tbuckley/cabot-search huggingface dataset:
Reduced salivary secretion contributes more to changes in the oral microbiome of patients with primary Sjögren’s syndrome than underlying disease
Authors: Taco A van der Meulen, Hermie J M Harmsen, Hendrika Bootsma, Silvia C Liefers, Arnau Vich Vila, Alexandra Zhernakova, Rinse K Weersma, Fred K L Spijkervet, Frans G M Kroese, Arjan Vissink
Journal: Annals of the Rheumatic Diseases (2018)

The oral microbiome of patients with primary Sjogren’s syndrome (pSS) differs from that of healthy individuals.1–3 Whether these changes are the consequence of reduced salivary secretion or specific for pSS is yet unknown. Therefore, the aim of our study was to assess whether patients with pSS have a specific oral microbiome compared with symptom controls (patients without SS, indicated as non-SS patients) and healthy controls (HCs).

To capture the overall bacterial composition in the mouth, we collected oral washings instead of buccal swabs from 121 consecutive patients referred for a diagnostic pSS workup and 14 volunteers without oral or ocular dryness (HCs). Patients fulfilling the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria were classified as pSS (n=36) and patients not fulfilling the criteria as non-SS (n=85) (table 1).4 

View this table:

Table 1 
Patient characteristics*



Bacterial composition was assessed with 16S rRNA gene sequencing of the V4 region. Reads were processed and diversity was analysed with QIIME V.1.9.1.5 All samples were equated to 8000 reads/sample. Comparative statistics were performed in R V.3.4.2.6 For details see online Supplementary text.

### Supplementary file 1

[SP1.docx] 

Alpha diversity, that is, the number of bacterial taxa and proportion in which each taxon is represented per sample was measured by the number of observed operational taxonomic units and Shannon index. Alpha diversity was similar between pSS, non-SS and HCs, indicating that oral washings of …
Targeting Pin1 by inhibitor API‐1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development
Authors: Wenchen Pu, Jiao Li, Yuanyuan Zheng, Xianyan Shen, Xin Fan, Jian‐Kang Zhou, Juan He, Yulan Deng, Xuesha Liu, Chun Wang, Shengyong Yang, Qiang Chen, Lunxu Liu, Guolin Zhang, Yu‐Quan Wei, Yong Peng
Journal: Hepatology (2018)

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that peptidyl‐prolyl cis ‐ trans isomerase NIMA‐interacting 1 (Pin1) participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with the Pin1 inhibitor (API‐1), a specific small molecule targeting Pin1 peptidyl‐prolyl isomerase domain and inhibiting Pin1 cis ‐ trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API‐1‐induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low exportin‐5 (XPO5) phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated serine‐proline motif of phosphorylated XPO5 and passivates phosphorylated XPO5. Pin1 inhibition by API‐1 maintains the active conformation of phosphorylated XPO5 and restores XPO5‐driven precursor miRNA nuclear‐to‐cytoplasm export, activating anticancer miRNA biogenesis and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Conclusion : Experimental evidence suggests that Pin1 inhibition by API‐1 up‐regulates miRNA biogenesis by retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1‐mediated miRNA biogenesis and unequivocally supporting API‐1 as a drug candidate for HCC therapy, especially for Pin1‐overexpressing, extracellular signal–regulated kinase–activated HCC. (H epatology 2018).
ASSOCIATION OF CHRONIC KIDNEY DISEASE WITH USE OF REVASCULARIZATION AND IN-HOSPITAL MORTALITY IN PATIENTS WITH CARDIOGENIC SHOCK COMPLICATING ACUTE MYOCARDIAL INFARCTION
Authors: Tanush Gupta, Dhaval Kolte, Sahil Khera, Kashish Goel, Pedro Villablanca, Wilbert Aronow, Anna Bortnick, Gregg C. Fonarow, Charanjit Rihal, Mark Menegus, Mario J. Garcia, Giora Weisz, Deepak Bhatt
Journal: Journal of the American College of Cardiology (2018)
Sudden Death in Heart Failure With Preserved Ejection Fraction
Authors: Muthiah Vaduganathan, Brian L Claggett, Neal A Chatterjee, Inder S Anand, Nancy K Sweitzer, James C Fang, Eileen O'Meara, Sanjiv J Shah, Sheila M Hegde, Akshay S Desai, Eldrin F Lewis, Jean Rouleau, Bertram Pitt, Marc A Pfeffer, Scott D Solomon
Journal: JACC Heart Failure (2018)
Дыхательный водородный тест в диагностике патологии желудочно-кишечного тракта
Authors: Yu.M. Stepanov, I.Ya. Budzak, I.S. Konenko
Journal: GASTROENTEROLOGY (2020)

