tbuckley/cabot-search huggingface dataset:
ACL injuries: the secret probably lies in optimising rehabilitation
Authors: Adam G Culvenor, Christian J Barton
Journal: British Journal of Sports Medicine (2018)

Since the first report of surgical repair for a ruptured cruciate ligament in 1895, a great deal of research has attempted to identify the optimal surgical technique. Today, the two mainstay choices are hamstring–tendon and bone–patellar tendon–bone autografts, with preferences differing around the globe.1

Systematic reviews of randomised controlled trials have identified very few differences in outcomes more than 2 years postoperatively between these two popular graft choices.2 Similarly, variations of surgical technique, such as double-bundle reconstruction, while potentially providing greater passive stability, offer no proven superior clinical or functional outcomes.3

Clinician’s and researcher’s quest for the Holy Grail—a quick return to sport without re-injury or increased osteoarthritis risk—has led to less conventional management approaches. This includes an alarming resurgence of synthetic ligaments as described in a recent BJSM blog (http://blogs.bmj.com/bjsm/2017/07/06/synthetics-ligaments-knee-deja-vu-innovation/). Do we really need to pursue unconventional surgical interventions that have failed to stand the test of time?

Perhaps the secret for clinicians and researchers lies not in chasing the next sexy surgical trend but in ensuring completion of an outstanding rehabilitation programme. …
Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma
Authors: W. Jurczak, P.L. Zinzani, G. Gaidano, A. Goy, M. Provencio, Z. Nagy, T. Robak, K. Maddocks, C. Buske, S. Ambarkhane, M. Winderlich, M. Dirnberger-Hertweck, R. Korolkiewicz, K.A. Blum
Journal: Annals of Oncology (2018)

This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells.Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate.Ninety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported.MOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL.NCT01685008.
Developing a screening platform for genetic and small molecule targets of cancer immunotherapy.
Authors: Ranjan Upadhyay, Aleksandra Wroblewska, Clara Koo, Brian Brown, Joshua Brody
Journal: Journal of Clinical Oncology (2018)

66 Background: The success of checkpoint blockade therapy is often dependent on CD8 T cell activation against tumor antigens. However, clinical benefit is only seen in a subset of patients, suggesting that there are other possibly targetable immunosuppressive pathways that are allowing the tumor to escape immune surveillance. Methods: A CD8 T cell that recognizes the EGFP 200-208 peptide epitope allowed for the use of EGFP as a model tumor antigen while monitoring expression levels at the single cell resolution. Using a lymphoma line expressing EGFP or mCherry as our antigen-positive and -negative cancer models, we employed 3 screening strategies: 1) a forward genetics approach in which we selected for tumor cells that had naturally developed resistance to killing by CD8 T cells; 2) a reverse genetics approach that involved the use of pooled CRISPR libraries to identify knockout clones with a selection advantage or disadvantage when pressured by activated T cells; and 3) small molecule libraries, including FDA-approved drugs, to identify compounds that increased antigen-specific CD8 T cell killing. Results: Despite antigen recognition and early activation in response to the resistant tumor line, T cells failed to produce effector cytokines and underwent apoptosis in a PD-L1 and CTLA-4 independent manner. Candidate genes mediating this phenotype were derived from expression differences between the original susceptible tumor line and the immunoedited resistant tumor line. The pooled CRISPR approach was validated in a curated library by identifying genes with known roles in T cell-mediated killing and antigen presentation, such as Fas, B2m, and Tap1, as well as known suppressive molecules such as BTLA and PD-L1. LDL receptor expressed on the cancer cell emerged as a possible novel suppressor of T cells. Decitabine and 4-cinnolinethiol, among other small molecules, emerged as possible enhancers of CD8 T cell activity. Conclusions: We have identified several gene candidates as potentially novel and targetable checkpoint-like molecules, as well as small molecule compounds that may be able to enhance the anti-tumor activity of CD8 T cells. Efforts are ongoing in order to validate these targets and to screen larger libraries.
The prevalence rates of major chronic diseases in retired and in-service Chinese military officers (2000–2016): a meta-analysis
Authors: Thermite Mara, Long-Teng Ma, Shuo Wang, Ling Wang, Fan Yang, Jia-Hui Song, Yi-Chun Cao, Jian-Hua Yin, Guang-Wen Cao
Journal: Military Medical Research (2018)

