tbuckley/cabot-search huggingface dataset:
Tracking of long-term B-cell memory responses using B-cell receptor (BCR) sequencing in prostate cancer (PC) patients (pts) treated with sipuleucel-T (sip-T).
Authors: Li Zhang, Harini Kandadi, Alan Paciorek, Nancy N. Chang, Nadeem Anwar Sheikh, Lawrence Fong
Journal: Journal of Clinical Oncology (2018)

309 Background: Sip-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sip-T’s induction of B-cell responses to PAP and other antigens correlates with improved survival (Sheikh 2013, GuhaThakurta 2015). Cancer vaccine-induced changes to BCR repertoire are unknown. To assess changes in BCR repertoire upon booster treatment, we compared patients retreated with sip-T (P10-1) to treatment-naïve patients (STRIDE). Methods: STRIDE pts (N = 52) received sip-T with concurrent or sequential enzalutamide for mCRPC (Petrylak 2015). P10-1 pts (N = 8) previously treated with sip-T for androgen-dependent PC were retreated with a booster course for mCRPC, after a median of 8.9 years (Beer 2017). Blood samples were collected at baseline (wk 0) and during (wk 2, 4)/post-sip-T (wk 6, 26, 52). Deep sequencing was performed using the ImmunoSEQ assay (Adaptive Biotechnologies). BCR diversity was assessed by clonality, and BCR dynamics by fold-change analysis (Zhang 2017). Results: BCR repertoire had significantly higher clonality in P10-1 vs STRIDE (wk 0: p = 0.003, wk 2: p &lt; 0.001, wk 4: p &lt; 0.001), suggestive of a more focused BCR repertoire. P10-1 also showed increased clonality from wk 0 to 4 (p = 0.063), whereas STRIDE showed a significant increase in clonality from wk 0 to 6 (p = 0.039), suggesting that BCR repertoire focused earlier in P10-1. Starting at wk 2, more clones remained in the repertoire in P10-1, indicating that sip-T stimulated immunologic memory early, after 1 st retreatment (p &lt; 0.05). There was less change over time (clonal shuffling) within the 100 most abundant baseline clones in P10-1 (p = 0.080), suggesting more relevant clones preexisted at baseline and enriched over time. After the first two sip-T infusions, more clones contracted in P10-1 (p = 0.027, p = 0.014), whereas more new clones were generated in STRIDE (p = 0.083, p = 0.003). Conclusions: Sip-T induces long-lasting changes in the BCR repertoire. Sip-T retreatment leads to quicker focusing of BCR repertoire than initial treatment. These results are consistent with sip-T inducing durable immunologic memory.
Government will cap legal fees in clinical negligence cases
Authors: Ingrid Torjesen
Journal: BMJ (2015)

The government has unveiled plans to cap legal fees charged by lawyers in clinical negligence claims, in an effort to save the NHS as much as £80m a year.

In 2013-14 claimants’ lawyers charged the NHS Litigation Authority £259m in legal fees for clinical negligence claims. Currently, no limit exists on the legal fees that can be charged.

Ben Gummer, health minister, said, “Unscrupulously, some lawyers have used patient claims to load grossly excessive costs onto the NHS and charge far more than the patient receives in compensation.”

In one case a lawyer …
Over-expression of mitochondrial creatine kinase in the murine heart improves functional recovery and protects against injury following ischaemia–reperfusion
Authors: Hannah J Whittington, Philip J Ostrowski, Debra J McAndrew, Fang Cao, Andrew Shaw, Thomas R Eykyn, Hannah A Lake, Jack Tyler, Jurgen E Schneider, Stefan Neubauer, Sevasti Zervou, Craig A Lygate
Journal: Cardiovascular Research (2018)

Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of ATP at times of high demand. We hypothesized that elevating MtCK would be beneficial in ischaemia-reperfusion (I/R) injury.Mice were created over-expressing the sarcomeric MtCK gene with αMHC promoter at the Rosa26 locus (MtCK-OE) and compared with wild-type (WT) littermates. MtCK activity was 27% higher than WT, with no change in other CK isoenzymes or creatine levels. Electron microscopy confirmed normal mitochondrial cell density and mitochondrial localization of transgenic protein. Respiration in isolated mitochondria was unaltered and metabolomic analysis by 1 H-NMR suggests that cellular metabolism was not grossly affected by transgene expression. There were no significant differences in cardiac structure or function under baseline conditions by cine-MRI or LV haemodynamics. In Langendorff-perfused hearts subjected to 20 min ischaemia and 30 min reperfusion, MtCK-OE exhibited less ischaemic contracture, and improved functional recovery (Rate pressure product 58% above WT; P < 0.001). These hearts had reduced myocardial infarct size, which was confirmed in vivo: 55 ± 4% in WT vs. 29 ± 4% in MtCK-OE; P < 0.0001). Isolated cardiomyocytes from MtCK-OE hearts exhibited delayed opening of the mitochondrial permeability transition pore (mPTP) compared to WT, which was confirmed by reduced mitochondrial swelling in response to calcium. There was no detectable change in the structural integrity of the mitochondrial membrane.Modest elevation of MtCK activity in the heart does not adversely affect cellular metabolism, mitochondrial or in vivo cardiac function, but modifies mPTP opening to protect against I/R injury and improve functional recovery. Our findings support MtCK as a prime therapeutic target in myocardial ischaemia.
Metabolic activity to predict clinical response and prognosis in esophageal adenocarcinoma patients treated with bimodality.
Authors: Kazuto Harada, Carol C Wu, Xuemei Wang, Dilsa Mizrak Kaya, Fatemeh Ghazanfari Amlashi, Quan Lin, Mariela A. Blum Murphy, Dipen M. Maru, Brian Weston, Jeffrey H Lee, Manoop S. Bhutani, Wayne Lewis Hofstetter, Quynh Nguyen, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2018)

127 Background: Patients with localized esophageal adenocarcinoma (L-EAC) who are not suitable for surgery receive definitive chemoradiation. However, there are no biomarkers or imaging variables to predict clinical complete response (cCR; negative bx and physiologic PET post chemoradiation) or prognosticate favorable overall survival (OS). We analyzed tumor metabolic activity by standardized uptake value (SUV) or total lesion glycolysis (TLG). Methods: 266 patients with L-EAC, who declined or were unsuitable for surgery, were analyzed. Cox proportional hazards regression model for OS was analyzed using categorized SUV (low; &lt; 6.5, moderate; 6.5-12.9, or high; ≥12.9) or TLG (low; &lt; 24.2, moderate; 24.2-82.6, or high; ≥82.6). Logistic regression model for cCR was analyzed using categorized SUV (low; &lt; 5.4 or high; ≥5.4) or TLG (low; &lt; 27.0 or high; ≥27.0). Results: Mean SUV and TLG were 12.8 ± 10.7 and 209 ± 376.8, respectively. Both SUV and TLG were significantly associated with the length of the tumor (p &lt; 0.0001) and clinical stage (p &lt; 0.0001). Higher SUV and TLG were significantly associated with shorter OS than low SUV and TLG (moderate SUV; HR 1.79, CI 1.19-2.69, high SUV; HR 2.82, 1.90-4.18, moderate TLG; HR 1.82, 1.14-2.90, high TLG; 3.16, 2.11-4.74). 68 patients (28%) achieved cCR and remained free of recurrence. In the multivariate logistic regression model, low SUV and low TLG highly predicted cCR without recurrence (low SUV; OR 3.15, 1.38–7.19, low TLG; OR 4.79, 2.28-10.08). Conclusions: Tumor metabolic activity is highly associated with prognosis and response to chemoradiation in patients with L-EAC not undergoing surgery. Further refinements (addition of biomarkers) could allow personalized care of these patients.
Initial Public Health Laboratory Response After Hurricane Maria — Puerto Rico, 2017
Authors: Jeniffer Concepción-Acevedo, Anita Patel, Carolina Luna-Pinto, Rafael González Peña, Rosa Ivette Cuevas Ruiz, Héctor Rivera Arbolay, Mayra Toro, Carmen Deseda, Victor R. De Jesus, Efrain Ribot, Jennifer-Quiñones Gonzalez, Gouthami Rao, Alfonsina De Leon Salazar, Marisela Ansbro, Brunilís B. White, Margaret C. Hardy, Joaudimir Castro Georgi, Rita Stinnett, Alexandra M. Mercante, David Lowe, Haley Martin, Angela Starks, Beverly Metchock, Stephanie Johnston, Tracy Dalton, Olga Joglar, Cortney Stafford, Monica Youngblood, Katherine Klein, Stephen Lindstrom, LaShondra Berman, Renee Galloway, Ilana J. Schafer, Henry Walke, Robyn Stoddard, Robin Connelly, Elaine McCaffery, Marie-Claire Rowlinson, Stephen Soroka, Darin T. Tranquillo, Anne Gaynor, Chris Mangal, Kelly Wroblewski, Atis Muehlenbachs, Reynolds M. Salerno, Matthew Lozier, Brittany Sunshine, Craig Shapiro, Dale Rose, Renee Funk, Satish K. Pillai, Eduardo O’Neill
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

