tbuckley/cabot-search huggingface dataset:
Regulating the regulator: Bhlhe40 directly keeps IL-10 in check
Authors: Leona Gabryšová, Anne O’Garra
Journal: The Journal of Experimental Medicine (2018)

In this issue of JEM, two complementary manuscripts by Huynh et al. (https://doi.org/10.1084/jem.20171704) and Yu et al. (https://doi.org/10.1084/jem.20170155) demonstrate that the transcription factor Bhlhe40 acts as a repressor of IL-10 production during infection with Mycobacterium tuberculosis or Toxoplasma gondii. Deletion of Bhlhe40 in both cases resulted in chronic infection and increased pathogen load as a consequence of increased IL-10 production.
Exhausted CD8+ cells (Tex) to predict response to PD-1 therapy in estrogen receptor (+) hormone therapy resistant breast cancer predictive of response to immune checkpoint inhibitors after epigenetic priming.
Authors: Pamela N. Munster, Manuela Terranova Barberio, Nela Pawlowska, Mark Moasser, Amy Jo Chien, Michelle E. Melisko, Hope S. Rugo, Kamran Abri, Armand Harb, Travis Deal, Adil Daud, Scott Thomas
Journal: Journal of Clinical Oncology (2018)

1044 Background: Immune checkpoint inhibitors have revolutionized cancer therapy, yet have limited efficacy in estrogen receptor (ER)+ breast cancer. Implicated factors include scarcity of tumor infiltrating lymphocytes (TILs), low PD-L1 expression, female gender and liver involvement. In vitro and in vivo studies suggest that epigenetic modulation with HDAC inhibitors modulate regulatory T cells (Treg) and change TIL composition which is further associated with the presence of a specific immune signature. Methods: Patients (pts) with (ER)+ metastatic breast cancer, who progressed on multiple prior therapies, were treated with tamoxifen in combination with vorinostat and pembrolizumab either immediately or after 3 weeks of epigenetic priming in a phase II trial. Comprehensive flow-cytometric immunophenotyping, PD-L1 staining and histone acetylation were evaluated on tumor and blood cells. Results: 34 patients (median age 56 years (32-81), heavily pretreated with a median of 5 (2-13) prior regimens received at least one dose of vorinostat and evaluable for response. Grade ¾ toxicities in 2 pts each (6%) included immune hepatitis, fatigue and thrombocytopenia. Grade 2 toxicities were pneumonitis and colitis in 3%, fatigue in 27% and thrombocytopenia in 12% pts. Six patients did not receive pembrolizumab due to rapid progression or toxicity. Clinical benefits rate defined as CR, PR and stable disease > 6m was seen in 5/28 (18%) pts. Tumor lymphocyte infiltration and PD-L1 expression were low. High expression of PD-1/CTLA-4 dual staining in CD8 cells of > 20% in tumor or blood was seen in 5 pts overall, 4/5 (80%) patients with benefit and in one other patient, who was withdrawn due to immune hepatitis in week 3. Both tumor and peripheral blood CD8 PD-1/CTLA-4 dual expression strongly correlated with time to progression and reduction in Foxp3+/CTLA-4high Treg population in tumors by vorinostat. Conclusions: Our data highlight the potential for patient selection based on exhausted CD8+ cells in blood or tumor to predict response to immune checkpoint inhibitors in a small subset of (ER)+ breast cancer patients. Clinical trial information: NCT02395627.
Survivorship of a survivorship clinic: System-wise lessons and challenges.
Authors: Opher Caspi, Karmit Haber, Ruth Attias, Noga Sela, Juliet Dreyer, Baruch Brenner
Journal: Journal of Clinical Oncology (2018)