Chronic diseases cause a tremendous burden to the military medical system. However, the prevalence rates of major chronic diseases among military officers remain unclear in China. China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database for Chinese Technical Periodicals (VIP), PubMed and Web of Science were searched for studies (from 2000 to 2016) concerning 6 major chronic diseases: hypertension, hyperlipidemia, diabetes mellitus, heart diseases, cerebrovascular diseases, and chronic obstructive pulmonary diseases (COPD) in Chinese military officers following strict inclusion and exclusion criteria. Three researchers independently extracted data from the included studies, and a fourth researcher reviewed and solved every disagreement. Statistical analysis was performed with STATA 14.0 and R 3.3.2. Heterogeneity was evaluated by the I 2 value. A random effect model was performed to combine the heterogeneous data. The Egger test was performed to test the publication bias. A total of 90,758 military officers derived from 75 articles were pooled together. Publication bias was only observed in 37 studies reporting heart disease (P Egger test = 0.01). The overall prevalence rates of hypertension, hyperlipidemia, diabetes mellitus, heart diseases, cerebrovascular diseases, and COPD were 46.6% (95% CI 41.8–51.5%), 30.9% (26.4–35.7%), 20.7% (16.5–25.7%), 48.2% (41.7–54.9%), 20.2% (14.8–26.9%) and 16.6% (12.9–21.0%), respectively. The prevalence rates of hypertension, diabetes, heart disease, cerebrovascular disease, and COPD, rather than hyperlipidemia, increased with age in Chinese military officers. Heart diseases (P Q-test < 0.001) and hypertension (P Q-test < 0.001) increased sharply in retired officers compared with officers in service. Cerebrovascular disease was more frequent in Northern Theater Command than in any other theater command (P Q-test < 0.001). Major chronic diseases heavily affect Chinese military officers, especially retirees. Medical intervention should be enforced on the prevention of cerebrovascular diseases in those working in cold areas in the north, as well as hypertension and heart diseases in retirees.
P014 FAM167A/BLK is a susceptibility locus in autoimmune diseases: characterisation of the FAM167 gene family
Authors: L Mentlein, GE Thorlacius, L Meneghel, JI Ramirez Sepulveda, S Brauner, A Espinosa, M Wahren-Herlenius
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Genome-wide association studies of multiple autoimmune diseases, including Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis have identified associations in the <i>FAM167A/BLK</i> locus. eQTL (expression quantitative loci) analyses in peripheral blood cells show a significantly increased expression of <i>FAM167A</i> for the disease associated genotypes. While <i>BLK</i> acts downstream of the B cell receptor, the function of <i>FAM167A</i> is unknown. Additionally, the role of the only homologous protein, its gene family member <i>FAM167B</i>, remains unexplored. <h3>Objectives</h3> To elucidate the potential role of these proteins in susceptibility, or pathogenesis of autoimmune disease, we aim to characterise the <i>FAM167</i> gene family by both bioinformatic and experimental approaches. <h3>Methods</h3> Public databases, including NCBI, GEO, Uniprot, CCLE, PhylomeDB were searched for information on the<i> FAM167</i> gene family and its two members. The FAM167 protein sequences were analysed with structure prediction tools including YASPIN and D2P2 server. The mRNA levels of the genes of interest were determined by qPCR analysis on organs from 12 week old C57BL/6 mice and cells of selected human cancer cell lines. <h3>Results</h3> After protein sequence analysis we found that the <i>FAM167</i> gene family shows no homology to any other annotated genes but is highly conserved in vertebrates. The FAM167A and FAM167B proteins don't comprise any previously known protein domains and are predicted to contain both helical and disordered protein structures. Based on the analysis of their protein structure prediction and their conservation we propose that the FAM167 proteins contain two distinct modules linked by a variable linker accounting for the different size of 24 and 18 kDa for FAM167A and B, respectively. Database research revealed that <i>FAM167A</i> is expressed in many cancer cell lines whereas <i>FAM167B</i> shows a specifically high expression only within melanoma lines according to CCLE. <i>FAM167A</i> expression was confirmed for the myeloma cell line LP1 and the monocytic cell line THP1 experimentally. High <i>FAM167B</i> expression was found in the melanoma cell line SKMEL28. Expression profiling of mouse organs collected from C57BL/6 mice revealed high expression of <i>Fam167a</i> in lung, spleen, skeletal muscle and brain. <i>Fam167b</i> had its peak expression in adrenal glands, kidney and liver, with low or no expression observed in other analysed organs. <h3>Conclusions</h3> The <i>FAM167A/B</i> genes show distinct expression profiles both at the organ and the cellular level. Further <i>in vitro</i> and <i>in vivo</i> studies will be implemented to unravel the function of this gene family. <h3>Disclosure of interest</h3> None declared
Revision of Scottish GP contract removes one in four QOF points
Authors: Tom Moberly
Journal: BMJ (2013)

