tbuckley/cabot-search huggingface dataset:
Circulating T <sub>FH</sub> cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity
Authors: Marios Koutsakos, Adam K. Wheatley, Liyen Loh, E. Bridie Clemens, Sneha Sant, Simone Nüssing, Annette Fox, Amy W. Chung, Karen L. Laurie, Aeron C. Hurt, Steve Rockman, Martha Lappas, Thomas Loudovaris, Stuart I. Mannering, Glen P. Westall, Michael Elliot, Stuart G. Tangye, Linda M. Wakim, Stephen J. Kent, Thi H. O. Nguyen, Katherine Kedzierska
Journal: Science Translational Medicine (2018)

Analysis of influenza-specific B cells during antigen exposure and tissue compartmentalization provides insights into human B cell memory.
Variable Response to Naltrexone in Patients With Hailey-Hailey Disease
Authors: Severine Cao, Evelyn Lilly, Steven T. Chen
Journal: JAMA Dermatology (2018)

cate that use of indoor tanning, which exposes users to intense levels of UV radiation, and the prevalence of sunburn, a biological indicator of overexposure to UV radiation, have decreased in recent years, particularly among adolescents and young adults. 5,6 Decreases in indoor tanning and sunburn would be expected to result in decreases in melanoma incidence rates over time.Although primary skin cancer prevention efforts have often focused on children, adolescents, and young adults, the steady increase in melanoma incidence rates among older adults indicates a need for efforts that promote skin cancer preventive behaviors throughout adulthood.Such efforts could focus on groups at high risk, such as outdoor workers and intentional tanners.
In the Balance
Authors: Aaron Richterman, Anand Vaidya, Jenifer M. Brown, David A. Braun, Martin A. Samuels
Journal: New England Journal of Medicine (2018)

A 71-year-old man presented to the emergency department with a 3-day history of changes in mental status. His partner noted that the patient had become more irritable than usual and was behaving as if other people were in the room with him when no one else was present. The patient had also had several episodes of uncontrollable laughter for no apparent reason. . . .
Recruitment and localization of eosinophils to glioma
Authors: Ralph Pero, Christopher Lipinski, Nancy Lee, James Lee
Journal: Cancer Research (2007)

558  Complex interplay between neoplasm and the peri-tumor microenvironment influences disease progression. Local release of a cadre of bioactive molecules by both tumor and stromal component cells leads to the recruitment of inflammatory cells the pathobiological significance of which has not been well delineated. Eosinophils have been observed in regions of tumor necrosis where they are thought to be involved in tissue remodeling. Indeed conditioned media from necrotizing tumor cells contain potent eosinophil chemoattractant(s). No information currently exists describing the role of eosinophil recruitment to CNS tumors, such as oligodendrogliomas and glioblastomas (GBM). Anti-MBP antibody (eosinophil-specific marker) staining of human brain tumor biopsies reveals that eosinophils localize to necrotic areas and the tumor rim. To further investigate specific localization pattern of eosinophils in glioma, purified, fluorescently-labeled eosinophils were injected ipsilaterally into the brains of athymic nude mice bearing established intracranial GBM xenografts. Twenty-four hours following eosinophil insertion, the mice were sacrificed and brains examined by fluorescence microscopy. Fluorescently-labeled eosinophils were observed exclusively surrounding tumor foci with none seen independent of tumor. Intriguingly, labeled eosinophils could be seen surrounding tumor foci in the contralateral hemisphere, which suggests a very dynamic honing process. Further studies are ongoing to determine the mode of eosinophil migration within the CNS and to compare outcomes of xenograft mice with and without eosinophil allografts.
Income inequality and depression: a systematic review and meta‐analysis of the association and a scoping review of mechanisms
Authors: Vikram Patel, Jonathan K. Burns, Monisha Dhingra, Leslie Tarver, Brandon A. Kohrt, Crick Lund
Journal: World Psychiatry (2018)

