tbuckley/cabot-search huggingface dataset:
Strain-level analysis of gut-resident pro-inflammatory viridans group Streptococci suppressed by long-term cotrimoxazole prophylaxis among HIV-positive children in Zimbabwe
Authors: Ethan K. Gough, Claire D. Bourke, Chipo Berejena, Annie Shonhai, Mutsa Bwakura-Dangarembizi, Andrew J. Prendergast, Amee R. Manges
Journal: Gut Microbes (2020)

Antimicrobials have become a mainstay of healthcare in the past century due to their activity against pathogens. More recently, it has become clear that they can also affect health via their impact on the microbiota and inflammation. This may explain some of their clinical benefits despite global increases in antimicrobial resistance (AMR) and reduced antimicrobial effectiveness. We showed in a randomized controlled trial of stopping versus continuing cotrimoxazole prophylaxis among HIV-positive Zimbabwean children taking antiretroviral therapy (ART), that continuation of cotrimoxazole persistently suppressed gut-resident viridans group streptococcal species (VGS) that were associated with intestinal inflammation. In this addendum, we provide a broader overview of how antibiotics can shape the microbiota and use high read-depth whole metagenome sequencing data from our published study to investigate whether (i) the impact of cotrimoxazole on gut VGS and (ii) VGS associated inflammation, is attributable to strain-level variability. We focus on S. salivarius, the VGS species that was most prevalent in the cohort and for which there was sufficient genome coverage to differentiate strains. We demonstrate that suppression of S. salivarius by cotrimoxazole is not strain specific, nor did stool concentration of the pro-inflammatory mediator myeloperoxidase vary by S. salivarius strain. We also show that gut-resident S. salivarius strains present in this study population are distinct from common oral strains. This is the first analysis of how cotrimoxazole prophylaxis used according to international treatment guidelines for children living with HIV influences the gut microbiome at the strain-level. We also provide a detailed review of the literature on the mechanisms by which suppression of VGS may act synergistically with cotrimoxazole's anti-inflammatory effects to reduce gut inflammation. A greater understanding of the sub-clinical effects of antibiotics offers new insights into their responsible clinical use.
The FGFR-inhibitor derazantinib (DZB) is active in PDX-models of GI-cancer with specific aberrations in FGFR.
Authors: Paul McSheehy, Felix Bachmann, Nicole Forster-Gross, Mahmoud El Shemerly, Mila Roceri, Laurenz Kellenberger, Heidi A Lane
Journal: Journal of Clinical Oncology (2020)

421 Background: DZB is an oral small-molecule Fibroblast Growth Factor Receptor 1/2/3 inhibitor (FGFRi) with clinical activity in FGFR2-fusion-positive cholangiocarcinoma. DZB was screened for activity in gastrointestinal cancer (GIC), by using a panel of GIC cell-lines, human tumor xenografts and 30 GIC patient-derived xenograft (PDX) models. Methods: DZB anti-proliferative potency was determined in 26 GIC cell lines to determine the GI50. The GIC cell-line, SNU-16 was grown s.c. in nude mice and treated daily for 3-weeks with DZB at the MTD of 75 mg/kg, p.o. Plasma and tumor were removed and analyzed for drug-levels and PD biomarkers to assess pathway inhibition. DZB (@MTD) was tested in the PDX-screen (15 biliary, 13 gastric and 2 colorectal cancer; n≥3/group) using models with FGFR-fusions, FGFR-mutations and/or differing FGFR copy-number (CN)/RNA-seq expression levels. Efficacy and tolerability were quantified as a dT/C (treated/control). Results: Cellular GI50s ranged from 0.02-20 μM; the most sensitive (GI50≤0.5 μM) had FGFR-fusions or high-expression. In mice, DZB induced stasis of SNU-16 tumors (dT/C∼0.0) and was well tolerated (dT/C &gt; 1.0); the plasma PK was dose-dependent with a Cmax of 2 μM (4 hr), a Cmin of 0.5 μM. DZB induced dose- and time-dependent changes in the MAPK-pathway and expression of downstream genes, consistent with its mode of action. In PDX-models, efficacy varied from no-response to 100% regression. Known driver-mutations were associated with partial-responses (best dT/C = 0.42), but models with FGFR-fusions, especially FGFR2-fusions, were very sensitive leading to stasis or strong-regression, particularly in gastric cancer. High-expression of FGFR2 was also associated with strong responses. There was no direct correlation between CN and high RNA-seq values suggesting amplification was not always a predictor of high expression. Endpoint PD-analyses of the PDX-models is ongoing to identify other potential stratifiers and PD-markers of response. Conclusions: DZB showed convincing activity in GIC-models with FGFR-fusions and/or high expression. A clinical trial is planned in patients with gastric cancer to investigate DZB as mono- and combination-therapy.
Author response: The human cough reflex has separate, distinct pathways
Authors: Alyn H. Morice, Michael M. Kitt, Anthony P. Ford, Andrew M. Tershakovec, Wen-Chi Wu, Kayleigh Brindle, Rachel Thompson, Susannah Thackray-Nocera, Caroline Wright
Journal: European Respiratory Journal (2020)