Changes to the GP contract in Scotland have been agreed for 2014-15, including the removal of one in four points from the Quality and Outcomes Framework (QOF).1

As part of the changes, agreed by the British Medical Association’s Scottish General Practitioners Committee and the Scottish government, 264 points will be removed from QOF, leaving a total of 659 points. To offset funding lost through …
MRDTI(磁気共鳴直接血栓画像)による同側の急性再発性深部静脈血栓症と残存血栓の鑑別
Authors: Tan Melanie, C Mol Gerben, J Van Rooden Cornelis, A Klok Frederikus, E Westerbeek Robin, Del Sol Antonio Iglesias, A Van De Ree Marcel, DE Roos Albert, V Huisman Menno
Journal: Blood (2014)
Abstract ES6-2: Do tumors overcome immune surveillance by blocking dendritic cell development
Authors: DG DeNardo
Journal: Cancer Research (2018)

Abstract Tumors must evade immune-surveillance in order to progress. To this end, tumor-induced inflammation expands immune-suppressive immature granulocytes and monocytes, while limiting the functions of immune-stimulatory conventional dendritic cells (cDCs). cDC1s, a cDC subset, activate CD8+ T cells through antigen cross presentation and are marked by CD141 in humans and CD103 or CD8α in mice. cDC1s support anti-tumor CD8+ T cell responses, but cDC1 numbers are limited within the tumor environment. To understand how cDC1s are restricted in the tumor, we interrogated their development in the bone marrow (BM). We found the program responsible for the expansion of immature granulocytes and monocytes from progenitors in the BM is simultaneously suppressing the generation of cDC1s, decreasing the systemic numbers of cDC1s in breast and pancreatic cancer patients. We found that tumor-induced granulocyte stimulating factor (GCSF) mediates the down-regulation of the transcription factor IFN regulatory factor 8 (IRF8) in BM progenitors. IRF8 loss reprograms the BM progenitors, reducing their potential to develop into cDC1s. We demonstration, independent of monocyte and granulocyte expansion, that tumor-induced loss of cDC1s reduces the systemic ability to mount anti-tumor CD8+ T cell responses. Further, systemic decreases in cDC1s in breast cancer patients correlate with reduced response to chemotherapy. These data suggest a new mechanism of immune-escape whereby tumors down-regulate cDC1 differentiation from BM progenitors to impair anti-tumor CD8+ T cell immunity. These data beg the question; are some patients unresponsive to immunotherapy because of tumor-induced impairments in dendritic cell development? Citation Format: DeNardo DG. Do tumors overcome immune surveillance by blocking dendritic cell development [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 ES6-2.
FDG PET/CT Findings of Erdheim–Chester Disease
Authors: Esma A. Akin, Murat Osman, Amy L. Ellenbogen
Journal: Clinical Nuclear Medicine (2018)

