tbuckley/cabot-search huggingface dataset:
The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
Authors: Sara Canovas Nunes, Martina Manzoni, Marco Pizzi, Elisa Mandato, Marilena Carrino, Laura Quotti Tubi, Renato Zambello, Fausto Adami, Andrea Visentin, Gregorio Barilà, Livio Trentin, Sabrina Manni, Antonino Neri, Gianpietro Semenzato, Francesco Piazza
Journal: Blood Cancer Journal (2018)

Abstract Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3 . Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression.
The effect of chemotherapy on the tumor immune microenvironment in non-small cell lung cancer (NSCLC): A single-institution retrospective analysis.
Authors: Michael Edward Devitt, Kristine E Gade, Richard Delmar Hall, Bethany J Horton, Edward B Stelow, Timothy Bullock, Ryan D. Gentzler
Journal: Journal of Clinical Oncology (2018)

155 Background: Platinum-doublet chemotherapy (chemo) is routinely used for treatment of early stage and metastatic NSCLC. Immunotherapy is a proven treatment in these patients as well. The presence of tumor infiltrating lymphocytes (TILs) has been shown to be prognostic of this disease; however, the effect of chemo on TILs and the tumor immune microenvironment in NSCLC has not been well studied. We tested the hypothesis that chemo results in a decrease in the presence of TILs in NSCLC. Methods: We retrospectively identified patients treated with neo-adjuvant platinum-doublet chemo who underwent surgical resection from 2007-2015 at the University of Virginia. The specimens were sectioned and IHC stained for CD8, FoxP3, and PD-L1. Two independent investigators assessed a central and a peripheral high power field of tumor for number of CD8 and FoxP3 positive TILs. An independent pathologist assessed tumor cell PD-L1 expression. The nonparametric Wilcoxon Mann Whitney test was used to compare measurements of TILs in chemo-exposed tissue to a control cohort from a database of NSCLC surgical specimens that had not received pre-operative therapy. Results: Of the 17 patients who met eligibility criteria, 11 had sufficient tissue for evaluation. Results are shown in Table 1. There was a significant decrease in CD8 and FoxP3 TILs in both the center and periphery in patients exposed to chemo. There was no difference in PD-L1 expression. Conclusions: These data suggest that platinum-doublet chemo significantly decreases the presence of cytotoxic and regulatory subsets of TILs without effecting PD-L1 expression. This study is limited by the lack of pre-treatment tumor samples to compare pre- and post-treatment TILs in individual patients. Further studies are warranted to evaluate the impact of decreased TILs in the setting of concurrent or sequential immunotherapy treatment with chemo in NSCLC. [Table: see text]
Walter Werner Holland: pioneer of European public health
Authors: Martin McKee, Peter Burney
Journal: BMJ (2018)

Walter Werner Holland was professor of clinical epidemiology and social medicine at St Thomas’ Hospital from1968 to 1994. He was born into a Jewish family in Czechoslovakia, and his father, who had previously helped Germans fleeing the Nazi regime, left for England immediately after the German occupation of Prague in 1939. By switching trains in Germany he crossed the border out of the country in a train that was not thoroughly searched. Soon after, Walter and his mother followed. Other family members were not so lucky; his grandmother perished in Theresienstadt concentration camp. Despite initially speaking little English, he was an accomplished student at Rugby School and subsequently at St Thomas’ Hospital Medical School. His interest in research was kindled when he was among a handful of students in his year to be selected for an intercalated BSc in physiology, graduating in 1951 and, subsequently, MBBS in 1954.

