tbuckley/cabot-search huggingface dataset:
Risk of Suicide Attempt Among Soldiers in Army Units With a History of Suicide Attempts
Authors: Robert J. Ursano, Ronald C. Kessler, James A. Naifeh, Holly Herberman Mash, Carol S. Fullerton, Paul D. Bliese, Alan M. Zaslavsky, Tsz Hin Hinz Ng, Pablo A. Aliaga, Gary H. Wynn, Hieu M. Dinh, James E. McCarroll, Nancy A. Sampson, Tzu-Cheg Kao, Michael Schoenbaum, Steven G. Heeringa, Murray B. Stein
Journal: JAMA Psychiatry (2017)

Mental health of soldiers is adversely affected by the death and injury of other unit members, but whether risk of suicide attempt is influenced by previous suicide attempts in a soldier's unit is unknown.To examine whether a soldier's risk of suicide attempt is influenced by previous suicide attempts in that soldier's unit.Using administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (STARRS), this study identified person-month records for all active-duty, regular US Army, enlisted soldiers who attempted suicide from January 1, 2004, through December 31, 2009 (n = 9650), and an equal-probability sample of control person-months (n = 153 528). Data analysis was performed from August 8, 2016, to April 10, 2017.Logistic regression analyses examined the number of past-year suicide attempts in a soldier's unit as a predictor of subsequent suicide attempt, controlling for sociodemographic features, service-related characteristics, prior mental health diagnosis, and other unit variables, including suicide-, combat-, and unintentional injury-related unit deaths. The study also examined whether the influence of previous unit suicide attempts varied by military occupational specialty (MOS) and unit size.Of the final analytic sample of 9512 enlisted soldiers who attempted suicide and 151 526 control person-months, most were male (86.4%), 29 years or younger (68.4%), younger than 21 years when entering the army (62.2%), white (59.8%), high school educated (76.6%), and currently married (54.8%). In adjusted models, soldiers were more likely to attempt suicide if 1 or more suicide attempts occurred in their unit during the past year (odds ratios [ORs], 1.4-2.3; P < .001), with odds increasing as the number of unit attempts increased. The odds of suicide attempt among soldiers in a unit with 5 or more past-year attempts was more than twice that of soldiers in a unit with no previous attempts (OR, 2.3; 95% CI, 2.1-2.6). The association of previous unit suicide attempts with subsequent risk was significant whether soldiers had a combat arms MOS or other MOS (ORs, 1.4-2.3; P < .001) and regardless of unit size, with the highest risk among those in smaller units (1-40 soldiers) (ORs, 2.1-5.9; P < .001). The population-attributable risk proportion for 1 or more unit suicide attempts in the past year indicated that, if this risk could be reduced to no unit attempts, 18.2% of attempts would not occur.Risk of suicide attempt among soldiers increased as the number of past-year suicide attempts within their unit increased for combat arms and other MOSs and for units of any size but particularly for smaller units. Units with a history of suicide attempts may be important targets for preventive interventions.
Systematic assessment with I-SCAN magnification endoscopy and acetic acid improves dysplasia detection in patients with Barrett’s esophagus
Authors: Gideon Lipman, Raf Bisschops, Vinay Sehgal, Jacobo Ortiz-Fernández-Sordo, Rami Sweis, Jose Esteban, Rifat Hamoudi, Matthew Banks, Krish Ragunath, Laurence Lovat, Rehan Haidry
Journal: Endoscopy (2017)