We thank J.A. Smith and co-workers for their interest in our paper [1]. Perhaps an even more ancient truth, that of William of Occam [2], should be applied to this discussion. The human cough reflex has separate, distinct pathways <http://bit.ly/2PZgybq>
Time-varying risk of microvascular complications in latent autoimmune diabetes of adulthood compared with type 2 diabetes in adults: a post-hoc analysis of the UK Prospective Diabetes Study 30-year follow-up data (UKPDS 86)
Authors: Ernesto Maddaloni, Ruth L Coleman, Olorunsola Agbaje, Raffaella Buzzetti, Rury R Holman
Journal: The Lancet Diabetes & Endocrinology (2020)
A pilot clinical trial of p53/p16-independent epigenetic therapy for pancreatic ductal adenocarcinoma (PDA).
Authors: Davendra Sohal, Smitha S. Krishnamurthi, Rita Tohme, Dale Randall Shepard, Alok A. Khorana, Yogen Saunthararajah
Journal: Journal of Clinical Oncology (2020)

699 Background: PDA treatment is limited to cytotoxic drugs. A key factor limiting their efficacy is TP53 mutations, omnipresent in PDA, which counter apoptosis-mediated cell kill. We evaluated a novel epigenetic approach using decitabine (Dec) to inhibit DNA methyltransferase 1 (DNMT1) and effect cancer cell cycle exits by epithelial-differentiation, combined with tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA) and thereby permit oral bioavailability and solid-tissue distribution of Dec. Methods: Open-label single-arm, IRB-approved clinical trial at Cleveland Clinic and University Hospitals for patients with metastatic PDA that had progressed on prior chemotherapy, ECOG PS of 0-2. Treatment was oral, weight-based, with Dec 10-20 mg, and THU 500-1000 mg daily, 5 days/week. Primary endpoint was DNMT1 protein levels at 16-week vs baseline biopsies. Results: From Apr to Aug 2017, we enrolled 13 patients. Median age was 65 (range 44-74) years; 7 (54%) males; 11 (85%) Caucasians. Median time from diagnosis was 13 (3.9-53.5) months, with a median of 2 (1-3) prior lines of therapy. Baseline ECOG PS was 0/1 in 12 (92%) patients. All patients started study drugs; median time on treatment was 35 (4-63) days, and on study 72 (25-105) days. The most frequent adverse events attributable to the study drugs were anemia (n=5), and anorexia, dehydration, nausea, fatigue, febrile neutropenia and decreased lymphocyte count, in 3 patients each; no deaths. Eight (62%) patients underwent evaluation scans at 8 weeks, showing stable disease in 1 patient and progression in 7. Common reasons for coming off of study drugs were progression (n=6), physician discretion (n=3), and adverse events (n=2). Overall, 6 patients died; median survival was 3.1 months, and patients did not reach the 16-week biopsy. Shifts in blood counts, a sensitive indicator of Dec systemic activity, were unexpectedly mild, and plasma CDA enzyme activity was increased versus other cancer and normal controls. Conclusions: This first-of-its-kind study demonstrated feasibility and safety of the novel oral epigenetic therapy. Systemically elevated CDA in these patients requires higher doses of THU; a trial accordingly refined is planned. Clinical trial information: NCT02847000.
Groin Pain Syndrome Known as Sports Hernia
Authors: Brian S. Zuckerbraun, Anthony R. Cyr, Craig S. Mauro
Journal: JAMA Surgery (2020)