CDC worked closely with the Puerto Rico Department of Health and other federal, state, and nongovernmental partners in providing technical support and aid in reestablishing laboratory operations during the emergency response after Hurricane Maria.
RCGP issues consultation on major plan to improve general practice
Authors: Caroline White
Journal: BMJ (2012)

More needs to be done to boost the profile and status of general practice to attract new entrants to the profession and to increase the skills of current GPs if the challenges facing UK healthcare are to be met, the Royal College of General Practitioners has said.

The college has set out an ambitious plan for the future of general practice over the next decade in a bid to ensure that there are enough GPs who are equipped to take on roles in health …
Association of changes in vaginal microbiome with oligoclonal T-cell expansion and early response to chemoradiation for cervical cancer.
Authors: Lauren Elizabeth Colbert, Andrea Delgado Medrano, Rebecca A. Previs, Patricia J. Eifel, Anuja Jhingran, Lois M. Ramondetta, Phillip Andrew Futreal, Amir A. Jazaeri, Robert Tyler Hillman, Michael M. Frumovitz, Kathleen M. Schmeler, Megan Mikkelson, Geena Mathew, Nadim Ajami, Pablo Okhuysen, Joseph Petrosino, Stephen M. Hahn, Ann Klopp
Journal: Journal of Clinical Oncology (2018)

8 Background: The composition of the vaginal microbiome has been shown to affect clearance of HPV virus and transformation to invasive cancer. Clinical studies correlating the vaginal microbiome with immune activation and response to cancer treatment are lacking. We profiled intratumoral T-cell clonality during radiation therapy and correlated it with the diversity of the vaginal flora. Methods: Thirty patients with newly diagnosed locally advanced cervical cancer were enrolled on a prospective study to characterize changes in the cervical microbiome during chemoradiation. Cervical samples were obtained before radiation therapy and during the 1st, 3rd, and 5 th week of radiation therapy. The vaginal microbiome was characterized using 16 sRNA gene sequencing to produce operational taxonomic units (OTU’s) representing individual bacterial species. Disease response was categorized as early response (ER), late response (LR), or nonresponse (NR) on the basis of clinical examination at brachytherapy and 3-month PET/CT. Twenty patients had T-cell receptor β sequencing of DNA performed using the ImmunoSEQ platform. The maximum productive frequency of the top three clones (MP3) was used to assess T-cell clonality. Results: Early response was associated with clonal T-cell expansion with an increase of MP3 of 11.1% during treatment as compared to a decline of 6.1% in patients with LR/NR (p = 0.05). Early response was also associated with lower quantity of observed OTU’s of vaginal microbiota (25.0 [SD 12.68]) vs patients with LR/NR (41.15 [SD = 23.3]) (p = 0·03). Increased MP3 was associated with increased abundance of Corynebacteriales (R = 0.90; p &lt; .0001) , Actinomycetales (R = 0.83; p &lt; .0001) and Bifidobacteriales (R = 0.82; p &lt; .0001) . Decreased MP3 was associated with increased abundance of lactobacillus (R = -0.61; p &lt; .0001). Conclusions: Increased diversity of the vaginal microbiome is negatively associated with outcome, supporting previous clinical studies in non-cancer settings. Specific vaginal bacterial species are associated with increased or decreased T-cell clonality at completion of radiation.
Integrative Omics
Authors: Robert W. McGarrah, Svati H. Shah
Journal: Circulation (2018)