Abstract Background and study aims Enhanced endoscopic imaging with chromoendoscopy may improve dysplasia recognition in patients undergoing assessment of Barrett’s esophagus (BE). This may reduce the need for random biopsies to detect more dysplasia. The aim of this study was to assess the effect of magnification endoscopy with I-SCAN (Pentax, Tokyo, Japan) and acetic acid (ACA) on dysplasia detection in BE using a novel mucosal and vascular classification system. Methods BE segments and suspicious lesions were recorded with high definition white-light and magnification endoscopy enhanced using all I-SCAN modes in combination. We created a novel mucosal and vascular classification system based on similar previously validated classifications for narrow-band imaging (NBI). A total of 27 videos were rated before and after ACA application. Following validation, a further 20 patients had their full endoscopies recorded and analyzed to model use of the system to detect dysplasia in a routine clinical scenario. Results The accuracy of the I-SCAN classification system for BE dysplasia improved with I-SCAN magnification from 69 % to 79 % post-ACA (P = 0.01). In the routine clinical scenario model in 20 new patients, accuracy of dysplasia detection increased from 76 % using a “pull-through” alone to 83 % when ACA and magnification endoscopy were combined (P = 0.047). Overall interobserver agreement between experts for dysplasia detection was substantial (0.69). Conclusions A new I-SCAN classification system for BE was validated against similar systems for NBI with similar outcomes. When used in combination with magnification and ACA, the classification detected BE dysplasia in clinical practice with good accuracy. Trials registered at ISRCTN (58235785).
The lysosomal protein cathepsin L is a progranulin protease
Authors: Chris W. Lee, Jeannette N. Stankowski, Jeannie Chew, Casey N. Cook, Ying-Wai Lam, Sandra Almeida, Yari Carlomagno, Kwok-Fai Lau, Mercedes Prudencio, Fen-Biao Gao, Matthew Bogyo, Dennis W. Dickson, Leonard Petrucelli
Journal: Molecular Neurodegeneration (2017)

Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments. Further, PGRN and Cat L co-localize in lysosomes of HEK293 cells, iPSC-derived neurons and human cortical neurons from human postmortem tissue. These data identify Cat L as a key intracellular lysosomal PGRN protease, and provides an intriguing new link between lysosomal dysfunction and FTLD.
Prognostic significance of genomic alterations of metastatic neuroblastomas.
Authors: Shahab Asgharzadeh, Roger Pique-Regi, Yuexian Tu, Richard Sposto, Hiroyuki Shimada, Antonio Ortega, Robert Seeger
Journal: Clinical Cancer Research (2007)

A36    Background:  Patients with metastatic neuroblastomas have quite different outcomes depending upon their age at diagnosis and  MYCN  amplification status. Accurate classification of patients, using genetic features of their tumors identified through microarray studies, would improve prediction of outcome and facilitate more appropriate selection of therapy.  Ob  jectives:  1) Develop algorithms for analysis of high-density single nucleotide polymorphism (SNP) arrays that would lead to improved identification of copy number alterations (CNA) in neuroblastoma tumors; 2) Identify subgroups of stage 4 neuroblastoma patients based on genomic features (amplifications or deletions) obtained from SNP arrays; and 3) Develop a genomic classifier that would improve prediction of outcome.  Method:  43 patients with metastatic neuroblastoma (15  MYCN  amplified, 28 non-amplified) tumors were analyzed using Affymetrix 50K Xba SNP arrays. A novel algorithm was developed using Sparse Bayesian Learning (SBL) to identify CNA. The accuracy of the algorithm was determined using simulated genomic data and four neuroblastoma cell lines’ data generated on Affymetrix 50K Xba, 250K Sty, 250K Nsp, and Illumina-550K platforms. Principal component analysis (PCA) was used to define regions with DNA copy number abnormalities and diagonal linear discriminant analysis (DLDA) was used to build and assess error rates of classifiers using combination of these regions. Loss of heterozygosity data were also used as features to build prognostic models.  Results : The SBL algorithm had greater accuracy identifying CNAs as compared to other algorithms (e.g. CBS, HMM, GLAD) and with 100-fold increase in computational speed as compared to CBS. SBL identified 106 major breakpoints in the 4 neuroblastoma cell lines tested of which 67% were represented on at least two microarray platforms. The concordance of SBL and CBS algorithms was 95% and the identified CNAs included all the major known neuroblastoma CNAs. In a proof of principle experiment, the PCAs for chromosomes 2p, 1p, and 19q were identified as the top features in a DLDA analysis distinguishing tumors based on their  MYCN  status. The cross validated error rate for this analysis was 15% (training error rate of 9%). Analysis of loss of heterozygosity data for the 28 patients whose tumors lacked MYCN amplification, identified low and high risk subgroup with PFS of 64% and 32%, respectively.  Conclusions : Accurate identification of genomic features of metastatic neuroblastomas from SNP arrays could be identified through a novel bayesian algorithm. These features can then be used to assign patients to low or high molecular risk groups even though their tumors are clinically indistinguishable.
Isolation of a novel peptide for targeted drug delivery into lung cancer
Authors: De-Kuan Chang, Chin-Tarng Lin, Han-Chung Wu
Journal: Cancer Research (2007)

