tbuckley/cabot-search huggingface dataset:
Establishing valid functional / PRO measures in cancer cachexia or sarcopenia to correlate with changes in Skeletal Muscle Mass Index (SMI): Results of a prospective study in patients with non-small cell lung cancer.
Authors: Alejandro Recio Boiles, Jose Nahun Galeas, Bayruch Goldwasser, Karla Sanchez, Jesus Del Santo Anampa Mesias, David Gordon, Richard Delmar Hall, Ryan D. Gentzler, Louise Ming-Wai Man, Patricia J Hollen, Richard J. Gralla
Journal: Journal of Clinical Oncology (2015)

e20676 Background: Interventional trials in cancer cachexia have endeavored to improve skeletal muscle mass (measured by SMI using DXA or CT) and to correlate changes with functional outcomes of benefit to the patient. While tests such as stair climb power and hand grip strength have been used, these measures are neither sufficiently sensitive in patients with cancer, nor do they evaluate outcomes of value to patients. Patient Reported Outcomes (PROs) such as EORTC, FACT and others, have been collected, but specific components useful to patients have not been identified as ones correlating highly with SMI. Recent large studies at baseline using the 3-Item Global Index (3IGI) of the LCSS quality of life and functional measure found a strong correlation predicting survival in non-small cell lung cancer and mesothelioma (Symanowski; Gralla, both ASCO 2014); thus the 3IGI appears to be a good factor for associating PROs with SMI changes. Methods: The LCSS was measured every 3 weeks; correlations of SMI changes with 3IGI scores were made at baseline and at a median of 14 weeks in patients with NSCLC receiving chemotherapy. SMI was measured by CT (Slice-O-Matic software) at the L1 vertebral level. A change in SMI by ± 4% was considered a threshold change of importance. Results: We enlisted 23 patients (48% male; medians: age 57, KPS 80%; baseline: BMI 24.3, SMI 59.9, with 38% of males < 55.4 SMI). 18 patients are evaluable at this time. 44% of patients had a change in SMI by ± 4%; of these 75% had either improvement or worsening of the 3IGI in the direction expected from the change in SMI (improved 3IGI with increased SMI; worsened 3IGI with decreased SMI). No clear relationship in SMI was observed with response to chemotherapy. Conclusions: Initial results suggest: 1) the 3IGI may be useful in identifying both positive and negative changes in SMI, when using a 4% threshold change; 2) a confirmatory larger evaluation should be conducted; and 3) no measure should be used in practice or clinical trials of cancer cachexia or sarcopenia unless it has demonstrated validity in patients with cancer. Funding in part: NIH / NCI 1 R01 CA157409-01A1 Clinical trial information: NCT01924416.
Malpractice should be investigated proactively and holistically to identify underlying causes
Authors: Simon R Peck
Journal: BMJ (2017)

I question what a public enquiry into the Paterson case will achieve.1 The facts are already in the public domain, and the theme of institutional failure to act effectively is familiar to us all. Much more useful, in my view, would be a review of how healthcare is regulated and how concerns might better be handled in future.

Malpractice does not occur in isolation, …
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease
Authors: Edwin M. Stone, Jeaneen L. Andorf, S. Scott Whitmore, Adam P. DeLuca, Joseph C. Giacalone, Luan M. Streb, Terry A. Braun, Robert F. Mullins, Todd E. Scheetz, Val C. Sheffield, Budd A. Tucker
Journal: Ophthalmology (2017)
Re: Thomas Powles, Robert A. Huddart, Tony Elliott, et al. Phase III, Double-blind, Randomized Trial that Compared Maintenance Lapatinib versus Placebo after First-line Chemotherapy in Patients with Human Epidermal Growth Factor Receptor 1/2-positive Metastatic Bladder Cancer. J Clin Oncol 2017;35:48–55
Authors: Pontus Eriksson, Gottfrid Sjödahl, Fredrik Liedberg
Journal: European Urology (2017)
A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis
Authors: Colin J. Ross, Fadi Towfic, Jyoti Shankar, Daphna Laifenfeld, Mathis Thoma, Matthew Davis, Brian Weiner, Rebecca Kusko, Ben Zeskind, Volker Knappertz, Iris Grossman, Michael R. Hayden
Journal: Genome Medicine (2017)

Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials. Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials. A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA). This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.
OCD in College Athletes
Authors: Lisa Cromer, Emily Kaier, Joanne Davis, Kathleen Stunk, S. Evelyn Stewart
Journal: American Journal of Psychiatry (2017)

