tbuckley/cabot-search huggingface dataset:
Brief Report: Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome
Authors: Rohan Sharma, Valerie M. Harris, Joshua Cavett, Biji T. Kurien, Ke Liu, Kristi A. Koelsch, Anum Fayaaz, Kaustubh S. Chaudhari, Lida Radfar, David Lewis, Donald U. Stone, C. Erick Kaufman, Shibo Li, Barbara Segal, Daniel J. Wallace, Michael H. Weisman, Swamy Venuturupalli, Jennifer A. Kelly, Bernardo Pons‐Estel, Roland Jonsson, Xianglan Lu, Jacques‐Eric Gottenberg, Juan‐Manuel Anaya, Deborah S. Cunninghame‐Graham, Andrew J. W. Huang, Michael T. Brennan, Pamela Hughes, Ilias Alevizos, Corinne Miceli‐Richard, Edward C. Keystone, Vivian P. Bykerk, Gideon Hirschfield, Gunnel Nordmark, Sara Magnusson Bucher, Per Eriksson, Roald Omdal, Nelson L. Rhodus, Maureen Rischmueller, Michael Rohrer, Marie Wahren‐Herlenius, Torsten Witte, Marta Alarcón‐Riquelme, Xavier Mariette, Christopher J. Lessard, John B. Harley, Wan‐Fai Ng, Astrid Rasmussen, Kathy L. Sivils, R. Hal Scofield
Journal: Arthritis & Rheumatology (2017)

Objective Sjögren's syndrome ( SS ) and systemic lupus erythematosus ( SLE ) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of ~10 to 1. Common X chromosome aneuploidies, 47, XXY and 47, XXX , are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. Methods We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single‐nucleotide polymorphism alleles, along with determining the karyotype of selected patients. Results Among ~2,500 women with SLE , we found 3 patients with a triple mosaic, consisting of 45,X/46, XX /47, XXX . Among ~2,100 women with SS , 1 patient had 45,X/46, XX /47, XXX , with a triplication of the distal p arm of the X chromosome in the 47, XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in ~1 in 25,000–50,000 live female births, while partial triplications are even rarer. Conclusion Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.
Primary high-grade myxofibrosarcoma/pleomorphic malignant fibrous histiocytoma: Percent myxoid component to improve outcome prediction.
Authors: Ann Yeelin Lee, Narasimhan P Agaram, Li-Xuan Qin, Murray F. Brennan, Samuel Singer
Journal: Journal of Clinical Oncology (2015)

10556 Background: Myxofibrosarcoma and pleomorphic malignant fibrous histiocytoma (PMFH) are aggressive genetically complex sarcomas. We investigated the association of percent myxoid component (MC) with disease-specific (DSS) and distant recurrence-free survival (DRFS) in primary high-grade myxofibrosarcoma and PMFH and determined the optimal %MC cutpoints for defining subgroups. Methods: Review of a prospective database identified 200 patients with primary, high-grade extremity/truncal myxofibrosarcoma or PMFH treated during 1992-2013. Histology was reviewed and %MC determined for each case. Optimal %MC cutpoints were determined from minimum p-value analysis of the entire cohort. DSS and DRFS were analyzed using the Kaplan-Meier method, log-rank test and Cox regression. Results: Median follow-up for survivors was 5.8 years. Median tumor size was 9.5 cm (range 2.5-30 cm). The optimal %MC cutpoints for both DSS and DRFS were 5% and 70%. Sarcomas with ≥ 5% MC were classified as myxofibrosarcoma (n = 128) and < 5% MC (n = 72) as PMFH. The 5-year DRFS was 64% for > 70% MC myxofibrosarcoma, 49% for 5-70% MC myxofibrosarcoma, and 23% for PMFH. %MC, tumor size, and age were independently associated with DSS, while %MC and size were associated with DRFS (Table). Conclusions: Percent MC is an important predictor of DSS and DRFS in primary high-grade myxofibrosarcoma and PMFH. Histology-based classification of %MC improves stratification of patient outcome and will aid in selection of patients for systemic therapy and clinical trials. Multivariate analysis of clinical and pathological variables associated with DSS and DRFS. Variable DSS: Multivariate HR (95% CI) DSS: p value DRFS: Multivariate HR (95% CI) DRFS: p value MC 5-70% (vs > 70%) 1.6 (0.9-3.0) 0.11 1.9 (1.1-3.3) 0.03 MC < 5% (vs > 70%) 2.8 (1.7-4.8) <0.001 3.6 (2.2-6.0) <0.001 Size (> = 8 cm vs < 8 cm) 2.5 (1.5-4.0) <0.001 2.3 (1.5-3.6) <0.001 Age (> = 65 years vs < 65 years) 1.6 (1.0-2.5) 0.03
Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis
Authors: Anusha N. Seneviratne, Andreas Edsfeldt, Jennifer E. Cole, Christina Kassiteridi, Maarten Swart, Inhye Park, Patricia Green, Tariq Khoyratty, David Saliba, Michael E. Goddard, Stephen N. Sansom, Isabel Goncalves, Rob Krams, Irina A. Udalova, Claudia Monaco
Journal: Circulation (2017)

Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions.We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation.Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ.IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.
A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults
Authors: Robert W Morton, Kevin T Murphy, Sean R McKellar, Brad J Schoenfeld, Menno Henselmans, Eric Helms, Alan A Aragon, Michaela C Devries, Laura Banfield, James W Krieger, Stuart M Phillips
Journal: British Journal of Sports Medicine (2017)

We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength.A systematic search of Medline, Embase, CINAHL and SportDiscus.Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation.Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM).Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm2 (51, 570)) and mid-femur CSA (7.2 mm2 (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM.Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.
FDA subset analysis of the safety of nivolumab in elderly patients with advanced cancers.
Authors: Harpreet Singh, Geoffrey Kim, Virginia Ellen Maher, Julia A. Beaver, Lee H. Pai-Scherf, Sanjeeve Balasubramaniam, Marc Robert Theoret, Gideon Michael Blumenthal, Richard Pazdur
Journal: Journal of Clinical Oncology (2016)

10010 Background: With recent FDA approvals of immune checkpoint inhibitors for the treatment of advanced cancer, an increasing number of elderly patients will be treated with immunotherapy. Nivolumab is an immune checkpoint inhibitor, currently approved for the treatment of advanced renal cell cancer, melanoma, and non-small cell lung cancer based on significant responses including benefit in overall survival. However, little is known about the safety of nivolumab in an elderly patient population. Methods: Eligible patients recieved at least one dose of nivolumab as a single agent while enrolled in a phase 3 registration trial for the treatment of advanced renal cell cancer (CA209025), melanoma (CA209066), or non-small lung cancer (CA209057 and CA209017). Adverse events which occurred up to 100 days after last dose of nivolumab based on standardized adverse event datasets submitted by the sponsor were included. Results: See table. Conclusions: Immune therapies can benefit patients across a wide range of tumors. Currently there is little known about the safety of nivolumab in elderly patients. This exploratory analysis suggests that nivolumab is well tolerated in the elderly population in terms of adverse events. These data should be validated in larger patient cohorts, with specifically targeted age ranges to reflect the aging cancer population. The inclusion of greater numbers of elderly patients in registration clinical trials will further inform clinicians on the safety of immune based therapies in the elderly. Adverse events by age in patients treated with nivolumab. Patients < 65 yrs (N=616) n% Patients ≥ 65 yrs (N=414) n% Patients ≥ 70 yrs (N=212) n% Grade 1-2 Adverse Events 584 (94.8) 394 (95.2) 202 (95.3) Grade 3-5 Adverse Events 360 (58.4) 259 (62.6) 152 (71.7) Serious Adverse Events 313 (50.8) 242 (58.5) 123 (58.0) All Adverse Events leading to Discontinuation 89 (14.4) 71 (17.1 42 (19.8) AEs Requiring Treatment with Immune Modulating Medication 256 (41.5) 196 (47.3) 110 (51.9) Select irAE's where immune modulating medication was initiated Diarrhea/colitis 15 (2.4) 17 (4.1) 11 (5.2) Pneumonitis 23 (3.7) 8 (1.9) 5 (2.4) Hepatitis 8 (1.3) 3 (0.7) 1 (0.5) Nephritis and renal dysfunction 6 (1.0) 8 (1.9) 7 (3.3) Rash 47 (7.6) 34 (8.2) 22 (10.4)
Peripheral and Alveolar Cell Transcriptional Programs Are Distinct in Acute Respiratory Distress Syndrome
Authors: Eric D. Morrell, Frank Radella, Anne M. Manicone, Carmen Mikacenic, Renee D. Stapleton, Sina A. Gharib, Mark M. Wurfel
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Heteroscedasticity was determined by linear regression: difference = a 1 b $ average, where b is the regression coefficient.r 2 is the square of the Pearson regression coefficient.
Locoregional therapies as a bridge to transplant in patients with hepatocellular carcinoma
Authors: S. S. Sakaria, R. Dhanasekaran, M. Pankonin, S. Parekh, J. S. Kauh, H. S. Kim
Journal: Journal of Clinical Oncology (2009)