Статья содержит информацию о современном методе оценки состояния тонкого кишечника — дыхательном водородном тесте. Отдельно анализируются 2 основных показания для его использования — синдром избыточного бактериального роста в тонкой кишке и лактазная недостаточность. Показаны теоретические и практические аспекты использования дыхательного водородного теста. Приведены основные положения 1-го Римского консенсуса по использованию дыхательного водородного теста. В статье представлены результаты собственных исследований.
MYOCARDIAL INFARCTION PRECLUDES COMPENSATORY MITRAL VALVE ENLARGEMENT IN THE DILATED LEFT VENTRICLE
Authors: Claudia Cote-Laroche, Marine Clisson, Marc-Andre Bouchard, Mark Handschumacher, Ons Marsit, Robert Levine, Philippe Pibarot, Marie-Annick Clavel, Jonathan Beaudoin
Journal: Journal of the American College of Cardiology (2018)
Enobosarm: A targeted therapy for metastatic, androgen receptor positive, breast cancer.
Authors: Beth Overmoyer, Pedro Sanz-Altamira, Ryan P. Taylor, Michael L. Hancock, James T. Dalton, Mary Ann Johnston, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2014)

568 Background: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer (BC) with 75-95% of estrogen receptor positive (ER+) and 50% of ER negative BCs expressing AR. Prior studies have shown that women with metastatic BC (MBC) who are progressing on tamoxifen subsequently respond to non-tissue-selective, synthetic androgens with overall response rates of 20-60%. Unfortunately steroidal androgens have unwanted virilizing effects which limit clinical use. Enobosarm, a nonsteroidal, tissue-selective, AR modulator (SARM), provides a novel targeted approach to exploit the therapeutic benefits of AR activation without virilization or estrogenic effects. Methods: A proof of concept, phase II study is examining efficacy and safety of enobosarm 9mg daily in 22 postmenopausal women with ER+ MBC who previously responded to adjuvant and/or salvage endocrine therapy. Treatment continues until disease progression (PD). Primary endpoint is clinical benefit response (CBR) by 6 months (m) defined as patients (pts) having a complete response (CR), partial response (PR), or stable disease (SD). CBR will be correlated with AR status of metastatic tumor biopsy. Serum prostate specific antigen (PSA) will be evaluated as a biomarker of AR activity. Results: Pt demographics: mean age 63.7 years, mean time from diagnosis 11 years, 68% prior chemo, 94% (15/16) AR+. After a median f/u of 85 days (d) (range 84-209d), preliminary results of 16 pts: 8 SD as best response, median duration 4.5m; 9 PD after a median 84d. Among pts who reached 6m, 3 are AR+ with SD and increased PSA. 7 have yet to reach 6m and no CR or PR has been observed. Enobosarm is well-tolerated, with no drug related serious adverse events. Conclusions: Enobosarm is well tolerated and demonstrates promise as a novel targeted therapy for AR+ MBC. The primary endpoint has been achieved, with 3/15 AR+ pts meeting statistical threshold for success. Serum PSA appears to be a surrogate marker for AR activity and disease response. Final analysis is due in June 2014. Clinical trial information: NCT01616758.
Prospective analysis of somatic and germline genetic alterations in patients with ampullary carcinomas.
Authors: Winston Wong, Eileen Mary O'Reilly, Anna M. Varghese, Kenneth H. Yu, Christine A Iacobuzio-Donahue, Jinru Shia, David Klimstra, Peter J. Allen, Maeve Aine Lowery
Journal: Journal of Clinical Oncology (2018)

