tbuckley/cabot-search huggingface dataset:
NHS pension: doctors’ views sought on “50:50” proposal
Authors: Abi Rimmer
Journal: BMJ (2019)

The government has launched a consultation on proposals that would allow senior clinicians to halve their pension contributions to avoid big tax charges.1

The “50:50” option, unveiled as part of the interim workforce plan for the NHS in England last month,2 will allow doctors to halve the rate of their pension growth in exchange for halving their contributions to the NHS pension scheme. Currently, the NHS scheme does not offer any flexibility in the rate at which the pension builds, with the highest earning consultants contributing 14.5% of their pensionable pay each month.

This has led to doctors taking early …
Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis?
Authors: Leo Rasche, Manoj Kumar, Grant Gershner, Rohan Samant, Rudy Van Hemert, Anke Heidemeier, Constantin Lapa, Thorsten Bley, Andreas Buck, James McDonald, Jens Hillengass, Joshua Epstein, Sharmilan Thanendrarajan, Carolina Schinke, Frits van Rhee, Maurizio Zangari, Bart Barlogie, Faith E Davies, Gareth J Morgan, Niels Weinhold
Journal: Theranostics (2019)

Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations.Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias.Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS).Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI.Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24%) NDMM patients.This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10 -10 ) and International Staging System 3 (P=0.0001)but not with gain(1q), and del(17p) or plasma cell gene signatures.The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden.While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome.Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions:The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM.
High-sensitivity C-reactive protein in chronic heart failure: patient characteristics, phenotypes, and mode of death
Authors: Pierpaolo Pellicori, Jufen Zhang, Joe Cuthbert, Alessia Urbinati, Parin Shah, Syed Kazmi, Andrew L Clark, John G F Cleland
Journal: Cardiovascular Research (2019)

Abstract Aims Plasma concentrations of high-sensitivity C-reactive protein (hsCRP) are often raised in chronic heart failure (CHF) and might indicate inflammatory processes that could be a therapeutic target. We aimed to study the associations between hsCRP, mode and cause of death in patients with CHF. Methods and results We enrolled 4423 patients referred to a heart failure clinic serving a local population. CHF was defined as relevant symptoms or signs with either a reduced left ventricular ejection fraction &amp;lt;40% or raised plasma concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP &amp;gt;125 pg/mL). The median [interquartile range (IQR)] plasma hsCRP for patients diagnosed with CHF (n = 3756) was 3.9 (1.6–8.5) mg/L and 2.7 (1.3–5.1) mg/L for those who were not (n = 667; P &amp;lt; 0.001). Patients with hsCRP ≥10 mg/L (N = 809; 22%) were older and more congested than those with hsCRP &amp;lt;2 mg/L (N = 1117, 30%). During a median follow-up of 53 (IQR 28–93) months, 1784 (48%) patients with CHF died. Higher plasma hsCRP was associated with greater mortality, independent of age, symptom severity, creatinine, and NT-proBNP. Comparing a hsCRP ≥10 mg/L to &amp;lt;2 mg/L, the hazard ratio for all-cause mortality was 2.49 (95% confidence interval 2.19–2.84; P &amp;lt; 0.001), for cardiovascular (CV) mortality was 2.26 (1.91–2.68; P &amp;lt; 0.001), and for non-CV mortality was 2.96 (2.40–3.65; P &amp;lt; 0.001). Conclusion In patients with CHF, a raised plasma hsCRP is associated with more congestion and a worse prognosis. The proportion of deaths that are non-CV also increases with higher hsCRP.
Antigens diagnoses in paraneoplastic neurological syndromes.
Authors: Halina Rudnicka, Agnieszka I. Jagiello Gruszfeld, Iwona Glogowska
Journal: Journal of Clinical Oncology (2012)