e15608 Background: Orthotopic liver transplantation (OLT) has been widely established as the definitive treatment for patients with HCC who fit within the Milan criteria. The limited availability of donor organs results in prolonged waiting periods leading to tumor progression and potential disqualification for OLT. As a result, there has been a rising interest in locoregional therapies that may stall tumor progression until a donor organ is available for transplantation. Methods: We reviewed patients with a diagnosis of HCC on the transplant list between 1998 and 2008. Of these patients, 72 patients received locoregional therapies (LRT). The various LRT consisted of transcatheter therapy alone (29 patients); combination transcatheter therapy and radiofrequency ablation (RFA) (33 patients), and RFA alone (10 patients). Kaplan Meier method with the log rank test and Cox proportional hazards method were used for survival analysis. Results: Of the 72 patients, 71% (51/72) were transplanted and 29% (21/72) dropped out. The reasons for drop-out from the transplant list included tumor progression (4.2%); condition deteriorated (11.1%); death (6.9%); refusal of transplant (2.7%); other causes (4.2%). The long term survival rates in the transplanted patients at 1 yr, 2 yrs and 5 yrs is 90%, 87% and 72%. The long term survival in the non-transplanted patients at 1 yr and 2 yrs is 47% and 33% respectively. Mean duration from the first LRT to OLT was 126 days (SD 208). In patients who dropped out, mean duration from the first LRT to the removal date was 143 days (SD 256). The mean post transplant follow-up period was 758 days (SD 527). No recurrence was found in the post transplant follow- up. Conclusions: Locoregional therapies can be effectively used as a bridging therapy to treat patients with HCC awaiting transplant. The long term recurrence-free survival in patients who received OLT after bridging therapies demonstrated 5-year survival rates of 72% and no recurrence after transplant. No significant financial relationships to disclose.
Candidate tumor-suppressor gene loci on chromosome 22q13, D22S284 marker, associated with the metastasis potential of human breast cancer
Authors: Anchalee Ratanavila, Ravat Panvichian, Sansanee Vongvaisyavarn, Surasak Leelaudomlipi, Uphin Visetpanich, Wanta Yingyong, Wiwat Tirapanich, Ekaphop Sirachainan
Journal: Cancer Research (2005)