Extensive media coverage of the 2016 Summer Olympics in Rio de Janeiro and the emergence of sports medicine as a subspecialty reflect elite athletes' important societal roles.While the optimization of athletes' physical performance is a priority, their mental health is largely ignored.Psychiatric studies of competitive athletes are nonexistent in the United States and are limited worldwide, despite risks to athletes that include sleep disruption, travel, low autonomy, and performance demands (1-3).Physicians are biased toward athletes' mental well-being (3, 4); moreover, athlete help-seeking is stigmatized (4).Obsessive-compulsive disorder (OCD) is a debilitating, treatable illness affecting 2.3% of adults, with subthreshold obsessive-compulsive symptoms occurring in 28.2% of adults (5).Competitive athletes' traits, including overresponsibility, perfectionism, and secrecy, mask OCD identification (4, 5).Calorie obsession, body hyperfocus, superstitions, and rituals are normative for athletes (2).We report findings from the first OCD study in collegiate athletes, derived from two data collection waves of a study on college athletic stress at
PERK signaling, but not eIF2α phosphorylation, protects tumor cells from the effects of Fatty Acid Synthase inhibitors.
Authors: Joy L. Little, Diane Fels, Meixia Bi, Constantinos Koumenis, Steven J. Kridel
Journal: Cancer Research (2006)

5071  Fatty Acid Synthase (FAS) expression is upregulated in many tumors to facilitate growth and proliferation. FAS is the sole enzyme responsible for synthesis of the fatty acid palmitate, a primary component of phospholipids in membranes, a critical element for post-translational modification and a precursor for the syntheses of long chain fatty acids. High levels of FAS in tumors correlate with poor prognosis and aggressive disease making FAS an attractive candidate for drug targeting in anti-tumor therapy. In fact inhibition of FAS by orlistat and other inhibitors, such as cerulenin and C75, have been shown to induce cell death in a number of different cancer cell lines and inhibit tumor growth in various models of cancer. The cellular mechanism of cell death has remained elusive however. We have demonstrated that treatment of tumor cells with small molecule inhibitors that target two different domains in FAS, orlistat and cerulenin, triggers activation of all three arms of the endoplasmic reticulum (ER) stress response. We have also shown that ER stress is activated prior to the onset of apoptosis, supporting the idea that ER stress is an upstream event in the cell death cascade. Mouse embryonic fibroblasts (MEFs) with a homozygous deletion of PERK that are transformed with kRas-V12, and HT-29 cells expressing a dominant negative PERK (ΔC-PERK) are hypersensitive to treatment with FAS inhibitors. Phosphorylation of eIF2α, and subsequent inhibition of protein translation, is the critical event in PERK signaling in response to ER stress. To further investigate the PERK pathway, we obtained MEFs with a homozygous knock in allele of eIF2α (S51A) that is unable to be phosphorylated by PERK. Surprisingly, these cells are not hypersensitive to treatment with FAS inhibitors, suggesting that eIF2α phosphorylation is not the only target of PERK activity when FAS is inhibited. HT-29 tumor cells that express a constitutively active GADD34 construct that facilitates dephosphorylation of eIF2α exhibit the same sensitivity as the S51A MEFs. Because cells with PERK mutations are hypersensitive to FAS inhibitor treatment, but cells with mutations downstream of PERK are not, we hypothesized that another target of PERK activity must be necessary. The only other substrate for PERK that has been identified is the redox sensitive transcription factor Nrf2, thus we hypothesize that Nrf2 is a pivotal player in the cellular response to FAS inhibitor treatment.
IMMU-16. PROGRAMMED DEATH LIGAND 1 EXPRESSION AND TUMOR INFILTRATING LYMPHOCYTES IN TUMORS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1 AND 2
Authors: Shiyang Wang, Benjamin Liechty, Seema Patel, Jeffrey Weber, Matija Snuderl, Matthias Karajannis
Journal: Neuro-Oncology (2017)

BACKGROUND: Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating subsets of patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We hypothesized that NF-associated tumors may express PD-L1 and therefore might be amenable to immunotherapy with immune checkpoint inhibitors. METHODS: We performed immunohistochemistry for PD-L1 (Spring Bioscience, clone SP142), CD3, CD20, CD8, and CD68 in 17 NF1-related tumors (11 dermal neurofibromas and 6 plexiform neurofibromas) and 20 NF2-related tumors (10 meningiomas and 10 schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with >5% membranous staining of tumor cells, in accordance with previously published biomarker studies. RESULTS: PD-L1 expression was detected in all tumors, with highest expression levels observed in plexiform neurofibromas and schwannomas. PD-L1 positive tumor cells with >5% membranous staining were observed in 6/6 (100%) of plexiform neurofibromas, 9/11 (82%) of dermal neurofibromas, 7/10 (70%) of schwannomas, and 4/10 (40%) of meningiomas. Sparse to moderate presence of CD68, CD3, or CD8 positive tumor-infiltrating lymphocytes (TILs) was found in 37/37 (100%) of tumor specimens. However, expression of CD20 positive lymphocytes was limited to rare cells detectable in 4/37 (11%) of tumors. CONCLUSION: Our findings indicate that adaptive resistance to cell-mediated immunity plays a major role in the tumor immune environment of NF1 and NF2 associated tumors. Expression of PD-L1 on tumor cells and presence of TILs suggests that these tumors may be responsive to immune therapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.
Ефективність лікування тривожно-депресивних розладів у хворих на гастроентерологічну патологію
Authors: S.V. Kosynska
Journal: GASTROENTEROLOGY (2020)