40 Background: Since the most efficient means by which cancer survivorship services should be delivered remain elusive, we conducted a qualitative study with key personnel at a Comprehensive Cancer Center in Israel in order to identify barriers and facilitators that need to be addressed system-wise so that the survivorship clinic gets truly integrated in the day-to-day operation of the Cancer Center. Methods: In-depth 1x1 interviews with 21 key personnel (oncologists, nurses, psycho-oncologists, and survivorship clinic staff) and 13 survivors who attended the clinic in one focus group plus a descriptive analyses of clinic visits. Results: 1,012 visits (out of 1,578 referrals; 64%) were made to the survivorship clinic from 12/2016 to 4/2017. Main reasons for decline to attend the clinic were: no interest, logistics, and no need for further visits beyond the initial visit. 16/21 (76%) personnel and all survivors supported the need for a specialized survivorship clinic, yet many thought its modus operandi should be restructured. Perceived strengths included: its multidisciplinary structure, its commitment to emotionally support survivors throughout their journey, and its focus on QOL in addition to medical issues. Main barriers identified were: sense of redundancy and overlap with other services, oncologists' lack of time to discuss survivorship issues and proactively refer to the clinic, and no real understanding of the exact goals of the clinic. Questions rose regarding the best time to first refer survivors to the clinic and regarding who is in charge of survivors in terms of who focuses on what issues. Suggestions for future directions included: improved communication with oncologists and the disease management teams, case selection based on needs rather than on time since treatment, and production of reports that show the clinic's added value. Conclusions: Studies like these can help define the optimal modes of function of a designated survivorship clinic. While both survivors and personnel express interest in such a clinic, its struggle to survive even 3.5 years after it opened its door stem from significant gaps which need to be addressed system-wise.
Developing a survivorship specific curriculum for an advanced practice provider fellowship.
Authors: Rachée Hatfield, Rupa Ghosh-Berkebile, Denise Schimming, Kristine Browning, Kristina Mathey, Dori Klemanski
Journal: Journal of Clinical Oncology (2018)

14 Background: Holistic oncology care combines cancer treatment with supportive care to meet the physical and psychosocial needs of the cancer survivor. Advanced Practice Providers (APPs) are prepared to deliver high-quality, comprehensive oncology care and are vital to survivorship care as the number of cancer survivors continues to rise. At a Midwest Comprehensive Cancer Center (CCC), an APP oncology-specific fellowship is an innovative year-long postgraduate clinical training program. For the first time, a 2 week rotation through this CCC’s survivorship department will be piloted to provide the fellow with a basic immersion into survivorship care. Methods: APP oncology fellowship graduates completed an open ended survey. They were asked to reflect on their experiences during the fellowship and provide feedback on how to improve course content, and resources that are essential to the delivery of survivorship care. APPs within the survivorship department and the APP fellowship lead educator were asked what objectives they thought were important to be met. Results: APPs fellowship graduates desired to learn more about the philosophy of survivorship care, latent and long term side effect management, creation and delivery of a treatment summary and survivorship care plan (TS/SCP), and specific strategies for executing a meaningful survivorship care visit. Networking with oncology providers was also important. Survivorship department APPs and the fellowship lead thought it was important to know how to do a holistic and supportive care assessment, create a TS/SCP, interpret and manage a distress screening tool and make appropriate supportive care referrals. Conclusions: Cancer survivorship is an integral part of holistic oncology care. As the number of cancer survivors continues to increase, so does the need for supportive care services throughout the cancer continuum. Feedback from those surveyed was used to help develop a survivorship specific curriculum for APP oncology fellows. Educating future APPs in the principles of survivorship care and available supportive care services will result in expert clinicians in survivorship care, and improve overall well-being and quality of life of cancer survivors.
Beyond Legalization — Dilemmas Physicians Confront Regarding Aid in Dying
Authors: Bernard Lo
Journal: New England Journal of Medicine (2018)

Interview with Dr. Bernard Lo on aid-in-dying laws and their implications for doctors. (08:34)Download Because 18% of the U.S. population lives in jurisdictions where physician aid in dying is legal, physicians need to anticipate that patients may inquire about it. But physicians may feel unprepared, uncertain, and uncomfortable when confronted with these conversations.
The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells
Authors: Federica Moalli, Xenia Ficht, Philipp Germann, Mykhailo Vladymyrov, Bettina Stolp, Ingrid de Vries, Ruth Lyck, Jasmin Balmer, Amleto Fiocchi, Mario Kreutzfeldt, Doron Merkler, Matteo Iannacone, Akitaka Ariga, Michael H. Stoffel, James Sharpe, Martin Bähler, Michael Sixt, Alba Diz-Muñoz, Jens V. Stein
Journal: The Journal of Experimental Medicine (2018)