10582 Background: At present, paraneoplasmatic neurological syndroms (PNS) are thought to be autoimmunological disorders. Neurological symptoms in PNS result from the disturbance of the nervous system, with a participation of the immune response triggered by the aberrant expression of the so-called onconeuronal antigens of a tumour. Very important for PNS diagnostics is the investigation of antineuronal antibodies (ANA) in the serum. Different types of ANA are frequently associated with specific tumors and with specific neurological syndromes.Investigations of serum ANA in patients with breast cancer with the symptoms of PNS. Methods: Investigations of ANA in serum were performed with the indirect immunofluorescence test but the type of ANA was analyzed by the Western Blot (WB) method . The presence of these antibodies which are included to the group of “the so called well characterized” is believed to be a definite (95 – 100%) determinant of the PNS diagnosis. Results: We examined 147 patients with breast cancer suspected to have PNS, hospitalized at Breast Cancer Clinic of the Institute of Oncology in Warsaw. The immunofluorescence test was positive in 92 patients, however in 24 patients the WB occurrence of “the well characterized” antibodies was found. In this group we observed: in 4 patients the cerebellar degeneration (anti-Yo, anti-Ma2); in 6 patients brainstem encephalitis and encephalomyelitis combined with sensory neuropathy (anti-Ma2, anti-CV2, anti-Yo, anti-Hu, anti-Ri); 4 myastenic syndrome (anti-Hu,anti-Ri,anti-Ma2/Ta); 5 sensory neuropathy (anti-Hu, anti-Yo, anti-Ma2, anti-Ri); and in single cases we also observed polyneuropathy: Guillain-Barre (Ma2): Miller-Fisher syndrom (anti-Ma2/Ta); cancer-associated retinopathy (anti-Yo); dermatomyositis (anti-Ri) and scleroderma (anti-Yo). Conclusions: Our analysis indicates that the investigation of the presence of ANA in the serum is the important in the diagnosis of PNS in patients with breast cancer. The types of ANA correspond to the individual paraneoplastic neurological syndromes which opens the proper methods of treatment in PNS.
Expression levels of nucleoside transporter hENT1 and dCK enzyme, as prognostic factors in patients with AML treated with cytarabine.
Authors: Carmen Corrales-Alfaro, Myrna Candelaria, Juan labardini-Mendez, Olga Gutierrez-Hernandez, Silvia Vidal-Millan, Ramiro Espinoza, Juan Ojeda
Journal: Journal of Clinical Oncology (2012)

6599 Background: Cytarabine has been set as the main drug included in different schemas for the treatment of AML patients. This drug requires inflow to the cell by the nucleoside transporter hENT1 and its activation rate is limited by dCK enzyme. Therefore decreased expression levels of these genes may influence response rate to this drug. Methods: AML patients &gt; 15 years, without previous treatment were included. After informed consent signature, peripheral blood was obtained and DNA was extracted by standard methodology. Amplification of hENT1 and dCK genes was done by RT-PCR. Clinical parameters were registered. All patients received cytarabine + doxorrubicine as induction regimen (7 + 3 schema). Descriptive statistics was used. Uni- and multivariate analysis was done to determine factors influencing on response and overall survival. This protocol was approved by local IRB. Results: From January till December 2011, 22 patients have been included. Median age was 36 years (15-72 y), 52.3 % were male. According with FAB classification, M2 subtype was the most frequent (28.5 %). All patients had an adequate performance status (ECOG 1 &amp; 2 = 34 &amp; 66 %, respectively). Cytogenetic risk was considered as intermediate risk in 38 %, followed by unfavorable in 28 %. Complete response was achieved in 58 %. Higher hENT1 expression levels was the only factor influencing on response and survival by Spearmen correlation analysis. Conclusions: These are preliminary results but are highly suggestive that pharmacogenetic analysis regarding cytarabine inflow may be decisive in AML patients. Our results require to be confirmed with a larger sample, and a longer follow-up.
Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence
Authors: Shao-Lai Zhou, Zheng-Jun Zhou, Zhi-Qiang Hu, Cheng-Li Song, Yi-Jie Luo, Chu-Bin Luo, Hao-Yang Xin, Xin-Rong Yang, Ying-Hong Shi, Zheng Wang, Xiao-Wu Huang, Ya Cao, Jia Fan, Jian Zhou
Journal: Journal of Hepatology (2019)

Early recurrence of hepatocellular carcinoma (HCC) after curative resection is common. However, the association between genetic mechanisms and early HCC recurrence, especially in Chinese patients, remains largely unknown.We performed whole-genome sequencing (49 cases), whole-exome sequencing (18 cases), and deep targeted sequencing (115 cases) on 182 primary HCC samples. Focusing on WNK2, we used Sanger sequencing and qPCR to evaluate all the coding exons and copy numbers of that gene in an additional 554 HCC samples. We also explored the functional effect and mechanism of WNK2 on tumor growth and metastasis.We identified 5 genes (WNK2, RUNX1T1, CTNNB1, TSC1, and TP53) harboring somatic mutations that correlated with early tumor recurrence after curative resection in 182 primary HCC samples. Focusing on WNK2, the overall somatic mutation and copy number loss occurred in 5.3% (39/736) and 27.2% (200/736), respectively, of the total 736 HCC samples. Both types of variation were associated with lower WNK2 protein levels, higher rates of early tumor recurrence, and shorter overall survival. Biofunctional investigations revealed a tumor-suppressor role of WNK2: its inactivation led to ERK1/2 signaling activation in HCC cells, tumor-associated macrophage infiltration, and tumor growth and metastasis.Our results delineate genomic events that characterize Chinese HCCs and identify WNK2 as a driver of early HCC recurrence after curative resection.We applied next-generation sequencing and conducted an in-depth genomic analysis of hepatocellular carcinomas from a Chinese patient cohort. The results delineate the genomic events that characterize hepatocellular carcinomas in Chinese patients and identify WNK2 as a driver associated with early tumor recurrence after curative resection.
A Randomized Double-Blind Placebo-Controlled Phase II Trial of Dendritic Cell Vaccine ICT-107 in Newly Diagnosed Patients with Glioblastoma
Authors: Patrick Y. Wen, David A. Reardon, Terri S. Armstrong, Surasak Phuphanich, Robert D. Aiken, Joseph C. Landolfi, William T. Curry, Jay-Jiguang Zhu, Michael Glantz, David M. Peereboom, James M. Markert, Renato LaRocca, Donald M. O'Rourke, Karen Fink, Lyndon Kim, Michael Gruber, Glenn J. Lesser, Edward Pan, Santosh Kesari, Alona Muzikansky, Clemencia Pinilla, Radleigh G. Santos, John S. Yu
Journal: Clinical Cancer Research (2019)