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with deposition of lipid-laden macrophages in numerous organs. A 74-year-old man with a history of coronary artery disease, hypertension, and hyperlipidemia presented with nonspecific symptoms including back pain, nausea, vomiting, vertigo, and left leg pain. A neutrophil-predominant elevated WBC count and a bone biopsy revealing histiocytic proliferation positive for CD68 and CD163 and negative for S100 was noted. FDG PET/CT, MRA, and CTA images were obtained. We review the radiologic hallmarks of ECD and demonstrate the radiologic manifestations of response to combined BRAF and MEK inhibitor treatment.
Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation
Authors: Prabhakaran Kumar, Alejandra Marinelarena, Divya Raghunathan, Vandhana K Ragothaman, Shikha Saini, Palash Bhattacharya, Jilao Fan, Alan L Epstein, Ajay V Maker, Bellur S Prabhakar
Journal: Cellular and Molecular Immunology (2018)
More junior doctors report heavy workloads, GMC survey finds
Authors: Abi Rimmer
Journal: BMJ (2016)

Over two fifths of junior doctors reported that their workload was heavy or very heavy, a General Medical Council survey has found.

On Thursday 14 July the GMC published the preliminary results of its national training survey in medical education and training in the United Kingdom. Of the junior doctors who responded to the survey, 43% described the rate of intensity of their work as heavy or very heavy, an increase of 2% from the 2015 survey. In 2014, 42% gave the same response.

Of the 54 563 doctors training in the UK who were surveyed by the GMC, 53 835 responded—a 99% response rate. The survey was open from 22 March to …
Changes in bone metabolism after gastric cancer surgery in men: A prospective observational study.
Authors: Yosuke Atsumi, Yasushi Rino, Hiroo Wada, Yuichi Kitani, Yukihiro Ozawa, Tsutomu Sato, Takashi Oshima, Norio Yukawa, Takaki Yoshikawa, Munetaka Masuda
Journal: Journal of Clinical Oncology (2018)

10 Background: Several reports have showed that bone disorders occur after gastric cancer surgery, however there are few studies that compared pre- and postoperative bone mineral density of the same patient. The purpose of this study was to assess changes in bone metabolism after gastric cancer surgery prospectively. Methods: We prospectively enrolled 39 men undergoing gastrectomy for early gastric cancer. We excluded women to avoid the effect of menopause. Patients with severe kidney disease requiring dialysis treatment, patients with severe liver disease and patients with treatment with bisphosphonates or any other bone-active drugs were also excluded. Dual energy X-ray absorptiometry (DEXA) was performed before and 1 and 2 years after surgery to evaluate bone mineral density (BMD). The serum levels of 1,25-dihydroxy vitamin D (1,25(OH) 2 VD), 25-hydroxy vitamin D (25(OH)VD), estradiol, and alkaline phosphatase (ALP) were measured before surgery and every three months until two years after surgery. Results: DEXA revealed that BMD was significantly decreased by 0.036±0.033 g/cm 2 at 12 months after gastrectomy (P &lt; 0.001). The serum ALP was significantly increased by 38.88±6.42 IU/l at 24 months after surgery (P = 0.013), and there was a marginally significant correlation between the changes in BMD and the changes in the serum ALP at 24 months after surgery; the correlation coefficient was -0.30 (P = 0.090). The serum 25(OH)VD was significantly decreased by 4.88±6.42 ng/ml at 24 months after surgery (P &lt; 0.001), however there was no significant correlation between the changes in BMD and the changes in the serum 25(OH)VD. The serum 1,25(OH) 2 VD and estradiol were not significantly changed before and after surgery. The factor significantly correlated to the reductions of BMD at 12 months after surgery included preoperative lower body mass index (BMI); the correlation coefficients was 0.37 (P = 0.025). Conclusions: This study showed a significant reduction in the BMD of gastric cancer patients at 12 months after gastrectomy and suggested that low preoperative BMI could be a high risk factor for the bone disorder after gastric cancer surgery.
PACEMAKER DEPENDENCY FOLLOWING TRANSCATHETER AORTIC VALVE IMPLANTATION: A SUBANALYSIS OF THE REPRISE III RANDOMIZED CONTROLLED CLINICAL TRIAL
Authors: Dean Kereiakes, Christopher Meduri, Raj Makkar, Axel Linke, Vasilis Babaliaros, Robert Stoler, Gregory Mishkel, David Gerard Rizik, Vijay Iyer, John Schindler, Dominic Allocco, Ian Meredith, Michael Reardon, Ted Feldman
Journal: Journal of the American College of Cardiology (2018)
Government offers concession on pension contribution rates
Authors: Caroline White
Journal: BMJ (2012)