308 Background: Ampullary carcinoma (AC) is a rare gastrointestinal cancer. Germline alterations (GA) in BRCA2 have been identified in patients with AC. Also, potentially targetable somatic alterations (SA) in other genes including ERBB2, and ELF3 have been identified in AC. MSKCC has implemented an opt-in strategy for germline (GT) and somatic genetic testing (ST) for patients with AC. Methods: Patients (pts) with pathologically confirmed AC were consented prospectively for ST using MSK-IMPACT (410 genes). A subset of pts was also consented for GT using MSK-IMPACT (76 genes) under an IRB approved protocol. Clinicopathologic features, treatment history and survival data were collected and analyzed. Results: N = 36 AC pts consented to ST from 9/2016 to 4/2017 of which 19/36 (52.7%) were male. Median age at diagnosis was 63 years, range 35-81. Pathology: 6/36 (16.7%) intestinal subtype, 19/36 (52.7%) pancreaticobiliary subtype, 4/36 (11.1%) mixed type, and 7/36 (19.4%) undifferentiated/other subtypes.29/36 (80.5%) pts had a family history of cancer. SA in KRAS 11/36 (30.5%), MDM2 (AMP) 6/36 (16.7%), ERBB2 3/36 (8.3%), PIK3cA 3/36 (8.3%), and ELF3 2/36 (5%) were seen in the highest frequency. 15/36 (41.6%) pts also consented for GT. Subgroup analysis revealed 4/15 (26.6%) pts with GA. Table 1 summarizes this subgroup. Conclusions: SA/GA in multiple genes including BRCA2, ERBB2/ELF3, and NTRK were observed. Also, novel GA in ATM (13%) and SA in MDM2 (AMP) (16.7%) were identified. Correlations of pathologic subtypes to clinical history, outcomes and mutations will be reported at the meeting. Further investigation of SA/GA in this disease is warranted given potential therapeutic and family screening implications. [Table: see text]
Just half of trainees approved for transfer moved locations in 2012
Authors: Zosia Kmietowicz
Journal: BMJ (2013)

Fewer than half of the 500 or so trainees who were approved to leave the place where they were training in 2012 were allocated a place in their desired new location, a BMJ Careers investigation has found.

The findings show that the proportion of trainees placed through the interdeanery transfer system has fallen steadily in the past three years: from 69% (329 of 475) in 2010 to 51% (255 of 496) in 2011 and 47% …
Response to Comment on de Carvalho et al. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years. Diabetes Care 2018;41:364–367
Authors: Luiz Sérgio F. de Carvalho, Alessandra M. Campos, Andrei C. Sposito
Journal: Diabetes Care (2018)

We thank Drs. Cao and Li for their comment (1) on our article (2). We also think that the tools available to check the risk of any rare adverse event, such as worsening type 2 diabetes or new-onset diabetes, lack precision. In our case, a large set of evidence and the potential clinical utility of therapy with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) provide plausibility for the investigation and relevance for the report.

A major limitation that we had to deal with in our meta-analysis is the fact that PCSK9i studies were not designed for testing the hypothesis and hence no information was available on the concomitant use and titration of antidiabetes medicines up or down. This drawback may certainly …
Param Jeet Singh Sandhu
Authors: Sukhpal Shergill
Journal: BMJ (2018)

Param Jeet Singh Sandhu (known to his friends as PJ) had a reputation for being a compassionate and caring GP with a dedicated following of devoted patients and staff. PJ defended the traditional holistic role of the general practitioner fervently, which was one of the many reasons why his patients respected and trusted him.

He took a passionate interest in supporting his GP …
GMC bans doctors from signing contracts containing “gagging” clauses
Authors: Clare Dyer
Journal: BMJ (2012)

Doctors should boycott “gagging” clauses in agreements with employers or contracting bodies that try to stop them raising concerns about patients’ safety or quality of care, new guidance from the General Medical Council recommends.

Mirror guidance for doctors in management roles will put them under a corresponding duty not to propose or condone contracts or agreements containing such clauses.

Gagging clauses still appear, despite NHS guidance as far back as 1999 that all trusts should “prohibit confidentiality ‘gagging’ clauses in contracts of employment and compromise agreements which seek to prevent the disclosure of information in the public interest.”

The House of Commons health select committee …
Real world experience of docetaxel in elderly patients with advanced prostate cancer.
Authors: Simon Yuen Fai Fu, Paula Barlow, Carmel Maree Jacobs, Fritha J. Hanning, Peter C.C. Fong
Journal: Journal of Clinical Oncology (2018)