<h3>Importance</h3> Groin pain in active individuals and athletes without clinical evidence of hernia or hip pathologic findings is challenging for health care clinicians and aggravating for those experiencing pain. Frequently called<i>sports hernia</i>or<i>athletic pubalgia</i>, many surgeons continue to refute the diagnosis because there is a lack of consensus and clear comprehension of the basic pathophysiologic features of this groin pain syndrome. <h3>Observations</h3> Understanding the anatomic and pathophysiologic findings of groin pain syndrome is necessary to appropriately treat this problem. In general, the level of evidence of the literature is of relatively low quality. Exercise-based therapy can be an effective first-line therapy in individuals who develop groin pain syndrome. Surgical therapies are typically reserved for those who experience nonoperative management failure. The common features of the varied surgical procedures include the resultant changes in the vectors of pull on the pubic bone or joint, the defects in the inguinal canal, and the inguinal sensory nerve compression or bowstringing. <h3>Conclusions and Relevance</h3> The diagnosis of nonhip, nonhernia, chronic groin pain is common. Understanding the diagnosis and treatment options may facilitate recovery and allow return to an active lifestyle and sport.
David Oliver: There’s no dignity in hospital gowns
Authors: David Oliver
Journal: BMJ (2020)

I’ve often wondered why on earth we routinely put so many patients into hospital gowns within minutes of their arrival at hospital.

Sometimes referred to as “dignity gowns,” such dignity as they afford is only in comparison to being stark naked. They don’t come in a wide range of sizes or lengths, and they’re open along the back. You tend to get what you’re given and make do. The effect is to leave patients with lots of exposed flesh, with underwear or buttocks intermittently displayed and a feeling of extreme vulnerability, not to mention being cold if they have no other layers to wear.

We should bear in mind that patients in hospital—even those attending for planned investigations or …
Circulating levels of soluble urokinase plasminogen activator receptor (suPAR) to predict outcome after resection of biliary tract cancer.
Authors: Sven H Loosen, Annemarie Breuer, Frank Tacke, Patrick Hamid Alizai, Tom Florian Ulmer, Christian Trautwein, Thomas Longerich, Christoph Roderburg, Ulf Peter Neumann, Tom Luedde
Journal: Journal of Clinical Oncology (2020)

572 Background: Surgical resection is the only curatively intended therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better preoperative stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has recently been associated with cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing resection of BTC. Methods: Tumor expression of uPAR, the membrane bound source of suPAR, was analyzed by IHC in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 BTC patients and 76 healthy controls. Results: A high tumoral uPAR expression was associated with an adverse outcome after BTC resection. In line, circulating levels of suPAR were significantly elevated in BTC patients compared to healthy controls and patients with primary sclerosing cholangitis (PSC). Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72ng/ml for BTC patients. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including clinicopathological parameters such as the tumor stage, markers of systemic inflammation or organ dysfunction and established tumor markers revealed suPAR as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative for acute kidney injury after tumor resection. Conclusions: Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might be useful to preoperatively identify the ideal candidates for tumor resection.
Tissue-specific pathways extrude activated ILC2s to disseminate type 2 immunity
Authors: Roberto R. Ricardo-Gonzalez, Christoph Schneider, Chang Liao, Jinwoo Lee, Hong-Erh Liang, Richard M. Locksley
Journal: The Journal of Experimental Medicine (2020)