Most countries have witnessed a dramatic increase of income inequality in the past three decades. This paper addresses the question of whether income inequality is associated with the population prevalence of depression and, if so, the potential mechanisms and pathways which may explain this association. Our systematic review included 26 studies, mostly from high‐income countries. Nearly two‐thirds of all studies and five out of six longitudinal studies reported a statistically significant positive relationship between income inequality and risk of depression; only one study reported a statistically significant negative relationship. Twelve studies were included in a meta‐analysis with dichotomized inequality groupings. The pooled risk ratio was 1.19 (95% CI: 1.07‐1.31), demonstrating greater risk of depression in populations with higher income inequality relative to populations with lower inequality. Multiple studies reported subgroup effects, including greater impacts of income inequality among women and low‐income populations. We propose an ecological framework, with mechanisms operating at the national level (the neo‐material hypothesis), neighbourhood level (the social capital and the social comparison hypotheses) and individual level (psychological stress and social defeat hypotheses) to explain this association. We conclude that policy makers should actively promote actions to reduce income inequality, such as progressive taxation policies and a basic universal income. Mental health professionals should champion such policies, as well as promote the delivery of interventions which target the pathways and proximal determinants, such as building life skills in adolescents and provision of psychological therapies and packages of care with demonstrated effectiveness for settings of poverty and high income inequality.
Cost per median overall survival month for abiraterone acetate and enzalutamide for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dominic Pilon, Patrick Lefebvre, Marykay Queener, Lorie Ellis
Journal: Journal of Clinical Oncology (2015)

e16080 Background: Phase 3 trials of abiraterone acetate plus prednisone (AA+P) or enzalutamide (ENZ) in asymptomatic/mildly symptomatic chemotherapy-naïve mCRPC patients demonstrated significant improvement in overall survival (OS). Clinical trials comparing the magnitude of OS benefit for AA+P to ENZ have not been completed. In the absence of head-to-head trials, indirect comparisons may be used to assess the cost effectiveness of these agents in mCRPC. To calculate the cost per median OS month in asymptomatic/mildly symptomatic chemotherapy-naive mCRPC patients treated with AA+P or ENZ. Methods: Median treatment duration and median OS data from published phase 3 trials and prescribing information (PI) were used to calculate cost per median OS month based on Wholesale Acquisition Costs (WAC) effective on 8/5/2014 for mCRPC patients treated with AA+P versus ENZ. Sensitivity analyses were performed to understand how variation in treatment duration and treatment-related monitoring recommendations influenced cost per median OS month. Results: The results demonstrated that AA+P was associated with lower cost per median OS month than ENZ (36% reduction; $2,888 vs. $4,513). The results and data used for calculations are shown in the TABLE. Sensitivity analyses showed treatment-related monitoring costs added approximately $64 per OS month for AA+P while assuming 17.5 months of therapy for AA+P would add $774 per OS month. In these sensitivity analyses scenarios, cost per median OS month remained lower for AA+P than for ENZ. Conclusions: This cost effectiveness analysis demonstrated that cost per median OS month is 36% lower for AA+P than for ENZ and remains lower for AA+P overall even when estimated AA+P treatment-related monitoring costs or equivalent duration of therapy are assumed. These results have important implications for population health decision makers evaluating relative value of therapies for this patient population. Treatment Median Treatment Duration (months) WAC Per 30 day Supply Total Drug Cost Median OS (months) Cost per Median OS Month AA+P 13.8 $7,387.53 $101,948 35.3 $2,888 ENZ 17.5 $8,355.03 $146,213 32.4 $4,513
A phase 1 study of the PI3K/mTOR inhibitor PQR309 evaluating safety, pharmacokinetics (PK) and pharmacodynamics (PD) in patients (pts) with advanced solid tumors.
Authors: Alex A. Adjei, Grace K. Dy, Yujie Zhao, Wen Wee Ma, Mateusz Opyrchal, Hatoon Bakhribah, Sandra M Jacob, Corrie O'Hara, Askia Dozier, Natasa Cmiljanovic, Barbara Todaro, William E. Brady, Debora Schmitz, Sasa Dimitrijevic
Journal: Journal of Clinical Oncology (2016)