During national service with the Royal Air Force, Walter was posted to the Central Public Health Laboratory Service to work on vaccines against adenoviruses, but, in what would prove a serendipitous mistake, the manufacturers inadvertently destroyed a batch of vaccine, and he was offered the chance …
Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?
Authors: Claudia R. Morris, David T. Mauger, Jung H. Suh, Wanda Phipatanakul, William J. Sheehan, James N. Moy, Ian M. Paul, Stanley J. Szefler, Daniel J. Jackson, Anne M. Fitzpatrick, Deborah Gentile, Erica Butler, Jennifer Maiolo, Sara Misplay, David Skoner, Glennys Smith, Jacqueline Pongracic, Rachel Robison, Iliana Flexas, Rajesh Kumar, Melanie Makhija, Nashmia Qamar, Christine Szychlinski, Fernando Martinez, Wayne Morgan, Cori Daines, Michael Daines, Valerie Bloss, Mark Brown, Katherine Chee, Sarah David, Clara S. Ehrman, Dima Ezmigna, Jamie Goodwin, Roni Grad, Anunya Hiranratta, Silvia Lopez, Andrea Paco, Janette Priefert, Natalie S. Provencio, Elizabeth Ryan, Monica Varela, Monica Vasquez, Rosemary Weese, Jesus Wences, Mindy Benson, Claudia Morris, Jung Suh, Jyothi Marbin, Jason Decker, Keonna Harrison, Dayna Long, Kelley Meade, Robert Mok, Cindy Nelson-Purdy, Dennis Ren, Hollie Stessel, Wanda Phipatanakul, William Sheehan, Jonathan Gaffin, Sachin Baxi, Lisa Bartnikas, Alisha Bouzaher, Christopher Burke, Matthew Cavanaugh, Julia Chen, Elizabeth Cunningham, Amparito Cunningham, James Friedlander, Enal Hindi, David Kantor, Lianne Kopel, Perdita Permaul, Deviko Rao, Melinda Rossi, Doris Schierembergg, Lynda Schneider, Jennifer Troung, Dale Umetsu, Joseph Zhou, Elliot Israel, Stanley Szefler, Fernando Holguin, Shean Aujla, John Broyles, Hey Chong, Patricia Dubin, Jonathan Finder, Todd Green, Lori Holt, Adam Kufen, Geoffrey Kurland, Rose Lanzo, David Nash, Julianne Parente, Catherine Smith, Jonathan Spahr, Daniel Weiner, Anne Fitzpatrick, Timothy Beaty, Shanae Wakefield Brown, Alice Bruce, Jennifer Dodds, Shaneka Douglas, Karen Freedle, Dawn Simon, Denise Whitlock, Ronina Covar, Tod Olin, Melanie Gleason, Gayle Spears, D. Sundstrom, Michael White, Kathryn Blake, John Lima, Jenny Batalla, Michelle Littlefield, Burnese Rutledge, Deanna Seymour, Jason Lang, Shanae Brown, Omar OquendoFlores, David Mauger, Ian Paul, Sue Boehmer, Loretta Doty, Beth Gern, Aimee Merchlinski, Jonathan Nelson, James Schmidt, Lindsay Texter, Angela Updegrave, Jennifer Zeller, Ronald Zimmerman, James Chmiel, Ross Myers, Kristie Ross, Daniel Craven, Amy DiMarino, Meeghan Hart, Leigh Kerns, Laurie Logan, Laura Veri, James Moy, Christopher Codispoti, Jun Fu, Grace Li, Diana Munoz-Mendoza, Shannon Stevens, Benjamin Thompson, Samantha Zitzer, Michaal Cabana, Stephen Lazarus, Ngoc Ly, Shannon Thyne, Jessica Bowman, Vicky Bowyer, Judy Gonzales-Vargas, Michelle McKean, Nancy Tran, Harsha Vardhan Kumar, Hengameh Raissy, Christina Batson, Lea Davies, Franceska Kelly, Esmeralda Morales, Abby Redway, Mary Spicher, Robert Lemanske, Daniel Jackson, Christine Sorkness, Lauren Kaminski, Megan Knutson, Shelly Olson, Sheila Turcsanyi, Tanya Watson, Stephen Peters, Adam Gower, Cheryl Wilmoth, Leonard Bacharier, Avraham Beigelman, Wanda Caldwell, Courtney Dula, Alysa Ellis, Caroline Horner, Lila Kertz, Tina Norris, Katherine Rivera-Spoljaric, Oscar Rodriguez, Robert Strunk
Journal: Journal of Allergy and Clinical Immunology (2018)
Weekly Versus Daily Dipeptidyl Peptidase 4 Inhibitor Therapy for Type 2 Diabetes: Systematic Review and Meta-analysis
Authors: Tomohide Yamada, Nobuhiro Shojima, Hisashi Noma, Toshimasa Yamauchi, Takashi Kadowaki
Journal: Diabetes Care (2018)

