tbuckley/cabot-search huggingface dataset:
Effector Function of Human Tumor-Specific CD8 T Cells in Melanoma Lesions: A State of Local Functional Tolerance
Authors: Alfred Zippelius, Pascal Batard, Verena Rubio-Godoy, Gilles Bioley, Danielle Liénard, Ferdy Lejeune, Donata Rimoldi, Philippe Guillaume, Norbert Meidenbauer, Andreas Mackensen, Nathalie Rufer, Norbert Lubenow, Daniel Speiser, Jean-Charles Cerottini, Pedro Romero, Mikaël J. Pittet
Journal: Cancer Research (2004)

Abstract Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.
Structure-based drug design identifies polythiophenes as antiprion compounds
Authors: Uli S. Herrmann, Anne K. Schütz, Hamid Shirani, Danzhi Huang, Dino Saban, Mario Nuvolone, Bei Li, Boris Ballmer, Andreas K. O. Åslund, Jeffrey J. Mason, Elisabeth Rushing, Herbert Budka, Sofie Nyström, Per Hammarström, Anja Böckmann, Amedeo Caflisch, Beat H. Meier, K. Peter R. Nilsson, Simone Hornemann, Adriano Aguzzi
Journal: Science Translational Medicine (2015)

The targeted chemical design of luminescent conjugated polythiophenes may yield new therapeutic compounds for treating prion diseases.
MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If
Authors: Barbara Schenk, Timo Imbach, Christian G. Frank, Claudia E. Grubenmann, Gerald V. Raymond, Haggit Hurvitz, Annick Raas-Rotschild, Anthony S. Luder, Jaak Jaeken, Eric G. Berger, Gert Matthijs, Thierry Hennet, Markus Aebi
Journal: Journal of Clinical Investigation (2001)

Deficiencies in the pathway of N-glycan biosynthesis lead to severe multisystem diseases, known as congenital disorders of glycosylation (CDG). The clinical appearance of CDG is variable, and different types can be distinguished according to the gene that is altered. In this report, we describe the molecular basis of a novel type of the disease in three unrelated patients diagnosed with CDG-I. Serum transferrin was hypoglycosylated and patients' fibroblasts accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation. Transfer of incomplete oligosaccharides to protein was detected. Sequence analysis of the Lec35/MPDU1 gene, known to be involved in the use of dolichylphosphomannose and dolichylphosphoglucose, revealed mutations in all three patients. Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of patients restored normal lipid-linked oligosaccharide biosynthesis. We concluded that mutations in the Lec35/MPDU1 gene cause CDG. This novel type was termed CDG-If.
Eccentric loading for Achilles tendinopathy — strengthening or stretching?
Authors: G T Allison, C Purdam
Journal: British Journal of Sports Medicine (2009)

The prescription of eccentric loading is considered as a mainstay of non-operative rehabilitation programmes for mid-substance chronic Achilles tendinopathy. Such exercises have some degree of clinical utility in comparison with concentric training and are often referred to as a strengthening programme. Yet the dose parameters of the eccentric loading do not reflect an optimal strengthening programme and specifically avoid the normal eccentric-concentric coupling typical of the stretch shortening cycle. This manuscript identifies the arguments and counterarguments for why eccentric loading rehabilitation is not an optimal strengthening programme. It is proposed that such exercises reflect a specific stretching programme directed at the passive structures. This has two important clinical implications. Firstly, this reinterpretation of the role of eccentric exercises may direct future research into the underlying mechanisms of tendinopathy and, secondly, it may reinforce the importance of adjunct sports specific strengthening programmes.
The Complexity Hypothesis Revisited: Connectivity Rather Than Function Constitutes a Barrier to Horizontal Gene Transfer
Authors: O. Cohen, U. Gophna, T. Pupko
Journal: Molecular Biology and Evolution (2010)