2560 Background: PQR is an oral pan-PI3K, mTORC1/mTORC2 inhibitor in clinical development. Methods: A Phase I trial of PQR to evaluate safety, PK and PD in pts with advanced solid tumors was performed, using the standard “3+3” design. Pts with ECOG PS of 0-1 were treated with escalating doses of PQR administered on a once daily continuous dosing schedule (qd). The dose limiting toxicity (DLT) period was the first 21 days of treatment. PK samples were obtained at predefined time points. Blood samples for the evaluation of glucose, insulin and c-peptide as PD markers were obtained at multiple time points. Results: 16 pts (11F:5M) were enrolled as of November 30 2015 and treated at 3 doses of PQR (80, 100 and 120 mg) qd. Median duration of therapy was 50 days (range 7 – 255). Adverse events (AEs) in ≥ 50% pts included fatigue, hyperglycemia, rash, nausea, vomiting, diarrhea and weight loss. Drug related grade 3 AEs seen in more than 1 pt were fatigue, hyperglycemia, rash and elevated transaminases. DLT’s were grade 3 fatique in 3 pts at 120mg and 1 pt at 100mg qd. However, dose interruptions at the 100mg dose indicated that this was not a tolerable dose. Thus the recommended phase II dose (RP2D) and MTD is 80 mg qd. PK analysis shows fast absorption (Tmax 1-2h), dose proportionality, an accumulation ratio of about 3.6 and an estimated T1/2 of 51 hours. Blood PD analysis demonstrated concentration dependent elevations in glucose, insulin and c-peptide within 2 hours after the administration of PQR. One pt with progressing mesothelioma had stable disease (SD) for 8.5 months. One pt each with leiomyosarcoma and ovarian cancer had SD for 3 months. Conclusions: Consistent with an earlier study, the MTD and RP2D of PQR is 80mg qd. Concentration dependent hyperglycemia has been confirmed as a mechanism-based toxicity and will be investigated as a PD marker. The concomittant increase in serum insulin suggests that insulin should not be the initial therapy to manage drug-induced hyperglycemia. Glucose transport inhibitors may be the treatment of choice in management of hyperglycemia. Recruitment in the 80mg qd expansion cohort with a focus on tumors with PI3 kinase pathway aberrations is ongoing. Clinical trial information: NCT02483858.
Indian clinical guidelines lack scope, rigour, and quality, study finds
Authors: Dinsa Sachan
Journal: BMJ (2018)

Most clinical practice guidelines in India do not meet international standards in either their scope, the way they were developed, or the independence of their authors, a study has found.1

Indian guidelines should be better regulated by introducing a central approval system, said lead researcher Soumyadeep Bhaumik, a former student of international public health at Liverpool School of Tropical Medicine, UK, and a former associate editor of The BMJ .

For the study, researchers examined 11 clinical practice guidelines for the four conditions that account for the highest disease burden in India—ischaemic heart disease, lower respiratory infections, chronic obstructive pulmonary disease, and tuberculosis.

These guidelines were …
Response to: ‘Is the PET/CT first choice for differential diagnosis of FUO/IUO?’ by Armagan <i>et al</i>
Authors: Verena Schönau, Georg Schett
Journal: Annals of the Rheumatic Diseases (2018)

We thank Dr Armagan and colleagues for their letter1 regarding our article entitled, ‘The value of 18F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study’.2

In their comment, Dr Armagan and colleagues ask whether a fixed cut-off level for the maximum standardised uptake value (SUVmax) in the 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) was …
Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial
Authors: Derek J Jonker, Louise Nott, Takayuki Yoshino, Sharlene Gill, Jeremy Shapiro, Atsushi Ohtsu, John Zalcberg, Michael M Vickers, Alice C Wei, Yuan Gao, Niall C Tebbutt, Ben Markman, Timothy Price, Taito Esaki, Sheryl Koski, Matthew Hitron, Wei Li, Youzhi Li, Nadine M Magoski, Chiang J Li, John Simes, Dongsheng Tu, Christopher J O'Callaghan
Journal: The Lancet. Gastroenterology & hepatology (2018)
Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma
Authors: Valerie Chew, Yun Hua Lee, Lu Pan, Nurul J M Nasir, Chun Jye Lim, Camillus Chua, Liyun Lai, Sharifah Nur Hazirah, Tony Kiat Hon Lim, Brian K P Goh, Alexander Chung, Richard H G Lo, David Ng, Rene L F Filarca, Salvatore Albani, Pierce K H Chow
Journal: Gut (2018)