Once-weekly dipeptidyl peptidase 4 inhibitors (weekly DPP-4is) were recently developed in addition to the once-daily agents (1), and weekly DPP-4is may improve compliance by reducing the burden of medication. Omarigliptin and trelagliptin are the weekly DPP-4is currently available in Japan. We performed a meta-analysis to assess the efficacy and safety of weekly DPP-4is compared with daily DPP-4is and placebo for type 2 diabetes.

This research was carried out according to a predetermined protocol (CRD42017069004) and followed the standard guidelines for conduct and reporting of systematic reviews and meta-analyses (Supplementary Appendices 1 and 2). We searched MEDLINE, EMBASE, and the Cochrane Library up to 16 September 2017. Prospective randomized double-blind trials of weekly DPP-4is performed in adults with type 2 diabetes using an intervention period of at least 12 weeks were identified. Studies were excluded if other aspects of treatment were targeted, if not double-blind (e.g., open-label or crossover), or if the follow-up period was <12 weeks. Studies of children and observational studies were also ineligible. We checked the reference lists of the original studies, review articles, and meta-analyses identified by our searches to find other eligible trials. There were no language restrictions. Two reviewers independently assessed the studies and extracted data. Bias was analyzed with the Cochrane Collaboration tool. Meta-analysis was performed by a …
Using grade of tumor recurrence after BCG to guide further therapy.
Authors: Roger Li, Michael J. Metcalfe, William Tabayoyong, Charles Guo, Graciela M. Nogueras-Gonzalez, Neema Navai, H. Barton Grossman, Colin P.N. Dinney, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2018)

523 Background: Tumors that recur after BCG therapy are considered to be high risk and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. We aimed to characterize the pattern of bladder cancer progression and cancer specific survival (CSS) in patients with recurrences dichotomized by low grade versus high grade after intravesical BCG treatment. Furthermore, to assess the safety of continued bladder sparing therapy in these patients. Methods: We performed an IRB approved review of our bladder cancer database. Overall, 146 NMIBC patients were found to have tumor recurrence after induction BCG with/without maintenance therapy, 38 with LG and 108 with HG tumors. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity and concurrent CIS were collected and compared between the two groups. The primary endpoint was PFS, with progression defined as the development of MIBC/distant metastasis. In addition, RFS, HG RFS, CFS, and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two-sided and p &lt; 0.05 was considered statistically significant. Results: As dichotomized by grade of recurrent tumor, estimated 5-year PFS was 85.6% (95% CI 60.8 - 95.2%) for those with LG recurrence and 67.9% (95% CI 54.1 – 78.4%) for those with HG recurrence. On KM analysis, patients whose initial LG recurrence on BCG therapy had improved subsequent RFS (5.2 vs. 2.8 yrs, p = 0.007), HG RFS (9.4 vs. 3.0 yrs, p &lt; 0.001), CFS (p &lt; 0.001), and compared to those who had a HG initial recurrence; CSS benefit approached significance (3.7 vs. 2 yrs, p = 0.12). Grade of tumor recurrence after BCG was an independent predictor of PFS (HR 3.7, 95% CI 1.3-10.9, p = 0.016). Conclusions: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/MUC. However, patients who have low grade recurrences on BCG still may progress and hence should be carefully counselled on bladder sparing therapy.
CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation
Authors: Carole Le Coz, Melissa Trofa, Camille M. Syrett, Anna Martin, Harumi Jyonouchi, Soma Jyonouchi, Montserrat C. Anguera, Neil Romberg
Journal: Journal of Allergy and Clinical Immunology (2018)
I'm expecting an offer of a job as locum consultant in Gibraltar for two weeks. Anyone got any advice?
Authors: James Sherifi
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
We must train more doctors to meet workforce shortages, says LMC leader
Authors: Abi Rimmer
Journal: BMJ (2015)

The UK needs to train more doctors to meet workforce shortages in general practice and other specialties, says Kieran Sharrock, medical director of Lincolnshire Local Medical Committee (LMC).