2266   Lung cancer is the leading cause of cancer-related mortality in the world. There are two major types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC makes up about 80 to 90 percent of the cases, and SCLC approximately 10 to 12 percent. The five-year survival rate is less than 15 % for patients with advanced NSCLC. Lack of tumor specificity remains a major problem for chemotherapies in which side effects prevent the delivery of drug dosages needed to eliminate the majority of cancer cells. Ligand-targeted therapy can, however, render chemotherapy more tumor specific and less toxic, and may used in the development of novel therapies for cancer. In this investigation, we isolated a novel peptide capable of binding to NSCLC cell lines from a phage-displayed peptide library. The NSCLC-targeting phage was able to bind to several NSCLC cell lines but not bind to normal cells. Targeting phage and synthetic targeting peptide were both able to recognize human pulmonary tumor specimens from lung cancer patients. In SCID mice bearing NSCLC xenografts, the targeting phage was able to target tumor masses specifically. Tumor targeting ability of targeting phage could be inhibited by the synthetic targeting peptide, but not by the control peptide. In addition, when synthetic targeting peptide coupled to liposomes containing anti-cancer drugs vinorelbine or doxorubicin, drug efficacy against human lung cancer xenografts improved and toxicity was reduced. This tumor-specific peptide may have great potential in helping drugs better target cells in the treatment of lung cancer and may be used in the design of targeted gene transfer vectors as well as diagnostic tools for this disease.
Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia
Authors: Deepti Lall, Robert H. Baloh
Journal: Journal of Clinical Investigation (2017)

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.
Transcatheter Therapy for Mitral Regurgitation Clinical Challenges and Potential Solutions
Authors: Paul Sorajja, Martin B. Leon, David H. Adams, John G. Webb, R. Saeid Farivar
Journal: Circulation (2017)

Severe mitral regurgitation is a common and complex disease that is associated with an adverse prognosis. For decades, surgical treatment has been the standard of care. Recently, multiple technologies for transcatheter mitral therapy have emerged, with the potential for both repair and replacement in patients with native mitral regurgitation. Transcatheter mitral technologies have potential as solutions for unmet clinical needs. Further rigorous clinical studies are needed to determine their efficacy and safety, as well as the appropriate patient candidates. These evaluations will help to define the role of transcatheter mitral therapy as a potentially exciting new strategy to improve the lives of patients with mitral regurgitation.
Microwave ablation in combination with chemotherapy versus chemotherapy in advanced non small cell lung cancer: A prospective, randomized, phase III clinical trial.
Authors: Zhig Wei, Xin Ye, Dian zhong Geng, Yu ting Dong, Chun tang Wang, Jing wang Bi, Ya hong Sun, Jun ye Wang, Qing liang Feng, Xing lu Xu, Ben hua Zhang, Li cheng Zhang, Hai peng Ren, Kai xian Zhang, Deng jun Sun
Journal: Journal of Clinical Oncology (2017)