T cells are actively scanning pMHC-presenting cells in lymphoid organs and nonlymphoid tissues (NLTs) with divergent topologies and confinement. How the T cell actomyosin cytoskeleton facilitates this task in distinct environments is incompletely understood. Here, we show that lack of Myosin IXb (Myo9b), a negative regulator of the small GTPase Rho, led to increased Rho-GTP levels and cell surface stiffness in primary T cells. Nonetheless, intravital imaging revealed robust motility of Myo9b-/- CD8+ T cells in lymphoid tissue and similar expansion and differentiation during immune responses. In contrast, accumulation of Myo9b-/- CD8+ T cells in NLTs was strongly impaired. Specifically, Myo9b was required for T cell crossing of basement membranes, such as those which are present between dermis and epidermis. As consequence, Myo9b-/- CD8+ T cells showed impaired control of skin infections. In sum, we show that Myo9b is critical for the CD8+ T cell adaptation from lymphoid to NLT surveillance and the establishment of protective tissue-resident T cell populations.
Development of an Essential Drugs List for Bosnia and Herzegovina
Authors: M Carballo, D Serdarevic, I Zulic
Journal: Journal of the Royal Society of Medicine (1997)

Part of the impact of the war in ex-Yugoslavia and especially Bosnia and Herzegovina was to limit the supply of therapeutic drugs they had used before the war. The difficulties encountered made the health care system temporarily dependent on humanitarian assistance agencies which applied the concept of essential drugs; and, after initial difficulties, national health staff adapted to the need to prescribe from a very limited range of drugs. Meanwhile, national drug policy and procurement and prescribing practices were reviewed by working groups and a national List of Essential Drugs was drawn up by national experts with international support. This list has now been passed into legislation.
Urgent hypertension as a biomarker for bevacizumab in the curative setting.
Authors: Nawal Kassem, Fei Shen, Guanglong Jiang, Laura Gardner, Santosh Philips, Anne M. O'Neill, Kathy D. Miller, Thomas Suter, David A. Cameron, George W. Sledge, Bryan Paul Schneider
Journal: Journal of Clinical Oncology (2018)

548 Background: Bevacizumab is FDA approved across many tumors including lung, colon, and glioblastoma. It is unclear which patients are destined to respond and/or experience the most toxicity. We previously demonstrated that bevacizumab-induced hypertension (HTN) in the metastatic breast cancer setting (E2100) was correlated with an improved overall survival (OS). In this study we evaluated the impact of bevacizumab-induced urgent HTN on outcome in the curative setting in E5103 and BEATRICE. We further evaluated for germline biomarkers to predict patients destined to experience HTN using whole exome sequencing (WES). Methods: Cases were defined as those who experienced urgent HTN (systolic blood pressure (SBP) > 180 mmHg) and controls included those with SBP < 160 mmHg. Log rank test was used to compare DFS and OS between cases and controls. WES was performed using germline DNA from patients in E5103 and BEATRICE. Exomes were enriched via Ion AmpliSeq Exome RDY kits. Templates were prepared on Ion Chef Systems and sequenced on Ion Proton Sequencers. Rare variants with a minor allele frequency < 3% and those which were predicted to be deleterious by standard protein prediction programs were retained. A gene-based, case-control analysis using SKAT was performed to generate level of significance. Results: There were 93 cases of urgent HTN and 3000 matched controls. Patients with urgent HTN had a markedly superior DFS (p-value = 0.01) and superior OS (p-value = 0.02). There was no effect seen in the control arm. We also identified rare variants in SLC7A7 as predictors of urgent hypertension. Conclusions: Urgent HTN is associated with improved outcomes in the curative setting. We have also identified rare variants associated with severe HTN through WES. Exploring the biology of those who experience bevacizumab-induced HTN may help explain the heterogeneity of outcomes and elucidate secondary drug targets.
Strategic planning for implementation of Commission on Cancer standard 3.3 in a tertiary academic center.
Authors: Dori Klemanski, Thomas Scharschmidt, Maria-Teresa Ramirez, Kristine Browning, Rupa Ghosh-Berkebile, Rachée Hatfield, Denise Schimming, Maryam B. Lustberg
Journal: Journal of Clinical Oncology (2018)