Objectives Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response. Design Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. Results TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8 + T cells, CD56 + NK cells and CD8 + CD56 + NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB + CD8 + T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8 + and CD4 + T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1 + /Tim-3 + CD8 + T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. Conclusion High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.
Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin
Authors: Wei Jiang, Xiaoyan Zhou, Zengxia Li, Kaiyu Liu, Weige Wang, Renke Tan, Xiaoji Cong, Jiaoyu Shan, Yanxia Zhan, Zhaomeng Cui, Lizhi Jiang, Quanfu Li, Suqin Shen, Meirong Bai, Yunfeng Cheng, Bin Li, Minjia Tan, Dengke K. Ma, Jun O. Liu, Yongjun Dang
Journal: Blood (2018)
Abstract 19433: Should Bilateral Internal Thoracic Artery Grafting be Used in Patients After Recent MI?
Authors: Dan Loberman, Rephael Mohr, Mohamad Medleg, Nachum Nesher, Zahi Aizer, Yoseph Paz, Dmitri Pevni, Yanai Ben Gal
Journal: Circulation (2015)

Introduction: Bilateral internal thoracic artery(ITA) grafting is associated with improved survival. However, many surgeons are reluctant to use this revascularization technique in patients after myocardial infarction (MI) due to the risk of sternal infection and the excellent survival benefit obtained with single ITA (SITA). Hypothesis: Long-term outcome of bilateral ITA (BITA) grafting, might be superior to single ITA and other conduits such as saphenous veins (SVG) and radial artery (RA) in patients with multi-vessels disease after recent MI. Methods: 871 patients who underwent BITA grafting after recent MI (&lt;3 months prior to surgery), between 1996 and 2010, Were compared with 527 who underwent CABG with SITA and SVG or RA. Results: Patients undergoing SITA were older, more often female, more likely to have COPD, EF&lt;30%, preoperative critical state, Diabetes, chronic renal failure (CRF), peripheral vascular disease (PVD) and emergency operation. In contrast, patients undergoing BITA grafting were more likely to have triple vessel disease and more often underwent CABG with three or more grafts and sequential grafts. Operative mortality of BITA patients was lower (3.0 % vs. 5.7%, in the SITA group p=0.01), Occurrences of sternal wound infection (3% vs 2%) and strokes (2.6% vs. 3%) were similar. Mean follow-up was 11.8 (95%CI 10.95-12.56) years. Kaplan Meier survival of BITA patients was better (70.3% vs.52.6% p&lt;0.001). Propensity score matching was used to account for differences between groups in preoperative characteristics. The 293 matched pairs thus created had similar preoperative characteristics. Kaplan Meier 10 year survival (67.3% versus 59%, p=0.325 log-rank test), and the Cox adjusted survival of the matched groups did not reach statistical significance (HR 1.57, p=0.091). However, survival of non- emergent BITA patients was better (HR 1.256 p=0.038). Age, COPD, CHF, CRF, PVD and left main were independent predictors of decreased survival. Off-pump operations were associated with improved survival (Cox model) Conclusions: This study suggests that long-term outcome of arterial revascularization with BITA can be better than that of SITA in non-emergency cases after recent MI with proper patient selection
Provider Types and Outcomes in Obstructive Sleep Apnea Case Finding and Treatment
Authors: Ken M. Kunisaki, Nancy Greer, Wajahat Khalil, Erin Koffel, Eva Koeller, Roderick MacDonald, Timothy J. Wilt
Journal: Annals of Internal Medicine (2018)