1886   Functional inactivation of tumor-suppressor gene(s) is an essential step in carcinogenesis and progression. Tumor-suppressor genes are generally inactivated by an intragenic point mutation in one allele and the subsequent loss of the corresponding (wild-type) allele, resulting in a condition known as “loss of heterozygosity”(LOH). Somatic alterations in microsatellite sequence due to a deletion or an insertion of one or more repeat units have been termed “microsatellite instabilities” (MSI). MSI is associated with defects in the DNA mismatch-repair machinery, and MSI has been detected in both hereditary and sporadic human cancer. MSI could lead to inactivation of other tumor-suppressor genes. In our previous study, using comparative genomic hybridization (CGH), it was found that primary breast cancer with metastasis (axillary node and/or distant metastasis) acquired deletion on chromosome 22q13 at higher frequency than primary breast cancer without metastasis (unpublished data), suggesting that this region might contain a tumor suppressor gene involved in the metastasis of breast cancer. The objective of this study was to identify the candidate tumor-suppressor gene loci on chromosome 22q13 by PCR-based microsatellite analysis. Sixty-two pairs of matched normal DNA and primary tumor DNA from patients of invasive breast cancer were analyzed by PCR, using 6 fluorescence-labeled primers for polymorphic microsatellite markers spanning chromosome 22q13 (D22S284, D22S276, D22S282, D22S1171, D22S1159, D22S274). The PCR products were electrophoresed on an ABI 310 genetic analyzer; Genescan 2.1 and Genotyper V.2.0 software were used for scanning and analysis of LOH and MSI. Statistical significant association was tested between the occurrence of genetic alterations in microsatellites and clinicopathological data of primary breast cancer in patients with or without metastasis. After excluding the non-informative results, the frequency of allelic alterations among breast cancer with metastasis (35 patients) at marker D22S284, D22S276, D22S282, D22S1171, D22S1159, D22S274, were 13/26(50%), 8/17(47%), 12/30(40%), 14/31(45.2%), 13/24(54.2%), 14/29(48.3%), respectively. In contrast, the corresponding frequency among breast cancer without metastasis (27 patients) were 3/19(15.8%), 8/12(66.7%), 5/23(21.8%), 6/23(26.1%), 13/20(65.0%), 6/19(31.6%), respectively. Comparison of these results with clinicopathological data revealed that allelic alteration at D22S284 significantly associated with breast cancer with metastasis (50% VS15.8%, p=0.04), while allelic alteration at other loci did not reach statistical significance. This data provides evidence suggesting that there may be a candidate tumor suppressor gene near D22S284 loci associated with the metastasis potential of sporadic human breast cancer.
Association analyses based on false discovery rate implicate new loci for coronary artery disease
Authors: Christopher P Nelson, Anuj Goel, Adam S Butterworth, Stavroula Kanoni, Tom R Webb, Eirini Marouli, Lingyao Zeng, Ioanna Ntalla, Florence Y Lai, Jemma C Hopewell, Olga Giannakopoulou, Tao Jiang, Stephen E Hamby, Emanuele Di Angelantonio, Themistocles L Assimes, Erwin P Bottinger, John C Chambers, Robert Clarke, Colin N A Palmer, Richard M Cubbon, Patrick Ellinor, Raili Ermel, Evangelos Evangelou, Paul W Franks, Christopher Grace, Dongfeng Gu, Aroon D Hingorani, Joanna M M Howson, Erik Ingelsson, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Terho Lehtimäki, Xiangfeng Lu, Yingchang Lu, Winfried März, Ruth McPherson, Andres Metspalu, Mar Pujades-Rodriguez, Arno Ruusalepp, Eric E Schadt, Amand F Schmidt, Michael J Sweeting, Pierre A Zalloua, Kamal AlGhalayini, Bernard D Keavney, Jaspal S Kooner, Ruth J F Loos, Riyaz S Patel, Martin K Rutter, Maciej Tomaszewski, Ioanna Tzoulaki, Eleftheria Zeggini, Jeanette Erdmann, George Dedoussis, Johan L M Björkegren, Heribert Schunkert, Martin Farrall, John Danesh, Nilesh J Samani, Hugh Watkins, Panos Deloukas
Journal: Nature Genetics (2017)
Prophylactic cranial irradiation (PCI) versus observation in radically treated stage III non-small cell lung cancer (NSCLC): A randomized phase III NVALT11 study.
Authors: Harry J.M. Groen, Anne-Marie C. Dingemans, Jose Belderbos, Caroline Tissing-Tan, Gertruda Herder, Tjeerd Haitjema, Fred Ubbels, Frank J Lagerwaard, Sherif El Sharouni, Jos Stigt, Egbert F. Smit, Harm van Tinteren, Vincent van de Noort, Dirk De Ruysscher
Journal: Journal of Clinical Oncology (2017)