9048 Background: Previous studies showed that advanced non small cell lung cancer (NSCLC) benefited from microwave ablation in combination with platium-based doublet chemotherapy. This prospective, randomized, phase III clinical trial aimed to determining the survival benefit and safety of MWA combined with chemotherapy compared with chemotherapy alone, which was registered in Clinical Trials. gov (NCT02455843). Methods: Patients with untreated, stage IIIB or IV NSCLC and at least one additional measurable site other than the primary tumor site were recruited. They were divided into MWA/chemotherapy group and chemotherapy group, the former received MWA in the primary tumor sites, followed by chemotherapy and the latter treated with chemotherapy only. The primary endpoint was progression-free survival (PFS), the second endpoint included objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: From Mar 1st, 2015 to Oct 31th, 2016, Two hundreds and eighty-six patients were enrolled, including 141 in MWA/chemotherapy group and 145 in chemotherapy group. Complete ablation was observed in 95.0 % patients. ORR were 38.3 % and 34.1 % in the MWA/chemotherapy group and chemotherapy group, respectively(p = 0.677). MWA prolonged PFS [MWA/chemotherapy group 7.3 (95 % CI,5.3–13.6) ms vs. chemotherapy group 5.2 (95 % CI, 4.0–12.4) ms, p = 0.003]. Multivariate analyses showed that MWA was an independent prognostic factor of PFS. OS was immature. AEs of MWA were observed in 67.4 % patients, mainly was pheumothorax, and only 15% needing chest tube insertion. No ablation associated death was observed. Chemotherapy-associated AEs were observed in 49.1 and 53.6 % of patients in the MWA/chemotherapy and chemotherapy group, respectively. Conclusions: MWA plus chemotherapy combination improved the PFS of advanced NSCLC compared to chemotherapy alone. Adverse events of MWA was tolerable. Clinical trial information: NCT02455843.
Inhibition of the novel immune checkpoint CEACAM1 to enhance anti-tumor immunological activity.
Authors: Gal Markel, Yair Sapir, Ilana Mandel, Motti Hakim, Rony Shaked, Edna Meilin, Terri McClanahan, Andrey Loboda, Sharon Hashmueli, Tehila Ben Moshe
Journal: Journal of Clinical Oncology (2016)

3044 Background: Blockade of co-inhibitory immune receptors has become a promising approach for cancer immunotherapy. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a recently characterized immune checkpoint. Expression of CEACAM1 on tumors induces a co-inhibitory signal to CEACAM1-positive T and NK cells through homophilic interactions. Methods: CM-24 (MK-6018) is a humanized anti-CEACAM1 IgG4 antibody with high affinity and selectivity for CEACAM1. The effect of CM-24 alone or in combination was examined in vitro using tumor-infiltrating lymphocytes (TIL) and peripheral blood mononuclear cells. The anti-tumor efficacy of CM-24 was studied in vivo in subcutaneous xenograft and lung metastasis models of melanoma treated with IV injection of mlanoma-reactive TIL. Gene expression analysis of CEACAM1 and other genes of potential relevance to patient response to CEACAM1 were examined in a large cohort of human tumor samples. Results: CM-24 was demonstrated to be a potent blocker of intercellular CEACAM1-CEACAM1 interactions and reversed the inhibition of activated lymphocytes by restoring the phosphorylation of ZAP70. In addition, CM-24 enhanced the anti-tumor activity of TIL in the melanoma xenograft and lung metastasis models. CM-24 also showed synergistic activity with immune checkpoint blockers targeting PD-1 or PD-L1. The gene expression analysis of CEACAM1 and other genes in 18,000+ solid tumor samples allowed us to identify tumor types which represent potential indications for CM-24 therapy and to identify gene expression profiles as candidate biomarkers of response to CM-24 as monotherapy or in combination with a PD-1 or PD-L1 antagonist. Conclusions: CM-24 increases the cytotoxic activity of lymphocytes against malignant cells and has shown effective anti-tumor activity in various in vitro and in vivo models. Treatment with CM-24 either as monotherapy or in combination with anti-PD-1 treatment such as pembrolizumab may be beneficial. First-in-man clinical trial with CM-24 is ongoing.
Revalidation plan could reduce burden on doctors, says BMA
Authors: Abi Rimmer
Journal: BMJ (2017)

A plan by the General Medical Council to improve revalidation could make the process less burdensome for doctors, the BMA has said.