Стаття присвячена проблемі лікування тривожно-депресивних розладів у гастроентерологічних хворих зі стійкою симптоматикою абдомінальної алгії та диспепсії. Для об’єктивізації психоемоційних розладів та вибору їх корекції застосовувалася шкала HADS. Виявлена висока частота тривоги — у 93,75 % таких хворих, депресії — у 81,25 %, їх поєднання — у 78,1 %. Оцінена ефективність гідазепаму при тривожних та есциталопраму при депресивних розладах. Показано, що застосування психокорекції дозволяє купірувати гастроентерологічні симптоми: абдомінальні алгії повністю минули в 71,9 % хворих, диспептичні скарги — у 86,9 %, а також зменшити тривожно-депресивні прояви.
Effect of point-of-care CD4 cell count results on linkage to care and antiretroviral initiation during a home-based HIV testing campaign: a non-blinded, cluster-randomised trial
Authors: Mitesh A Desai, Dancun O Okal, Charles E Rose, Richard Ndivo, Boaz Oyaro, Fredrick O Otieno, Tiffany Williams, Robert T Chen, Clement Zeh, Taraz Samandari
Journal: The Lancet HIV (2017)
C-kit mRNA expression in pancreatic adenocarcinoma and matched stromal tissue: Prognostic and therapeutic implications.
Authors: Peter Philipp Grimminger, Craig Stephens, Dirk Waldschmidt, Stephanie H. Astrow, Hans-Michael Steffen, Jack Hsiang, Gary Zeger, Arnulf H Hölscher, Martin K. H. Maus
Journal: Journal of Clinical Oncology (2014)

e15185 Background: Pancreatic adenocarcinoma is one of the most aggressive malignancies with poor overall survival rates. C-Kit is a transmembrane receptor tyrosine kinase known to affect various characteristics of certain in various solid cancers. This study investigated the prognostic significance of tumorous c-Kit mRNA expression in pancreatic carcinoma. Methods: FFPE tumor specimens from 58 patients with resectable pancreatic cancer, who underwent surgery and adjuvant chemotherapy with gemcitabine, were evaluated. In 25 cases, tumor and stromal tissue had a sufficient quality and quantity for microdissection and mRNA analysis. Specifically designed primers and probes were used to detect mRNA expression levels of c-Kit by quantitative RT-PCR in reference to beta-actin. Results: C-Kit expression was detected in 23 matched pancreatic stromal and tumor tissues. No significantly different c-Kit mRNA expression between stromal (median 1.69, range: 0.55- 6.42) and tumor (median 1.67, range: 0.31- 3.84) tissue was found (p=0.086 (n.s.)). The best cut-off for c-Kit (0.87) was calculated using bootstrap-like simulations. 19 of 23 pts (82%) showed high tumor c-Kit expression. In microscopically complete (R0) resected tumors, high tumor c-Kit mRNA expression correlated significantly with improved overall survival (p<0.032, log rank test). C-Kit expression in stromal tissue did not correlate with outcome. Conclusions: C-Kit expression is not significantly reduced in tumor tissue compared to matched pancreatic stromal tissue, confirming previous results. High mRNA c-Kit expression is a favorable prognostic marker for pancreatic cancer. A possible potential of c-Kit as a predictive marker for gemcitabine-based chemotherapy or as a possible molecular target (Imatinib-based treatment) has to be evaluated in future studies.
DIPG-11. NEURAL PRECURSOR CELL:GLIOMA INTERACTIONS MEDIATE TUMOR COLONIZATION OF THE SUBVENTRICULAR ZONE BY DIPG
Authors: Elizabeth Y. Qin, Dominique Cooper, Keene Abbott, Alan MacKay, Chris Jones, Hannes Vogel, Peter Jackson, Michelle Monje
Journal: Neuro-Oncology (2017)