Great strides have been made in dissecting the genetics of cardiovascular disease (CVD) through genome-wide association studies and whole exome/ genome sequencing, although the full heritability remains to be elucidated.Furthermore, biological insights into the associations of common variants with complex traits are often lacking.Although static DNA variation is at the core of variability between humans, viewed in isolation it can provide only a snapshot of the complex landscape of the dynamic, temporal evolution of CVD.One powerful approach to attempt to harness this dynamic variability is to study intermediate phenotypes that are more proximal to genomic variation than complex clinical end points.Although they can be difficult to measure accurately given the temporal nature of CVD, when analyzed on the foundation of the static genome, integrated studies can identify genomic loci that influence disease through these intermediate biomarkers.This principle underlies quantitative trait loci (QTL) studies, where genetic variation is integrated with other omics data (eg, transcriptomics, metabolomics, proteomics).Once these associations are established, the genetic variants and biomarkers can then be studied in a focused manner to determine what, if any, causal relation they have to the disease of interest.In addition, if done at the genome-wide level, these studies provide a valuable resource to identify possible functional effects of disease-associated genetic variants.The CVD community is just beginning to embark on such integrative studies that capitalize on the large amount of molecular data now available in CVD cohorts.In this issue of Circulation, Benson et al 1 do just this, elegantly harnessing the power of the proteome to further our understanding of CVD genetics.Integrating genome-wide and exome array genetic data with proteomic data profiled by using a novel aptameter-based multiplex assay, they identify protein QTL (pQTL) in the Framingham Heart Study (FHS).Specifically, they performed pQTL analysis in the FHS Offspring cohort (n=759) on 156 proteins that they had previously identified as being associated with the Framingham CVD 10-year risk score. 2 They then performed validation studies in the MDCS (Malmö Diet and Cancer Study) (n=1421).Their results highlight the multifaceted output that can be extracted from population-based studies.First, taking advantage of the family-based structure of FHS, they show that a large amount of variance (>20%) in the majority protein levels (≈92%) can be explained by heritable factors, whereas the clinical components of the Framingham CVD risk score explain the same degree of variance in only 16% of the proteins.Genome-wide association studies of the 156 proteins identified 120 pQTLs that reached genome-wide significance in FHS, with 75 validating in MDCS.Four of the pQTLs had been identified as CVD risk loci in the large CAR-
The Hippo Signaling Pathway in Pancreatic β-Cells: Functions and Regulations
Authors: Amin Ardestani, Kathrin Maedler
Journal: Endocrine Reviews (2017)

Hippo signaling is an evolutionarily conserved pathway that critically regulates development and homeostasis of various tissues in response to a wide range of extracellular and intracellular signals. As an emerging important player in many diseases, the Hippo pathway is also involved in the pathophysiology of diabetes on the level of the pancreatic islets. Multiple lines of evidence uncover the importance of Hippo signaling in pancreas development as well as in the regulation of β-cell survival, proliferation, and regeneration. Hippo therefore represents a potential target for therapeutic agents designed to improve β-cell function and survival in diabetes. In this review, we summarize recent data on the regulation of the Hippo signaling pathway in the pancreas/in pancreatic islets, its functions on β-cell homeostasis in physiology and pathophysiology, and its contribution toward diabetes progression. The current knowledge related to general mechanisms of action and the possibility of exploiting the Hippo pathway for therapeutic approaches to block β-cell failure in diabetes is highlighted.
Abstract MP005: Plasma Phospholipid Concentration of Palmitoleic Acid is Associated with an Increased Risk of Heart Failure in Male Physicians
Authors: Luc Djousse, Natalie Weir, Gregory Kotler, Naomi Hanson, Michael Tsai, J M Gaziano
Journal: Circulation (2012)