The government has signalled that it is prepared to consider flatter pension contribution rates for doctors rather than the proposed “tiered” system in 2015, when the current final salary NHS pension scheme is replaced by a career average scheme.

In a letter sent to the BMA’s chairman of council, Mark Porter, the health secretary, Jeremy Hunt, said that no decision had yet been made about how exactly pension contributions would be tiered after 2015 and seemed to adopt a more conciliatory tone than his predecessor.

The BMA, which has fiercely opposed the government’s public sector pensions legislation currently working its way …
Endoscopic management of a thalamic tumour causing obstructive hydrocephalus in a child
Authors: Angela Khanna, Charlotte Burford, Nida Kalyal, Jose Lavrador, Ahilan Kailaya-vasan, Viviana Minichini, Bassel Zebian
Journal: Neuro-Oncology (2018)

Thalamic tumours are uncommon lesions and their management uncertain. They are predominantly astrocytic and can be low or high grade, unilateral or bilateral. One of the challenges they pose is their relative inaccessibility. We present a case of a unilateral thalamic tumour causing obstructive hydrocephalus which we managed endoscopically. A 12-year-old male presenting with a three-week history of progressive headaches associated with nausea and vomiting. He had a single episode of self-limiting left sided upper and lower limb weakness as well as facial droop. Imaging demonstrated a right thalamic tumour with intraventricular extension, causing obstruction of the aqueduct of Sylvius and hydrocephalus. We performed an endoscopic debulking of the tumour achieving subtotal resection and restored the CSF pathways. We also performed an endoscopic third ventriculostomy and inserted an aqueductal stent in anticipation of future tumour growth. The child made an excellent post-operative recovery with resolution of the symptoms. Post-operative imaging demonstrated the subtotal debulking and resolution of the hydrocephalus. The lesion was consistent histologically with a glioblastoma grade IV and the child went on to have adjuvant treatment. This case demonstrates the safety and efficacy of the endoscopic transventricular approach to thalamic tumours, allowing significant debulking as well as management of the hydrocephalus. The technique deserves consideration in centres with the appropriate equipment and experience.
Endocrine Late Effects in Childhood Cancer Survivors
Authors: Wassim Chemaitilly, Laurie E. Cohen, Sogol Mostoufi-Moab, Briana C. Patterson, Jill H. Simmons, Lillian R. Meacham, Hanneke M. van Santen, Charles A. Sklar
Journal: Journal of Clinical Oncology (2018)

Endocrine complications are highly prevalent in childhood cancer survivors. Approximately 50% of survivors will experience at least one hormonal disorder over the course of their lives. Endocrine complications often are observed in survivors previously treated with radiation to the head, neck, or pelvis. We provide an overview the most common endocrine late effects seen in survivors, including hypothalamic-pituitary dysfunction, primary thyroid dysfunction, obesity, diabetes mellitus, metabolic syndrome, and decreased bone mineral density. Primary gonadal injury is discussed elsewhere in this series. Given a variable latency interval, a systematic approach where individuals are periodically screened on the basis of their risk factors can help to improve health outcomes by prompt diagnosis and treatment of evolving endocrinopathies. These recommendations must be revised in the future given changes and improvements in cancer treatment over time.
Royal colleges call on future government to end top-down NHS reorganisations
Authors: Abi Rimmer
Journal: BMJ (2015)

The Academy of Medical Royal Colleges has called on the future government not to instigate a top-down reorganisation of the health service.

The academy has published a manifesto for 2015 outlining areas of concern to its members (www.aomrc.org.uk/general-news/pn-manifesto.html), which it has described as a “call to action for the …