revealed the strongest signals of selection related to metabolic adaptation to cold, whereas Sumatran tigers show evidence of weak selection for genes involved in body size regulation. We recommend detailed investigation of local adaptation in Amur and Sumatran tigers prior to initiating genetic rescue.
Mechanism and reversal of drug-induced nephrotoxicity on a chip
Authors: Aaron Cohen, Konstantinos Ioannidis, Avner Ehrlich, Shaun Regenbaum, Merav Cohen, Muneef Ayyash, Sigal Shafran Tikva, Yaakov Nahmias
Journal: Science Translational Medicine (2021)

The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (
Covid-19: GPs could get extra funding to boost vaccine uptake in hard-to-reach groups
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Covid-19: GPs could get extra funding to boost vaccine uptake in hard-to-reach groups Gareth IacobucciGeneral practices could be offered "additional discretionary payments" to improve uptake of the covid-19 vaccine in hard-to-reach groups such as deprived and minority ethnic communities.
Intravenous ketamine and progressive cholangiopathy in COVID-19 patients
Authors: Vincent Mallet, Kilian Bock, Paul Doumbe Mandengue, Nicolas Dufour, Torsten Voigtlaender, Jean-Damien Ricard, Pierre Isnard, Vincent Frochot, Emmanuel Letavernier, Lucile Moga, Amandine Landrieux, Pierre-Emmanuel Rautou, Nathalie Pons-Kerjean, Anaïs Vallet-Pichard, Laurent Chouchana, Coralie Gernez, Carole Burger, Anne Scemla, Christian de Tymoski, François Depret, Emmanuel Dudoignon, Lionel Lamhaut, Rémi Flicoteau, Géraldine Rousseau, Jean-Paul Duong Van Huyen, Jean-Michel Correas, Heiner Wedemeyer, Stanislas Pol
Journal: Journal of Hepatology (2021)

Ketamine, a nonbarbiturate general anaesthetic drug, has been proposed, off-label, as a second-line agent for maintenance sedation of patients with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation, including those with Coronavirus infectious disease 2019 (COVID-19).1 Cholangiopathy is reported after chronic exposure to ketamine, including in drug users and in burned patients.2,3 We observed 5 COVID-19 patients from 5 distinct tertiary centers (1 in Germany, and 4 in France) with cholangiopathy after exposure to intravenous ketamine, between March 20, 2020 and April 6, 2020, during the first pandemic wave in Europe.