Horizontal gene transfer (HGT) is a prevalent and a highly important phenomenon in microbial species evolution. One of the important challenges in HGT research is to better understand the factors that determine the tendency of genes to be successfully transferred and retained in evolution (i.e., transferability). It was previously observed that transferability of genes depends on the cellular process in which they are involved where genes involved in transcription or translation are less likely to be transferred than metabolic genes. It was further shown that gene connectivity in the protein–protein interaction network affects HGT. These two factors were shown to be correlated, and their influence on HGT is collectively termed the "Complexity Hypothesis". In this study, we used a stochastic mapping method utilizing advanced likelihood-based evolutionary models to quantify gene family acquisition events by HGT. We applied our methodology to an extensive across-species genome-wide dataset that enabled us to estimate the overall extent of transfer events in evolution and to study the trends and barriers to gene transferability. Focusing on the biological function and the connectivity of genes, we obtained novel insights regarding the "complexity hypothesis." Specifically, we aimed to disentangle the relationships between protein connectivity, cellular function, and transferability and to quantify the relative contribution of each of these factors in determining transferability. We show that the biological function of a gene family is an insignificant factor in the determination of transferability when proteins with similar levels of connectivity are compared. In contrast, we found that connectivity is an important and a statistically significant factor in determining transferability when proteins with a similar function are compared.
Advantages of deformation indices over systolic velocities in assessment of longitudinal systolic function in patients with heart failure and normal ejection fraction
Authors: Erberto Carluccio, Paolo Biagioli, Gianfranco Alunni, Adriano Murrone, Valeria Leonelli, Paola Pantano, Emilia Biscottini, Walter J. Paulus, Giuseppe Ambrosio
Journal: European Journal of Heart Failure (2010)
Painful Amputation Stumps and Phantom Limbs
Authors: W. R. Russell
Journal: BMJ (1949)

BRITISH '~~~~~~~~~~~~~~~~~~~~~~~~~~~~~MEDICA,L JOUPRNAL sore throats.In 1943 he had been accepted as a first-class life by an insurance company, the blood pressure then being 130/ 90 mm.Hg.In June, 1948, he was admitted to Westminster Hospital for tonsillectomy, and on pre-operative examination was found to have a blood pressure of 230/150 mm.Hg with pulsus alternans.There was no other cardiovascular abnor- mality, except that the fundi revealed exudates, haemorrhages, and vascular changes.The blood urea, however, was 120 mg. per 100 ml., and the urea clearance 26% of normal.Whilst in hospital he was free from syinptoms and sympathectomy was not performed, on account of his poor renal function.He died from uraemia three months later. Summary and ConclusionsTwenty-four cases of severe hypertension which have under- gone lumbo-dorsal sympathectomy are presented.Their pre- operative state is described, and the results of operation are discussed.The following conclusions are reached: (1) the chances of permanently lowering the blood pressure are slight;(2) retinopathy, when present, may improve considerably;(3) there is not enough evidence to indicate clearly the effect in hypertensive heart disease-some patients may appear to improve temporarily, but this is unlikely with severe disease; (4) operation causes striking symptomatic relief, with nptable gain in weight; and (5) in prmary malignant hypertension the malignant phase may disappear.In a properly selected case the relief is greater than that which can be obtained by medical treatment alone.Such cases are not numerous.The operation should be limited to severe and rapidly progressive cases with severe symptoms referable to their hypertensive state which comply with the following conditions: age less than 50 years, the renal function should be good, there should be no evidence of coronary or cerebral artery disease, and there should be no severe heart disease or heart failure.Operation in early and mild cases is not advisable.
Clinical evaluation of geriatric outpatients with suspected heart failure: value of symptoms, signs, and additional tests
Authors: Irène Oudejans, Arend Mosterd, Johanna A. Bloemen, Mark J. Valk, Edwin van Velzen, Jos P. Wielders, Nicolaas P. Zuithoff, Frans H. Rutten, Arno W. Hoes
Journal: European Journal of Heart Failure (2011)
HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes
Authors: Kedar Narayan, Chih-Ling Chou, AeRyon Kim, Isamu Z Hartman, Sarat Dalai, Stanislav Khoruzhenko, Scheherazade Sadegh-Nasseri
Journal: Nature Immunology (2006)
Prediction of effective genome size in metagenomic samples.
Authors: Jeroen Raes, Jan O Korbel, Martin J Lercher, Christian von Mering, Peer Bork
Journal: Genome biology (2007)

Abstract We introduce a novel computational approach to predict effective genome size (EGS; a measure that includes multiple plasmid copies, inserted sequences, and associated phages and viruses) from short sequencing reads of environmental genomics (or metagenomics) projects. We observe considerable EGS differences between environments and link this with ecologic complexity as well as species composition (for instance, the presence of eukaryotes). For example, we estimate EGS in a complex, organism-dense farm soil sample at about 6.3 megabases (Mb) whereas that of the bacteria therein is only 4.7 Mb; for bacteria in a nutrient-poor, organism-sparse ocean surface water sample, EGS is as low as 1.6 Mb. The method also permits evaluation of completion status and assembly bias in single-genome sequencing projects.
How well can we practically apply asthma guidelines
Authors: Alan Kaplan, Nadia Griller, Louis Phillipe Boulet, Samir Gupta
Journal: European Respiratory Journal (2013)