313 Background: Docetaxel (D) chemotherapy is a standard of care in men with advanced prostate cancer (APC), both metastatic castration sensitive (CS) and castration resistant (CR) disease. The risk of significant toxicities may deter D use in elderly patients. We aim to evaluate the real world efficacy and tolerability of D in men with APC. Methods: Between 04/2014 and 05/2017, data from men aged ≥75 with APC treated at Auckland City Hospital with 3 weekly D were retrospectively collected from the genitourinary medical oncology database. Results: 33 (CS 12, CR 21) men were identified. 70% had PSA decline ≥50% (CS 92%, CR 57%). Median time to next line of therapy was 0.5 y in the CR arm. One third (n = 2/6) of CR patients on opioid had improved pain control with D. 75% had upfront dose reduction (DR). The median dose intensity was 21 mg/m 2 /wk (CS) and 18 mg/m 2 /wk (CR). 9 patients had dose escalation after upfront DR, all but 3 needed DR later, and none was escalated to 75 mg/m 2 . 58% (CS 75%, CR 48%) completed 6 cycles, and only 6% (n = 2) completed 6 cycles at 75 mg/m 2 . 24% had ≥G3 hematological toxicities. Febrile neutropenia rate was 12% (CS 8%, CR 14%). Pegfilgrastim was used in 1 CS and 1 CR men. Admission rate was 39% (CS 25%, CR 48%), 77% (CS 100%, CR 70%) was treatment related, and 23% (CR 30%) due to malignancy. 15% (CS 25%, CR 9%) required RBC transfusions. 33% CR men progressed while on treatment, and two deaths from pneumonitis and disease progression were noted. Conclusions: Docetaxel is active in elderly men with APC. Toxicities are manageable but can be life-threatening. Admission is frequent especially in CR patients. Proactive dose reduction should be considered to balance benefits vs. risks in this population. [Table: see text]
IMPACT OF PERIPROCEDURAL MYOCARDIAL BIOMARKER ELEVATION ON MORTALITY FOLLOWING PERCUTANEOUS CORONARY INTERVENTION: A POOLED PATIENT-LEVEL (N=13452) ANALYSIS OF CONTEMPORARY STENT TRIALS
Authors: Hector Manuel Garcia Garcia, Eugene McFadden, Clemens von Birgelen, Tessa Rademaker-Havinga, Neal Kleiman, David Cohen, Kevin Kennedy, E. Camenzind, Laura Mauri, Philippe Steg, William Wijns, Sigmund Silber, Gerrit-Anne van Es, Patrick Serruys, Stephan Windecker, Donald Cutlip, Pascal Vranckx
Journal: Journal of the American College of Cardiology (2018)
Survey analysis: Assessing the needs of immunotherapy patients, caregivers, and health care providers.
Authors: Anabella Aspiras, Nicholas James Power, Maria Belen Gonzalo
Journal: Journal of Clinical Oncology (2018)