To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma.We conducted a double-blinded randomized phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1+ and/or -A2+-resected patients with residual tumor ≤1 cm3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 [autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2] or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter.ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (P = 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit.PFS was significantly improved in ICT-107-treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.
Search for biomarkers of stage II/III gastric cancer and development of individualized therapy.
Authors: Takashi Oshima, Naoya Sakamoto, Takaki Yoshikawa, Yasushi Rino, Chikara Kunisaki, Wataru Yasui, Toshio Imada, Munetaka Masuda
Journal: Journal of Clinical Oncology (2013)

4068 Background: Standard therapy for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. Treatment outcomes are expected to be further improved by the development of individualized therapy based on new biomarkers. We have extracted mRNA from frozen specimens of gastric cancer to construct a cDNA bank and searched for new biomarkers of stage II/III gastric cancer. We report currently available results. Methods: The study group comprised 256 patients with stage II/III gastric cancer in whom at least 5 years had passed since surgery (among whom 149 received S-1 as adjuvant chemotherapy). A total of 130 genes were selected on the basis of the results of comprehensive DNA microarray analyses and extraction from serial analysis of gene expression (SAGE) libraries, and other studies. Relative expression levels of each gene in gastric cancer tissue and adjacent normal mucosa were measured by quantitative PCR, and the relations between clinicopathological factors and treatment outcomes were studied. In addition, using 9 types of gastric cancer cell lines, we knocked down the new cancer biomarkers obtained in this study with small interfering RNA (siRNA) and performed functional analysis. Results: In patients with resected stage II/III gastric cancer, INHBA, IGF-1R, CLDN7, and DPD genes were independent prognostic factors. In the subgroup of patients who received S-1-based adjuvant chemotherapy, IGF-1R, INHBA, SULF1, REG4, MMP11, and KIAA1199 genes were independent prognostic factors. Knockdown of the KIAA1199 gene with siRNA markedly inhibited the proliferative and invasive activities of the gastric cancer cell lines and lowered resistance to 5-fluorouracil. Conclusions: Investigatory studies of new biomarkers of gastric cancer identified prognostic factors for patients with resected stage II/III gastric cancer and those who received adjuvant chemotherapy with S-1. At present, the development of small molecule drugs that target KIAA1199 and the joint development of risk stratification tools with the goal of individualized therapy for stage II/III gastric cancer are ongoing.
Defining and Evaluating Overdiagnosis in Mental Health: A Meta-Research Review
Authors: Brett Thombs, Kimberly A. Turner, Ian Shrier
Journal: Psychotherapy and Psychosomatics (2019)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Overdiagnosis is thought to be common in some mental disorders, but it has not been defined or examined systematically. Assessing overdiagnosis in mental health requires a consistently applied definition that differentiates overdiagnosis from other problems (e.g., misdiagnosis), as well as methods for quantification. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; Our objectives were to (1) describe how the term “overdiagnosis” has been defined explicitly or implicitly in published articles on mental disorders, including usages consistent &lt;i&gt;(overdefinition, overdetection)&lt;/i&gt; and inconsistent &lt;i&gt;(misdiagnosis, false-positive test results, overtreatment, overtesting)&lt;/i&gt; with accepted definitions of overdiagnosis; and (2) identify examples of attempts to quantify overdiagnosis. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; We searched&lt;b&gt;&lt;i&gt;&lt;/i&gt;&lt;/b&gt;PubMed through January 5, 2019. Articles on mental disorders, excluding neurocognitive disorders, were eligible if they used&lt;b&gt;&lt;i&gt;&lt;/i&gt;&lt;/b&gt;the term “overdiagnosis” in the title, abstract, or text. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; We identified 164 eligible articles with 193 total explicit or implicit uses of the term “overdiagnosis.” Of 9 articles with an explicit definition, only one provided a definition that was partially consistent with accepted definitions. Of all uses, 11.4% were consistent, and 76.7% were related to misdiagnosis and thus inconsistent. No attempts to quantify the proportion of patients who were overdiagnosed based on overdetection or overdefinition were identified. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; There are few examples of mental health articles that describe overdiagnosis consistent with accepted definitions and no examples of quantifying overdiagnosis based on these definitions. A definition of overdiagnosis based on diagnostic criteria that include people with transient or mild symptoms not amenable to treatment (overdefinition) could be used to quantify the extent of overdiagnosis in mental disorders.
Abstract 140: BMI- and Gender-specific Increase of MAP2K3/p38 Activity in Human Cardiac Hypertrophy
Authors: Mackenzie Newman, Aniello M Infanto, Michael J Watson, Robert W Hull, Han-Gang Yu
Journal: Circulation Research (2016)