Background: Plasma fatty acids in the de novo lipogenesis including plamitoleic acid have been associated with a higher risk of blood pressure and type 2 diabetes (two major risk factors for heart failure -HF). However, limited data are available on the association between plasma levels of palmitoleic acid and HF risk. Objective: To test the hypothesis that plasma palmitoleic acid concentration is associated with an increased risk of HF. In a secondary aim, we examined whether stearoyl-CoA desaturase indices, cis -vaccenic acid, and oleic acid were associated with HF risk. Methods: We used a prospective nested case-control design for this project among participants of the Physicians' Health Study. For each of the 788 HF cases, we used the risk set method to randomly select a control among all eligible controls at the time of the index case occurrence. Each control was matched on age, year of birth, race, and time of blood collection of the index case. We used gas chromatography to measure plasma phospolipid fatty acids on frozen blood samples collected between 1997 and 2001 on study subjects free of HF. HF events were ascertained via annual follow-up questionnaires and validated in a subsample through review of medical records (positive predictive value 91% -- 50 confirmed out of 55 self-reported cases). Results: Mean age was 58.7 ± 8.0 years. In a conditional logistic regression controlling for matching factors, odds ratios (95% CI) for HF were 1.0 (reference), 1.00 (0.75–1.33), 1.22 (0.91–1.64), and 1.48 (1.10–1.99) across consecutive quartiles of palmitoleic acid (p trend 0.005). Additional adjustment for body mass index, smoking, alcohol intake, exercise, prevalent diabetes and coronary disease, marine omega-3 fatty acids, hypertension treatment, and plasma stearic acid did not alter the results [OR: 1.0, 1.00 (0.72–1.37), 1.23 (0.89–1.72), and 1.51 (1.06–2.15) from the lowest to the highest quartile, p trend 0.014]. When analyzed as a continuous variable, each standard deviation increase of plasma palmitoleic acid was associated with a 15% higher odds of HF [OR: 1.15 (1.01–1.31)] in a multivariable adjusted model. In a secondary analysis, plasma phospholipid oleic acid (18:1n−9) and cis-vaccenic acid (18:1n−7) were not associated with the odds of HF. Indices of stearoyl-CoA desaturase-1 (16:1n−7 to 16:0 ratio) and desaturase-2 (18:1n−9 to 18:0 ratio) were not significantly associated with the odds of HF. Conclusion: Our data showed that plasma concentration of palmitoleic acid is positively associated with the risk of HF in male physicians. This suggests that fatty acids in the de novo lipogenesis may play a role in the development of HF.
Regulation of the tumor suppressor PLZF and prostate cancer prognosis.
Authors: Konrad Hermann Stopsack, Travis A. Gerke, Svitlana Tyekucheva, Lorelei A. Mucci, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2018)

137 Background: PLZF ( ZBTB16) is an androgen-regulated tumor suppressor gene. Homozygous PLZF deletions are seen in a proportion of localized as well as castration-resistant prostate cancers (PC). Since PTEN has been shown to regulate PLZF expression in vitro, we hypothesized that PTEN status impacts PLZF expression in men with PC. We further hypothesized that low PLZF is associated with a poorer PC prognosis. Methods: We studied patients diagnosed with PC during prospective follow-up of the Health Professionals Follow-up Study (HPFS; n = 254) and the Physicians’ Health Study (PHS; n = 150). We performed whole transcriptome profiling of tumor specimens from cancer diagnosis and, in a subset of patients ( n = 253), a genomically-validated immunohistochemistry for PTEN. Patients were followed for metastases and PC-specific mortality (lethal cancer) after primary treatment for a median of 14 years. Univariable linear and multivariable logistic regression models for cancer outcomes, adjusted for age and calendar year, were used. For validation, the association of PTEN copy number variations and PLZF mRNA expression was assessed in The Cancer Genome Atlas (TCGA) primary PC cohort (n = 333). Results: Loss of PTEN protein expression was associated with lower PLZF expression (–0.72 standard deviations [SD]; 95% CI, –0.38 to –1.06; p &lt; 0.001; HPFS and PHS cohorts), as were copy number variations in PTEN (TCGA cohort; –0.46 SD for deep deletions vs. diploid status; 95% CI, –0.13 to –0.79; p = 0.006) . PLZF expression did not differ significantly by Gleason grade in any cohort (all p &gt; 0.09). In both the HPFS and PHS cohorts, the 25% of patients with the lowest PLZF expression were significantly more likely than those with higher expression to have progression to lethal cancer. This association was independent from Gleason grade, PTEN loss, and a signature of androgen receptor signaling (adjusted odds ratio for lethal cancer, 2.69; 95% CI, 1.18 to 6.14; p = 0.019). Conclusions: Loss of PTEN expression is associated with lower expression of PLZF amongst primary PC not exposed to ADT. In line with its action as a tumor suppressor, low PLZF expression is associated with lethal PC. Whether further suppression of PLZF with ADT worsens outcomes in advanced PC needs further study.