8502 Background: Brain metastases are one of the major sites of tumor failure in patients (pts) with radically treated stage III NSCLC. The value of PCI in these pts remains unsettled. This study is designed to investigate whether PCI reduces the incidence of symptomatic brain metastases (sBM). Methods: Pts were randomized between observation and PCI after concurrent or sequential chemo-RT with or without surgery. PCI dose was left to the physician(36 Gy/18F, 30 Gy/12F, 30 Gy/10F). Pts were registered before randomization, those progressing after chemo-RT were not randomized. Pts were followed for sBM (defined as increased intracranial pressure, headache, nausea, vomiting, cognitive, affective disturbances, seizures, focal neurological symptoms andMRI/CT), side effects, survival, quality of life (QLQ-C30, EuroQol 5D). The primary endpoint is the proportion of patients developing sBM. Randomizing 300 pts the study has 90% (2-sided p = 0.05) power to detect 17% decrease in pts developing sBM at 24 months (mo). Results: Between 2009 and 2015, 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. In 2013 due to slow accrual, it was decided to reduce the number of randomized pts to 175 pts. With 75 events a 2-sided log-rank test would have 80% power to detect HR 0.52 and alpha 0.05. One pt in PCI arm was withdrawn after randomization. Pts characteristics were male (n = 114, 66%); adeno/squa/other 72 (41%), 62 (36%), 40 (23%); PS 0/1/2 66 (38%), 99 (57%), 9 (5%); stage IIIA/B 93 (53%), 80 (46%), unknown 1 (1%). Median follow up was 48.5 mo (95% CI, 39 - 54). Proportion of pts with sBM was 4/86 (4.6%) in PCI and 25/88 (28.4 %) in observation (p &lt; 0.00001). Seven (8.1%) pts in PCI and 26 (29.7%) pts in observation arm had BM on imaging (p &lt; 0.001). Median time to sBM was not reached in either arm. Median OS was 24.2 mo in PCI and 21.9 mo in observation arm (p = 0.52). Global QoL at 3 mo was worse in PCI arm (p = 0.02) but not afterwards. Conclusions: PCI significantly decreases the proportion of patients developing both symptomatic BM without influencing overall survival. PCI decreases 3 months global quality of life measures but not beyond. Clinical trial information: NTR 1601.
Chronic hepatitis B: divide and conquer?
Authors: Michael Nassal
Journal: Gut (2017)

Chronic hepatitis B (CHB) puts 250 million people or more at a greatly increased risk to develop terminal liver disease.1 The causative agent, hepatitis B virus (HBV), is a small hepatotropic DNA virus that replicates via reverse transcription.2 Persistence of infection is the combined result of an inadequate host immune response3 and the stability of a special episomal form of the virus genome termed covalently closed circular (ccc) DNA.4 5 Associating with host and viral proteins into a minichromosome, cccDNA serves as template for all viral RNAs and thus progeny virions (figure 1). A true cure of CHB would thus require elimination of cccDNA from a patient’s liver; this is rarely achieved by current CHB therapies with type I interferon or nucleos(t)ide analogues (NAs) which inhibit HBV reverse transcription. Also, none of the new anti-HBV drugs in clinical development,6 including entry inhibitors such as Myrcludex-B (Myr-B)7 which block the interaction between HBV and its receptor Na+-taurocholate cotransporting polypeptide (NTCP; figure 1), directly target cccDNA. Not even recovery from acute self-limited hepatitis B appears to eradicate all cccDNA molecules although their number (corresponding to at least the ~1010 infected hepatocytes at the peak of infection) is massively reduced by the immune system within a few weeks,3 mostly with fully maintained liver function.



Figure 1 
Hepatitis B virus (HBV) covalently closed circular (ccc) DNA synthesis and immune-mediated loss. (A) HBV cccDNA synthesis and amplification from relaxed circular (rc) DNA. Hepatitis B virions exploit the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) as entry receptor into human hepatocytes. After the envelope is stripped off, the nucleocapsids (NC) transport the rcDNA genome to the nucleus where conversion into cccDNA takes place. cccDNA associates with host and viral factors into a minichromosome (not shown) that serves as transcription template for the viral RNA; …