Introduction: MAP2K3 is a stress-induced kinase and its role cardiac hypertrophy has been controversial: while in vitro studies have displayed a positive correlation in activity with hypertrophy, in vivo studies have shown a negative association. Its direct downstream target, p38α MAPK, has been shown to be in activated in hypertrophic and failed hearts, but this has not been explored with regard to gender or BMI. Hypothesis: Early activation of p38 MAPK in hypertrophy is influenced by gender and BMI. Methods: Human heart samples were grouped into non-failed (NF), left ventricular hypertrophy (LVH), and NF without LVH (control). BMI &lt; 25 was considered “lean”, 25 &lt; BMI &lt; 30 was considered overweight, and BMI &gt; 30 was considered “obese”. RNA-Seq was used to generate cardiac gene expression profiles. Immunoblots were used to examine protein expression of MAP2K3, p38, and activated p38 (pp38; phospho-T180 and Y182). Results: We found that MAP2K3 mRNA levels were increased in obese males by 134% with LVH compared to non-LVH controls (FPKM: LVH = 19.2±3.5, n=3; non-LVH = 8.2±1.9, n=3; FPKM = Fragments Per Kilobase of transcript per Million mapped reads), without statistical significance (p&gt;0.05). MAP2K3 protein expression was 5-fold higher in LVH (1.24±0.20, n=9) versus non-LVH hearts (0.25±0.03, n=15) (p&lt;0.0001). Within all LVH hearts sampled, MAP2K3 protein expression is higher only in male overweight or obese (1.21±0.22, n=7) over lean (0.52±0.04, n=6) (p&lt;0.05). No differences were detected in gene expression profiles of the four isoforms of p38 and total p38 protein expression levels between LVH and NF groups (p&gt;0.05). Activated-p38 was detected in LVH without failure. Levels of p38 activation are higher in overweight/obese than in lean male group (pp38/p38 ratio: M_BMI&gt;25 = 0.63 ± 0.03 (n=7), M_BMI&lt;25 = 0.41 ± 0.12 (n=3), p&lt;0.05). For BMI&gt;25, levels of activated p38 are also higher in male (0.63 ± 0.03, n=7) than in female (0.08 ± 0.01, n=3) (p&lt;0.0001), independent of LVH. Conclusions: We found increased protein expression of MAP2K3 and phosphorylation of p38 in cardiac hypertrophy positively associated with male obese human hearts.
Abstract 11449: Result of Moderate Hypothermia Circulatory Arrest With Selective Antegrade Cerebral Perfusion in Pediatric Cardiac Surgery
Authors: Pierre Maminirina, Carine Pavy, Olivier Baron
Journal: Circulation (2018)

Introduction: To assess the feasibility and outcome of the moderate hypothermia circulatory arrest technique with selective antegrade cerebral perfusion in the neonatal period. Methods: Retrospecti...
Pazopanib or methotrexate–vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): a non-comparative, randomised, open-label, multicentre, phase 2 study
Authors: Maud Toulmonde, Marina Pulido, Isabelle Ray-Coquard, Thierry Andre, Nicolas Isambert, Christine Chevreau, Nicolas Penel, Emmanuelle Bompas, Esma Saada, François Bertucci, Celeste Lebbe, Axel Le Cesne, Patrick Soulie, Sophie Piperno-Neumann, Stephen Sweet, Fabiola Cecchi, Todd Hembrough, Carine Bellera, Michèle Kind, Amandine Crombe, Carlo Lucchesi, François Le Loarer, Jean-Yves Blay, Antoine Italiano
Journal: The Lancet Oncology (2019)