Background: Obstructive sleep apnea (OSA) diagnosis and care models rely on sleep specialist physicians (SSPs) and can be expensive and inefficient. Purpose: To assess OSA case-finding accuracy and comparative effectiveness of care by non–sleep specialists (NSSs) and SSPs. Data Sources: MEDLINE and CINAHL from January 2000 through July 2017. Study Selection: English-language trials or observational studies comparing case finding or care by SSPs versus providers not specifically trained as SSPs (NSSs) for adults with suspected or diagnosed OSA. Data Extraction: One investigator extracted data and assessed risk of bias and strength of evidence, with confirmation by a second investigator. Primary outcomes were patient-centered (mortality, access to care, quality of life, patient satisfaction, adherence, symptom scores, and adverse events). Intermediate outcomes included resource use, costs, time to initiation of treatment, and case finding. Data Synthesis: Four observational studies (n = 580; mean age, 52 years; 77% male) reported good agreement between NSSs and SSPs on appropriate diagnostic testing and classification of OSA severity (low-strength evidence). Five randomized trials and 3 observational studies (n = 1515; mean age, 52 years; 68% male) found that care provided by NSSs and SSPs resulted in similar quality of life, adherence, and symptom scores (low-strength evidence). Evidence was insufficient for access to care and adverse events. Limitations: Many outcomes were reported infrequently or not at all. Many NSSs had extensive training or experience in sleep medicine, which limits generalizability of findings to providers with less experience. Conclusion: Care by NSSs and SSPs resulted in similar outcomes in adults with known or suspected OSA. Studies are needed to determine care model implementation and reproducibility of results in nonacademic settings and among less experienced NSSs. Primary Funding Source: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42016036810 [full Veterans Affairs Evidence-based Synthesis Program report])
Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study
Authors: Gabriella Ferlazzo, Erika Mohr, Chinmay Laxmeshwar, Catherine Hewison, Jennifer Hughes, Sylvie Jonckheere, Naira Khachatryan, Virginia De Avezedo, Lusine Egazaryan, Amir Shroufi, Stobdan Kalon, Helen Cox, Jennifer Furin, Petros Isaakidis
Journal: The Lancet Infectious Diseases (2018)
Man wins right to take assisted dying case to Court of Appeal
Authors: Anne Gulland
Journal: BMJ (2018)

A retired lecturer with advanced motor neurone disease has been granted permission to appeal a decision rejecting his challenge to the current law on assisted dying.

Noel Conway, from Shropshire, was given a diagnosis of amyotrophic lateral sclerosis, a form of motor neurone disease, in 2014. He says that the current law banning assisted dying is incompatible with his human rights, …
Correction: How I do colonoscopy
Authors: Jerome Waye, Siwan Thomas-Gibson
Journal: Endoscopy (2018)

Correction Waye JD, Thomas-Gibson S. How I do colonoscopy Endoscopy 2018, DOI: 10.1055/s-0043-124969 The institute affiliation of Siwan Thomas-Gibson has been corrected. This was corrected in the online version on February 9, 2018
Role of PAK1 and PAK2 kinases in Snail phosphorylation and in the epithelial-mesenchymal transition
Authors: Salam Shaaban, Matthew O'Connor, Iain Mulford, Stuart Thomson, John Haley, Jonathan Pachter
Journal: Cancer Research (2007)

1025   The epithelial-mesenchymal transition (EMT) can convert epithelial tumor cells to a more metastatic phenotype characterized by enhanced cell migration and invasion, increased resistance to anoikis and apoptosis, and greater resistance to chemotherapy or molecular targeted therapeutics. PAK1 was reported to phosphorylate Snail, a transcriptional repressor that acts as a master regulator of the epithelial-mesenchymal transition, on serine 246. Ser246 phosphorylation by PAK1 in MCF7 breast cancer cells was reported to be important for Snail translocation to the nucleus where it could repress target genes such as E-cadherin, aromatase, and occludin. Here we present supporting evidence for a positive role of both PAK1 and PAK2 kinases in a TGFβ-driven EMT model. We show that TGFβ treatment of the epithelial H358 NSCLC cell line results in downregulation of epithelial markers (E-cadherin, ErbB3) and upregulation of mesenchymal markers (N-cadherin, Snail, ZEB1). siRNA oligos targeting both PAK1 and PAK2 abolished many of the EMT marker changes induced by TGFβ, whereas siRNA oligos targeting only PAK1 or PAK2 alone were insufficient to suppress these EMT marker changes. Importantly this effect was correlated with the inhibition of Snail phosphorylation on Ser246, translocation to the nuclear compartment, and protein accumulation. In addition, expression of the PAK1 auto-inhibitory domain (AID), which acts as a dominant negative inhibitor of both PAK1 and PAK2 function, was demonstrated to inhibit Snail phosphorylation and nuclear localization in HeLa cells. These findings indicate that dual inhibition of PAK1 and PAK2 may be a promising approach to inhibit Snail-mediated EMT for treatment of cancer.