58 Background: The Commission on Cancer (CoC) enacted a new accreditation standard (3.3) in 2012 to ensure cancer survivors treated with curative intent receive a Treatment Summary and Survivorship Care Plan (SCP) upon treatment completion. Accredited institutions reported challenges to meeting the standard such as lengthy completion time, lack of reimbursement, and limited personnel. In 2014, the CoC clarified 3.3 to allow a 5 year phased launch for institutions to be compliant by 2019. Yet, academic cancer centers continued to report difficulty in meeting annual targets. Methods: Annual goals for provision of SCPs to eligible survivors at The James Cancer Hospital were met in 2015 (10%) and 2016 (25%). Existing processes were not sufficient to meet the goal of 50% in 2017. Multiple stakeholders developed a performance improvement plan (PIP) to revise institutional practices to create a sustainable SCP delivery model. The Cancer Registry provided analytic case volumes. Results: Institutional barriers to SCP delivery included inconsistent data collection, multiple versions of a SCP, lack of personnel, a 3+ month wait time for information from Cancer Registry, and lack of provider awareness. Major tenets of the PIP were to: (1) integrate the SCP into the electronic medical record, (2) improve collection and accuracy of data, (3) initiate a hybrid (integrative and consultative) model of SCP delivery in which dedicated Advanced Practice Providers (APPs) are employed through a centralized survivorship center, (4) include provision of SCP as a metric on APP professional practice evaluations, (5) educate disease groups with high volumes of SCP eligible patients, (6) provide a quality scorecard, and (7) review eligibility criteria and the timeliness of Cancer Registry. Implementation of the PIP increased performance as the number of SCPs provided in January to September 2017 (n = 884) surpassed volume from the previous 2 years (2015 n = 617; 2016 n = 786). Conclusions: Academic cancer centers with high volumes of SCP eligible survivors often contend with barriers to meeting CoC standard 3.3. Implementation of the PIP, which improved performance in 2017, will be continually evaluated to meet the standard by 2019.
Communicating with children about parental cancer: The devil in the details.
Authors: Cynthia Moore, Sarah Shea, Kristin Russell, Mary Susan Convery, Paula K. Rauch
Journal: Journal of Clinical Oncology (2018)

81 Background: Parents with dependent children express concerns about cancer’s impact on children, and describe challenges with communication, such as deciding how to share news of a diagnosis (Asbury et al., 2014). Though open communication may contribute to better adjustment in children (Lindqvist et al., 2007), little is known about how parents typically talk to children at different developmental stages about their illness, and how soon information is shared after diagnosis. Methods: Five clinicians from a well-established parent guidance program provided 109 consultations to patients (68% female) treated in an urban Comprehensive Cancer Center and/or their co-parent. Consults occurred in outpatient offices (29%), inpatient units (37%) and by telephone (34%). Afterward, clinicians completed a questionnaire about parents’ communication with their children about cancer. Descriptive statistics summarize information shared by patient groups with different characteristics. Results: Children of patients ranged in age from several months old to mid-20’s. Cancer was recurrent in nearly 30% and metastatic in over half, and time since initial diagnosis ranged from within the past month to over 3 years ago. 39% of parents diagnosed in the past month had referred to their illness as “cancer” to children; 67% of those diagnosed 1-3 months ago, and 80-82% of parents diagnosed 4 or more months ago had named the illness “cancer.” Only 27% of parents whose oldest child was between 3-6 yrs, vs. 92% of parents whose oldest child was 18-21 years, used the term “cancer.” Clinician ratings indicated that 42% of parents with eldest child of 3-6 yrs would strongly agree that open communication about the illness would benefit children, vs. 61% of parents whose oldest child was 18-21 years. Conclusions: Many parents believe open communication about their cancer diagnosis will benefit children, yet about a fifth of parents had not used the word “cancer,” even three or more years after initial diagnosis. Language used to describe the illness to children relates both to children’s developmental stage and recency of the diagnosis. Results have implications for the design of parent guidance interventions.
Analysis of Genetic Variation Indicates DNA Shape Involvement in Purifying Selection
Authors: Xiaofei Wang, Tianyin Zhou, Zeba Wunderlich, Matthew T Maurano, Angela H DePace, Sergey V Nuzhdin, Remo Rohs
Journal: Molecular Biology and Evolution (2018)