Sharrock said that practices in Lincolnshire were struggling to recruit GPs, a problem faced by practices across the country. The …
The impact of American Indian and Alaska Native ethnicity on the presentation and surgical treatment of gastric cancer: An NCDB analysis from 2004-2014.
Authors: Brooke Vuong, Samuel Jacob Klempner, Trang Nguyen, Stephanie Young, Ahmed Dehal, Amanda Graff-Baker, Shu-Ching Chang, Anton J. Bilchik, Melanie Goldfarb, Trevan D Fischer
Journal: Journal of Clinical Oncology (2018)

13 Background: American Indian/Alaska Natives (AI/ANs) with gastric adenocarcinoma (GC) have an incidence and mortality nearly double that of matched Non-Hispanic Whites (NHW) in historical data sets. However, the impact of AI/AN ethnicity on disease presentation and treatment is underrepresented in gastric cancer epidemiologic studies and has not been evaluated in a contemporary population. Methods: The National Cancer Data Base (NCDB) was queried from 2004-2014 to identify patients with gastric cancer who identify as AI/AN or NHW. Patient demographics, tumor characteristics, and treatment details, including surgical quality metrics, were compared using Chi-square and Student's t-tests. Results: There were 22,286 NHW and 115 AI/AN GC patients with complete staging information. Compared to NHW, AI/ANs were younger (age ≤65) at diagnosis (p &lt; 0.001), which translated to a younger median age at death (NHW:70 years, AI/ANs:60 years, p &lt; 0.001). AI/ANs more often lived over 100 miles from their treatment facility (p &lt; 0.001) in non-metropolitan cities (p &lt; 0.001). Stage distribution was not different for the AI/AN population when compared to the NHW population: 37% vs. 35% Stage I; 33% vs. 37% Stage II; 10% vs. 11% Stage III; and 19% vs. 16% Stage IV (p = NS). However, AI/ANs had a higher rate of signet ring cell histology and linitis plastica (26% vs. 15%, p = 0.002) compared to NHWs. More AI/AN patients compared to NHW patients had delays over eight weeks to initiation of treatment, 19% vs. 11% (p = 0.008). There were no statistically significant differences for surgical quality metrics, including type of surgery, rate of ≥15 lymph nodes retrieved, margin positivity, or 30-day mortality (p = NS). Conclusions: Both biological and social disparities are evident for AI/ANs with gastric cancer. AI/ANs develop and die from gastric cancer at younger ages compared to NHWs and present with higher rates of aggressive histology. They also travel longer distances for treatment and experience greater treatment delays. These features may partly underlie the higher mortality rates previously described.
Introduction of #PancChat: A novel Twitter platform to inform and engage the pancreatic cancer community.
Authors: Allyson J. Ocean, Niraj Jaysukh Gusani, Muhammad Shaalan Beg, Anirban Maitra, Julissa Viana, Allison Rosenzweig, Fatima Zelada-Arenas, Andrew Whiteley, Cassie Huneke, Cindy Price Gavin, Susan Randel, Lisa M Frame
Journal: Journal of Clinical Oncology (2018)