135 Background: As the use of cancer immunotherapy increases, unique challenges emerge for both patients undergoing immunotherapy and the clinical staff who care for them. To better understand these challenges, the Cancer Support Community (CSC) conducted surveys of patients, caregivers, and healthcare staff (e.g. oncologists, nurses, social workers) at nine oncology centers across the country. Methods: Needs assessments were conducted through paper and online surveys between August and September, 2017. The analysis is based upon a cross-sectional survey of adult (18 years old and older) cancer patients, caregivers, and healthcare providers. 93 healthcare providers, 65 patients, and 21 caregivers completed the survey. Descriptive statistics and statistical analyses were performed using SPSS Version 24; analyses of association used a significance level of .05. Results: Findings from this analysis yielded important provider perspectives and illustrated targeted areas of patient and caregiver concern. Of note, while only about one-third of patients and caregivers (31% and 38%, respectively) indicated that it was important to understand the science of immunotherapy, nearly half of healthcare providers (46%) reported that educational resources should go “quite a bit” in-depth into immunotherapy science. Also, although caregivers reported greater difficulty finding information about immunotherapy, the majority of both patients (55%) and caregivers (85%) identified managing treatment-related side effects as their foremost education need. Conclusions: CSC’s analysis revealed valuable insights in both clinical care and patient education. Needs assessment results will inform the development and implementation of Immunotherapy &amp; Me, a CSC pilot program to determine whether layering in patient education and care-management tools leads to improved patient and clinical outcomes. CSC’s needs assessments conclude that for both patients and providers, treatment-related side effects are top-of-mind. This underscores the importance of developing turnkey resources to help patients and healthcare providers manage immunotherapy-related side effects – an express goal of the Immunotherapy &amp; Me pilot.
I have passed the Professional and Linguistic Assessments Board (PLAB) part 1 examination and now I want to do a clinical attachment before taking PLAB part 2. How do I go about this?
Authors: Jo Constable
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>
P049 Characterisation of the antibody response to a citrullinated peptide derived from porphyromonas gingivalis pad in RA
Authors: N Kharlamova, B Brynedal, N Sherina, K Eriksson, T Lindberg, M Hansson, L Israelsson, J Steen, V Malmström, L Alfredsson, K Amara, K Lundberg
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Anti-citrullinated protein antibodies (ACPA) – a hallmark of rheumatoid arthritis – antedate joint inflammation. Based on the epidemiological association between RA and periodontal disease (PD),<sup>1</sup> it has been suggested that break of tolerance to citrullinated proteins may occur in the gum mucosa. This hypothesis is primarily based on the unique feature of <i>Porphyromonas gingivalis</i> (<i>P.g</i>) – a keystone pathogen in PD – to express a bacterial version of the peptidyl arginine deiminase enzyme (denoted <i>P.</i>PAD), capable of autocitrullination.<sup>2</sup> <h3>Objectives</h3> In the present study, we have investigated the antibody response against CPP3, a citrullinated peptide derived from <i>P.</i>PAD, in order to address the hypothesis that <i>P.g</i> may drive ACPA-production. <h3>Methods</h3> <h3>This study included</h3> 2,859 RA cases and 4864 controls from the Epidemiological Investigation of RA (EIRA) cohort; 65 PD patients and 59 periodontally healthy individuals; and 218 monoclonal antibodies, derived from RA B cells. Reactivity with citrullinated <i>P.g</i> and human antigens was assayed by ELISA and/or multiplex. Associations with genetic risk factors and smoking were determined by logistic regression. Monoclonal antibody mutations were analysed by IgBLAST comparison. <h3>Results</h3> Anti-CPP3 IgG was detected in 11% of RA, 10% of PD and &lt;2% of controls, with higher levels in RA compared to PD. These antibodies clustered outside the classical ACPA response, associated with smoking, but not with major genetic risk factors. Two CPP3-reactive monoclonal antibodies were identified; one which cross-reacted with citrullinated human vimentin and had extensive mutations, indicating antigen-driven clonal selection and affinity maturation. <h3>Conclusions</h3> Based on these data, we propose that <i>P.g</i> infection triggers an antibody response to CPP3, which cross-reacts with citrullinated human proteins by mechanisms of molecular mimicry. Future studies should address whether anti-CPP3 IgG could serve as a biomarker to identify individuals with PD at increased risk for RA. <h3>References</h3> . Fuggle NR, Smith TO, et al. Hand to mouth: A systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Frontiers in Immunology2016;7:80. . Quirke AM, et al. Heightened immune response to autocitrullinated porphyromonas gingivalis peptidylarginine deiminase: A potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Annals of the Rheumatic Diseases2014;73(1):263–269. <h3>Disclosure of interest</h3> None declared
Abstract P2-07-04: Molecular regulators of resistance and relapse in chemorefractory triple-negative breast cancers
Authors: BA Hancock, Y-H Chen, JP Solzak, MN Ahmad, DC Wedge, D Brinza, C Scafe, J Veitch, R Gottimukkala, W Short, RV Atale, M Ivan, SS Badve, BP Schneider, KD Miller, M Radovich
Journal: Cancer Research (2018)

Abstract Triple-Negative Breast Cancer (TNBC) accounts for approximately one-fifth of breast cancer incidence but disproportionately high mortality. Two-thirds of early-stage TNBCs are resistant to pre-surgical chemotherapy and highly prone to relapse within 3 years. Morever, no advanced therapies are indicated for patients with these cancers. We have embarked on a comprehensive genomic analysis of chemoresistant TNBC to gain an in-depth understanding of molecular entities driving chemoresistance and relapse. By collecting somatic mutation and copy number, RNA-sequencing, and outcome data in the context of a phase II post-neoadjuvant clinical trial, we have uncovered several molecular mechanisms behind these aggressive cancers. Through the analysis of matched pairs sampled before and after chemotherapy, we have discovered multiple means by which tumors are able to overcome the effects of chemotherapy including clonal evolution of high-level oncogene amplification, repression of the in situ immune system, and upregulation of the stem cell-related MEK-ERK and JAK-STAT pathways. Investigation into factors related to prognosis revealed important correlations between relapse and immune and JAK-STAT signaling. Finally, using a novel method of demarcating loss-of-function of p53, which we have termed graduated inactivation, we discovered additional associations between p53 loss and relapse, mortality, and MYC signalling. Citation Format: Hancock BA, Chen Y-H, Solzak JP, Ahmad MN, Wedge DC, Brinza D, Scafe C, Veitch J, Gottimukkala R, Short W, Atale RV, Ivan M, Badve SS, Schneider BP, Miller KD, Radovich M. Molecular regulators of resistance and relapse in chemorefractory triple-negative breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-04.