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells prominent at barrier sites. Although precursors are found in blood, mature ILC2s can enter the circulation after small intestinal perturbation by migratory helminths and move to distant tissues to influence the local reparative response. Using fate-mapping and methods to bypass the lung or intestinal phases of Nippostrongylus brasiliensis infection, we show that blood ILC2s comprise heterogeneous populations derived from distinct tissues that are dependent on alarmins matched to the receptor profile of the specific tissue ILC2s. Activation of local ILC2s by tissue-specific alarmins induced their proliferation, lymph node migration, and blood dissemination, thus systemically distributing type 2 cytokines. These studies uncover a possible mechanism by which local innate responses transition to systemic type 2 responses by extrusion of activated sentinel ILC2s from tissue into the circulation.
Coronavirus: NHS staff get power to keep patients in isolation as UK declares “serious threat”
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The UK government has declared that the incidence or transmission of the novel coronavirus 2019-nCoV constitutes a serious and imminent threat to public health.

The announcement means that England’s health secretary, Matt Hancock, can enact regulations to ensure that the public is “protected as far as possible from the transmission of the virus.” This includes designating Arrowe Park Hospital, Merseyside, and the Kents Hill Park hotel and conference centre, Milton Keynes, as isolation facilities.

It also means that NHS staff members have “strengthened powers” to keep patients in isolation if public health professionals believe there to be a “reasonable risk an individual may have the virus.”

As at 10 February eight people in the UK had tested positive for 2019-nCoV. Globally, the virus has spread to 28 countries, with more than 40 000 cases and 900 deaths.

Hancock said, “Clinical advice has not changed about …
A phase Ib/II study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer (mCRC) in patients with a KRAS mutation.
Authors: Heinz-Josef Lenz, Daniel H. Ahn, Maya Ridinger, Mark G. Erlander, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2020)

TPS265 Background: FOLFOX (5-flourouracil, leucovorin, oxaliplatin) and FOLFIRI (fluorouracil, leucovorin, irinotecan) in combination with targeted agents are standard-of-care options for patients for mCRC with response rates &gt;50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 4% for FOLFIRI + bevacizumab and treatment options are limited in particular for the 50% of patients harboring a RAS mutation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase, master regulator of G2/M cell-cycle progression and genome wide RNAi screens identified PLK1 to be synthetic lethal for KRAS mutated tumor cells inducing cell cycle arrest and apoptosis. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrated single agent activity and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated cells showed higher sensitivity to onvansertib than isogenic KRAS wild-type cells. PLK1 inhibition is a potential target in KRAS-mutated mCRC and onvansertib + FOLFIRI may provide a new second-line treatment option. Methods: The primary objective of this single-arm Phase 1b/2 study (NCT03829410) is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. The phase 1b will determine the MTD or RP2D using a traditional 3+3 design, with onvansertib initial dose at 12 mg/m 2 . The phase 2 will enroll 26 patients at the RP2D to further assess the safety of the combination and to evaluate preliminary anti-tumor activity measured by objective response rate (ORR, RECIST v1.1). Based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory studies include quantitation of KRAS circulating tumor DNA (ctDNA) and genomic studies of circulating tumor cells and ctDNA to determine altered pathways associated with patient response. Clinical trial information: NCT03829410.
Retrospective analysis for efficacy and safety of nivolumab in advanced gastric cancer patients (pts) with malignant ascites.
Authors: Akinori Sugaya, Shunsuke Ueyama, Hirosumi Suzuki, Takeshi Yamada, Yoshiyuki Yamamoto, Toshikazu Moriwaki, Ichinosuke Hyodo
Journal: Journal of Clinical Oncology (2020)