242 Background: Twitter provides a platform for health care stakeholders to disseminate information about diseases to patients, caregivers, and doctors. Chats are especially effective because participants can interact directly with experts. Pancreatic cancer (PC) conversations on Twitter previously were sporadic and inconsistent. The authors report the creation of #PancChat, a first-of-its-kind Tweet Chat developed to provide relevant, credible, and timely information to the PC community. A collaboration between leading PC organizations, a pharmaceutical company, and an academic oncologist, PancChat is an example of successful outreach using an accessible communications tool. Methods: Launched in April 2016, the hour-long monthly chat is a live event publicized and promoted through multiple social media channels and major news outlets. It is moderated and focused around a pre-selected topic. The hashtag #PancChat is used to filter specific chatter into a single conversation. Participants include patients, caregivers, physicians, researchers, top ASCO social media influencers, AACR members, and advocacy organizations. Moderators and participants are drawn from 23 academic institutions. The PancChat team corresponds with participants and replies to tweets that are not addressed during the chat. Results: Since its inception, PancChat has had a total of 28 million impressions (the total number of times each tweet is seen) from 16 chats, averaging 1.75 million per chat. Popular topics include clinical trials (1.4 million), familial/hereditary PC (2.9 million), and early detection (2.2 million). The average engagement rate is 72% which measures how much people interact with a tweet by clicking or sharing links. From April 2016-August 2017 there were 8,502 tweets using #PancChat. Conclusions: Impression and engagement numbers show that this novel PancChat platform fulfills a need for the PC community. The narrow focus of each chat provides an opportunity to learn about the disease, research, and clinical trials. Participants return knowing that they will interact with PC experts. The popularity of PancChat among patients and doctors confirms the power of social media to reach a specific community.
BMA should campaign for more flexible working, say medical academics
Authors: Abi Rimmer
Journal: BMJ (2014)

The BMA should campaign for more flexible working arrangements for all doctors, the BMA’s Medical Academic Staff Committee has said.

Speaking at the Conference of Medical Academic Representatives in London last week, Lucy-Jane Davis, a specialty trainee in public health, presented a motion calling for flexible and individualised working arrangements to be used to support doctors with caring responsibilities.

The motion, which was supported by delegates at …
Making the best use of clinical radiology services: Referral guidelines. Sixth edition
Authors: Amy Davis
Journal: BMJ (2007)

I'm sure that, like me, you can remember being a house officer making the long trek to the radiology department armed with your request form. You had been told by your consultant not to return to the ward without a guarantee the test would “happen today.” You would have to face down the radiologist, asking for a test to be done urgently, and, like me, you probably had no idea why you wanted the test or why it had to be done “today.”

As much as I hated doing this, I am sure …
On the Regulatory Evolution of New Genes Throughout Their Life History
Authors: Jia-Yu Zhang, Qi Zhou
Journal: Molecular Biology and Evolution (2018)

Every gene has a birthplace and an age, that is, a cis-regulatory environment and an evolution lifespan since its origination, yet how the two shape the evolution trajectories of genes remains unclear. Here, we address this basic question by comparing phylogenetically dated new genes in the context of both their ages and origination mechanisms. In both Drosophila and vertebrates, we confirm a clear "out of the testis" transition from the specifically expressed young genes to the broadly expressed old housekeeping genes, observed only in testis but not in other tissues. Many new genes have gained important functions during embryogenesis, manifested as either specific activation at maternal-zygotic transition, or different spatiotemporal expressions from their parental genes. These expression patterns are largely driven by an age-dependent evolution of cis-regulatory environment. We discover that retrogenes are more frequently born in a pre-existing repressive regulatory domain, and are more diverged in their enhancer repertoire than the DNA-based gene duplications. During evolution, new gene duplications gradually gain active histone modifications and undergo more enhancer turnovers when becoming older, but exhibit complex trends of gaining or losing repressive histone modifications in Drosophila or vertebrates, respectively. Interestingly, vertebrate new genes exhibit an "into the testis" epigenetic transition that older genes become more likely to be co-occupied by both active and repressive ("bivalent") histone modifications specifically in testis. Our results uncover the regulatory mechanisms underpinning the stepwise acquisition of novel and complex functions by new genes, and illuminate the general evolution trajectory of genes throughout their life history.