On 20 July the GMC published a plan1 to implement the recommendations made by Keith Pearson’s report, Taking Revalidation Forward , which was published earlier this year.2 In that report Pearson, chair of Health Education England and the GMC’s revalidation advisory board, said that more should be done to make clear what are …
Identification of cellular factors involved in the apoptotic response of tumor cells to HDAC inhibitors.
Authors: Laura R. Saunders, Dwayne A. Bisgrove, Eric Verdin
Journal: Cancer Research (2004)

2446   Histone deacetylase (HDAC) inhibitors induce a reversible growth arrest in primary cells while causing most transformed cell lines to undergo apoptosis. This property has made this class of drugs attractive candidates as chemotherapeutic agents for cancer. HDAC inhibitors suppress the deacetylase activity of class I and II HDACs (HDACs 1-11), induce histone hyperacetylation and modulate gene transcription through chromatin remodeling, leading to the activation of genes involved in cell growth and survival. The most dramatic consequence of HDAC inhibition is seen at the G2/M checkpoint where the acetylation status of the histone proteins is essential in determining whether mitosis proceeds. Tumor cells fail to arrest at G2/M in response to HDAC inhibitors and the resultant aberrant mitosis could represent the trigger for apoptosis. However, the precise molecular mechanisms underpinning the induction of apoptosis by HDAC inhibitors in tumor cells has not been elucidated. In order to identify cellular targets that contribute to the ability of HDAC inhibitors to induce apoptosis, we used a retroviral gene trap vector to mutagenize the HCT116 cell line, a colon cancer cell line that is highly sensitive to HDAC inhibitors in terms of apoptosis. The mutagenized HCT116 population was treated with trichostatin A (TSA), an HDAC inhibitor, at concentrations that normally kill wild-type HCT116 cells. Resistant clonal cell lines were obtained that are 5 to 100-fold more resistant to TSA than the parental cell line. While several clones are uniquely resistant to TSA, several clones show cross-resistance to other apoptosis inducing agents such as camptothecin, staurosporin and doxorubicin, indicating that the molecular mechanism triggered by these drugs might intersect. We are currently cloning the site of integration of the mutagenic retrovirus in our resistant cell lines to identify the genes that, when disrupted, lead to TSA resistance. This unique approach will allow us to identify cellular genes that are involved in the apoptotic response of tumor cells to HDAC inhibitors. The identification of such genes could also prove helpful in predicting which tumor types will be sensitive to treatment with HDAC inhibitors.
Plasma is more sensitive than cellular analysis for detecting JAK2 mutations and determining zygosity
Authors: Maher Albitar, Wanlong Ma, Xi Zhang, Iman Jilani, Hagop Kantarjian, Francis Giles
Journal: Clinical Cancer Research (2007)

B53   The dominant gain-of-function V617F point mutation in the  JAK2  gene is considered the most important molecular abnormality, characterizing patients with non-chronic myeloid leukemia (CML)-myeloproliferative disease (MPD). Recently, 4 somatic gain-of-function mutations affecting  JAK2  exon 12 have been reported in patients with V617F-negative polycythemia vera (PV). We previously reported that plasma is enriched with tumor-specific DNA and RNA and provides more sensitive detection of homozygous/hemizygous V617F mutation, relative to cellular analysis. To expand on these findings, we tested 634 consecutive, paired plasma and cell samples for V617F and exon 12  JAK2  mutations in patients clinically suspected of having MPD other than CML. All testing was performed using direct bidirectional sequencing of RNA. We also quantified the level of V617F mutant RNA  in all plasma and cell samples by measuring the intensity of the mutant (T) peak relative to the wild-type (G) peak_after normalization to the surrounding similar (T or G) peaks_using Surveyor software (Softgenetics, State College, PA). The V617F mutation was detected in 151 plasma samples but only 140 (93%) cell samples. No sample was positive by cells but negative by plasma. Of the 151 V617F-positive plasma samples, 58 (38%) were classified as homozygous/hemizygous by plasma analysis, but only 36 (24%) by cell analysis. None of the 634 samples had exon 12 mutations, in cells or plasma. Additional testing of 130 plasma samples from patients with confirmed MPD also failed to demonstrate exon 12  JAK2  mutations. The relative level of mutant  JAK2  transcript was significantly higher in plasma than in cell samples ( P   JAK2  mutation in patients with MPD. Furthermore, the exon 12  JAK2  mutations are extremely rare.