Noncoding DNA sequences, which play various roles in gene expression and regulation, are under evolutionary pressure. Gene regulation requires specific protein-DNA binding events, and our previous studies showed that both DNA sequence and shape readout are employed by transcription factors (TFs) to achieve DNA binding specificity. By investigating the shape-disrupting properties of single nucleotide polymorphisms (SNPs) in human regulatory regions, we established a link between disruptive local DNA shape changes and loss of specific TF binding. Furthermore, we described cases where disease-associated SNPs may alter TF binding through DNA shape changes. This link led us to hypothesize that local DNA shape within and around TF binding sites is under selection pressure. To verify this hypothesis, we analyzed SNP data derived from 216 natural strains of Drosophila melanogaster. Comparing SNPs located in functional and nonfunctional regions within experimentally validated cis-regulatory modules (CRMs) from D. melanogaster that are active in the blastoderm stage of development, we found that SNPs within functional regions tended to cause smaller DNA shape variations. Furthermore, SNPs with higher minor allele frequency were more likely to result in smaller DNA shape variations. The same analysis based on a large number of SNPs in putative CRMs of the D. melanogaster genome derived from DNase I accessibility data confirmed these observations. Taken together, our results indicate that common SNPs in functional regions tend to maintain DNA shape, whereas shape-disrupting SNPs are more likely to be eliminated through purifying selection.
Role of the circadian system in cardiovascular disease
Authors: Saurabh S. Thosar, Matthew P. Butler, Steven A. Shea
Journal: Journal of Clinical Investigation (2018)

All species organize behaviors to optimally match daily changes in the environment, leading to pronounced activity/rest cycles that track the light/dark cycle. Endogenous, approximately 24-hour circadian rhythms in the brain, autonomic nervous system, heart, and vasculature prepare the cardiovascular system for optimal function during these anticipated behavioral cycles. Cardiovascular circadian rhythms, however, may be a double-edged sword. The normal amplified responses in the morning may aid the transition from sleep to activity, but such exaggerated responses are potentially perilous in individuals susceptible to adverse cardiovascular events. Indeed, the occurrence of stroke, myocardial infarction, and sudden cardiac death all have daily patterns, striking most frequently in the morning. Furthermore, chronic disruptions of the circadian clock, as with night-shift work, contribute to increased cardiovascular risk. Here we highlight the importance of the circadian system to normal cardiovascular function and to cardiovascular disease, and identify opportunities for optimizing timing of medications in cardiovascular disease.
Prospective study of chemotherapy-induced <i>clostridium difficile </i>infection in lung cancer patients.
Authors: Yukihiro Toi, Shunichi Sugawara, Takao Kobayashi, Yousuke Kawashima, Tatsuhiko Koizumi, Keito Okazaki, Masatoshi Takahara, Tomoya Kuda, Akiko Tanaka, Osamu Ishimoto, Yoshihiro Honda
Journal: Journal of Clinical Oncology (2012)

e19521 Background: Diarrhea after antibiotic treatment is primarily ascribed to the development of mucosal lesion for which Clostridium difficile infection (CDI) is held responsible. Evidence on CDI in patients on chemotherapy without antibiotic treatment prior to chemotherapy is on the rise. However there have been few reports describing diarrhea in relation to regimens of chemotherapy. The aim of our study was to find out whether the incidence of CDI in patients on cancer chemotherapy increases even in the absence of prior antibiotic treatment. Methods: From March 2010 through September 2011, we investigated the presence of Clostridium difficile (C.difficile) and its toxin in any patients undergoing diarrhea while receiving cytotoxic anticancer agents or epidermal growth factor receptor tyrosine kinase inhibitors. Whenever Grade2 or worse diarrhea defined by the Common Terminology Criteria for Adverse Events version4 occurred, we examined their stool samples for anaerobic culture and simultaneously tested for toxins A and B. A case of CDI is defined by the presence of symptoms (usually diarrhea) and either a stool test positive for C.difficile toxins or toxigenic C.difficile according to criteria of the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Results: A total of 345 consecutive patients (492 in terms of chemotherapy -regimens) were enrolled in this study. 36 of 492 regimens (7.3%) showed Grade2 or worse diarrhea. CDIs without prior antibiotic exposure were confirmed in as many as 8 out of these 36 regimens (22.2%). CDI was more frequently observed in patients of the regimens including S-1 or irinotecan than other anticancer drugs. Conclusions: CDI may remain undetected among patients who had diarrhea defined as above unless due attention is paid to this possibility. It is highly recommended to perform tests for the detection of C.difficile toxins so that necessary measures can be instituted without delay in the treatment of diarrhea of patients on chemotherapy. Further analysis for drugs specificity and prevention against CDI is necessary.