The lateral ventricle subventricular zone (SVZ) stem cell niche is thought to be a sanctuary site for high-grade gliomas, and is thus critical for tumor survival and recurrence. This is true for both adult glioblastoma and pediatric high-grade gliomas such as diffuse intrinsic pontine glioma (DIPG). In DIPG, a devastating childhood brain cancer characterized by its diffusely infiltrating nature, the SVZ is not only an anatomical site of frequent spread, but also a site of clinically significant growth. We have sought to understand how and why DIPG and other high-grade gliomas spread so frequently to the SVZ, and hypothesized that this predilection is mediated by interactions between the glioma cells and the neural precursor cells that normally reside in the SVZ. Our present studies support this hypothesis of neural precursor cell:glioma cell communication, showing that SVZ neural precursor cells secrete chemoattractant signals toward which DIPG cells home. Biochemical and proteomic studies on factors secreted by SVZ neural precursor cells reveal a discrete list of candidate proteins. Necessity and sufficiency testing implicate the neurite outgrowth-promoting factor pleiotrophin, along with three binding partners (secreted protein acidic and rich in cysteine (SPARC), SPARC-like protein 1, and heat shock protein 90B), as key mediators of this chemoattractant effect. Ongoing studies further investigating the molecular pathways involved seek to expand on these observations to identify potentially targetable mechanisms for high-grade glioma therapy.
Level of knowledge and attitude towards sport-related concussion among the general?public
Authors: Andrew J Gardner, Frances Kay-Lambkin, Sandy R Shultz, Grant L Iverson
Journal: British Journal of Sports Medicine (2017)

Objective To investigate attitudes and knowledge of concussion. Design Online survey. Setting Online questionnaire for the general public. Participants Athletes, coaches, parents, sports administrators, and fans, aged 18–80 years. Assessment A 75 question survey about the respondents’ concussion knowledge, sources of that knowledge, and attitudes toward injury. Outcome measures Frequency of responses. Main results Of the 210 respondents who initiated the survey, there were 146 complete datasets. Respondents identified themselves as fans (46%), athletes (43%), coaches (20%), parents (18%), and administrators (13%). Most (85%) claimed to have little to average level of knowledge regarding concussion, the main source of knowledge for 26% of respondents was the media, and 59% had no knowledge of concussion guidelines (only 21% of respondents had heard of the Consensus Statement on Concussion in Sport), although 74% claimed to have knowledge of return-to-play guidelines. When considering reporting a concussion during a game, 77% considered it to be important, 77% beneficial, 74% valuable, 49% brave, and 21% easy. Most respondents indicated that it was extremely serious to experience headaches or dizziness after a blow to the head (54%), extremely important not to participate in physical activity when experiencing signs of concussion (67%), and extremely important to report concussion signs (77%). Respondents’ indicated that it was extremely important for players to be informed about: how concussions occur (67%), concussion prevention (67%), and what to do following concussion (82%). Some respondents (34%) strongly agreed that athletes are undereducated about concussion. Conclusions Public knowledge about concussion is modest. Competing interests Andrew Gardner has a clinical practice in neuropsychology involving individuals who have sustained sport-related concussion (including current and former athletes). He serves, in a voluntary capacity, as a member of the Australia Rugby Union (ARU) concussion advisory group. He has received travel funding from the Australian Football League (AFL) to present at the Concussion in Football Conference in 2013. Previous grant funding includes the NSW Sporting Injuries Committee, the Brain Foundation and the Hunter Medical Research Institute (HMRI), supported by Jennie Thomas. He is currently funded through the HMRI, supported by Anne Greaves. Frances Kay-Lambkin: None. Sandy Shultz: None. Grant Iverson has been reimbursed by the government, professional scientific bodies, and commercial organisations for discussing or presenting research relating to mild TBI and sport-related concussion at meetings, scientific conferences, and symposiums. He has a clinical and consulting practice in forensic neuropsychology involving individuals who have sustained mild TBIs (including professional athletes).
Erratum: Myocardial infarction redefined - A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction (Journal of the American College of Cardiology (2000) 36 (959-969))
Authors: J. S. Alpert, K. Thygesen, E. Antman, J. P. Bassand
Journal: Journal of the American College of Cardiology (2001)
Including pride and its group-based, relational, and contextual features in theories of contempt
Authors: Gavin Brent Sullivan
Journal: Behavioral and Brain Sciences (2017)

Abstract Sentiment includes emotional and enduring attitudinal features of contempt, but explaining contempt as a mixture of basic emotion system affects does not adequately address the family resemblance structure of the concept. Adding forms of individual, group-based, and widely shared arrogance and contempt is necessary to capture the complex mixed feelings of proud superiority when “looking down upon” and acting harshly towards others.
Decitabine Followed By Clofarabine, Idarubicin, and Cytarabine (DAC-CIA) in Relapsed/Refractory Acute Myeloid Leukemia (AML)
Authors: Nitin Jain, Farhad Ravandi, Guillermo Garcia-Manero, Gautam Borthakur, Tapan M. Kadia, Elias J. Jabbour, Naveen Pemmaraju, Naval Daver, Courtney D DiNardo, Marina Konopleva, Yesid Alvarado, Koichi Takahashi, Christopher B. Benton, Allison Pike, Sherry Pierce, Jorge E. Cortes, Hagop M. Kantarjian
Journal: Blood (2016)