392 Background: Nivolumab is a standard of care as the later-line therapy for advanced gastric cancer. However, there are few data about efficacy and safety of nivolumab for pts with malignant ascites. Methods: We conducted a multicenter retrospective study for pts with advanced gastric cancer who received nivolumab alone from Oct. 2017 to Feb. 2019. Pts were divided into two groups; high ascites burden (HAB) with moderate or massive ascites and non-HAB with none or a small amount of localized ascites at pelvis and/or liver surface. Results: A total of 72 pts (23 pts with HAB and 49 pts with non-HAB) were evaluable. The HAB group had more pts with young (median 62 vs 70 years), female (35 vs 14 %), no prior gastrectomy (63 vs 35 %) and poor performance status (PS &gt; 1; 26 vs 10 %), compared to the non-HAB group. Disease control rate was 44% (95% CI 23-64%) in the HAB group and 57% (95% CI 43-71%) in the non-HAB group. Ascites decreased in 4 pts (17%) and completely disappeared in 2 pts (8.7%) in the HAB group. These 6 pts were all male and had prior ramucirumab treatment with a mean neutrophil-lymphocyte ratio 2.1 (from 0.85 to 3.7) at the initiation of nivolumab. After 5 months of follow up period, disease progression or death events for progression-free survival (PFS) occurred in 74% of the HAB group and 53% of the non-HAB group. Median PFS was 1.0 (95%CI 0.5-1.5) and 2.6 (95%CI 0.9-7.4) months in pts with HAB and non-HAB, respectively. PFS rates at 6 months were 31% in the HAB group and 33% in the non-HAB group. Immune-related adverse events occurred in 26% of the HAB group and 16% of the non-HAB group including one and two pts with grade 3 or 4 events, respectively. There was no treatment-related death in both groups. Conclusions: Although pts with HAB showed trends of worse outcomes compared with those with non-HAB, nivolumab was suggested to provide a survival benefit to some pts with HAB, and was tolerable in the HAB group.
Connective tissue disease-associated interstitial lung disease
Authors: R.P. Oliveira, R. Ribeiro, L. Melo, B. Grima, S. Oliveira, J.D. Alves
Journal: Pulmonology (2020)

Connective tissue diseases (CTD) are frequently associated with interstitial lung disease (ILD), significantly impacting their morbidity and mortality.Analyze the experience of an autoimmune specialized unit on treating CTD-ILD and characterize the population based on most frequent diseases, imaging patterns, lung function tests results, serology and treatment. Assess mortality and mortality predictors in these patients.Retrospective, descriptive and statistical analysis of the CTD-ILD patients followed up at an autoimmune diseases unit during a 6-year period.Over the study period, 75 patients with CTD-ILD were treated with a mean follow-up of 49 ± 31 months. The most frequent CTD were systemic sclerosis and rheumatoid arthritis. ILD was diagnosed prior to CTD in 8% of patients and concomitantly in 35%. Nonspecific interstitial pneumonia was the CT pattern in 60% and 35% had an isolated diminished DLCO on lung function tests. Pulmonary hypertension was present in 12% and it was the single most important mortality predictor (OR 14.41, p = 0.006). Corticosteroids are the mainstay of treatment but biologics were prescribed in 39% of the patients (mostly tocilizumab and rituximab). Two scleroderma patients were recently treated with nintedanib.ILD is a potential complication of every CTD and can impose a dramatic burden on these patients. The clinical relevance of ILD together with their early expression in the course of the disease underlines the importance of the presence of chest physicians in these units.
Incidence and outcomes of infective endocarditis after transcatheter aortic valve implantation versus surgical aortic valve replacement
Authors: L. Fauchier, A. Bisson, J. Herbert, T. Lacour, T. Bourguignon, C. Saint Etienne, A. Bernard, P. Deharo, L. Bernard, D. Babuty
Journal: Clinical Microbiology and Infection (2020)