Much effort is expended to create Asthma clinical practice guidelines (CPGs) which compile the best evidence currently available. Their implementation is limited by complexity, lack of clarity, and failure to address various practical aspects of daily patient management.  We analyzed pharmacotherapy recommendations in the latest Canadian Thoracic Society (CTS) asthma CPG (2010 guidelines/2012 update) from the primary care perspective, in order to identify practice-based gaps. We reviewed therapeutic initiation, escalation, and de-escalation in adults, and identified questions which arose when attempting to  implement recommendations practically. We also searched for guidance provided by other recent international asthma guidelines (BTS/SIGN and GINA) in these specific areas.  The following three clinical questions arose from the CTS guideline (where recommendations were made but provided insufficient guidance): 1) when to initiate controller therapy; 2) how long after treatment initiation or escalation to evaluate for effect; and 3) when and how to de-escalate therapy when control is established. We also attempted to create a set of decision rules for therapeutic escalation and de-escalation amongst currently available asthma therapies. Though some of these issues addressed in other guidelines, none provided practical guidance as to how to manage all possible clinical scenarios.  Day to day clinical dilemmas are often not explicitly addressed in the current CPGs which limits their practical implementability in daily patient care. One potential solution to this issue would be the active involvement of primary care end-users in the guideline writing process to help authors to identify these areas at the guideline development stage.
Phase II study of sequentially administered low-dose mitomycin-C (MMC) and irinotecan (CPT-11) in women with metastatic breast cancer (MBC)
Authors: E Mrozek, J Kolesar, D Young, J Allen, M Villalona-Calero, C L Shapiro
Journal: Annals of Oncology (2008)

Preclinical studies show that mitomycin-C (MMC) followed by irinotecan (CPT-11) is synergistic. Therefore, we evaluated the toxicity and efficacy of sequentially administered low-dose MMC and CPT-11 in patients (pts) with pretreated metastatic breast cancer (MBC). Secondary objective was to evaluate the correlation between MMC-induced topoisomerase I (TOPO I) expression and NAD(P)H:quinone oxireductase 1 (NQO1) genotypes in peripheral blood mononuclear cells (PBMC) and efficacy or toxicity of the regimen.Thirty-two pts received MMC i.v. 6 mg/m(2) day 1 and CPT-11 i.v. 125 mg/m(2) days 2 and 8 every 28 days for maximum of six cycles. TOPO I expression and NQO1 reductase genotyping in 23 of 32 (72%) pts were assayed by PCR.The median time to progression (TTP) was 4.7 months (95% confidence interval 4.0-5.4 months). TOPO I expression was increased 5- to 10-fold and 20- to 30-fold in PBMC at 24 and 168 h, respectively. There was no relationship between these markers and efficacy or toxicity of the regimen.Sequential low-dose MMC and CPT-11 was active and tolerable by pretreated MBC pts. Future trials should focus on less pretreated MBC pts and sequential tumor biopsies to test the hypothesis that increased intratumoral expression of TOPO I is related to efficacy.
THE ORIGIN AND DEVELOPMENT OF NERVOUS DISTURBANCES EXPERIMENTALLY PRODUCED
Authors: W. HORSLEY GANTT
Journal: American Journal of Psychiatry (1942)

The most striking features in this study have been the importance of the individual and the extension of the effects of the conflict for years after its original use as well as the extension to new systems later during the life of the dog. The most important therapeutic indication is the detection of susceptible animals by measuring the reactions under strain, and preventing the progress of the strain to that point at which a permanent breakdown occurs. Once the disturbance is thoroughly established, therapy is difficult. Improvement has been seen with a complete change of environment—removal to farm life for 18 months. Rest in the environment of conflict was unavailing.
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency
Authors: I. Sadaf Farooqi, Giuseppe Matarese, Graham M. Lord, Julia M. Keogh, Elizabeth Lawrence, Chizo Agwu, Veronica Sanna, Susan A. Jebb, Francesco Perna, Silvia Fontana, Robert I. Lechler, Alex M. DePaoli, Stephen O’Rahilly
Journal: Journal of Clinical Investigation (2002)

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4+ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.
Policies for Healthier Communities: Historical, Legal, and Practical Elements of the Obesity Prevention Movement
Authors: Samantha K. Graff, Manel Kappagoda, Heather M. Wooten, Angela K. McGowan, Marice Ashe
Journal: Annual Review of Public Health (2012)

The U.S. population is facing an obesity crisis wrought with severe health and economic costs. Because social and environmental factors have a powerful influence over lifestyle choices, a national obesity prevention strategy must involve population-based interventions targeted at the places where people live, study, work, shop, and play. This means that policy, in addition to personal responsibility, must be part of the solution. This article first describes the emergence of and theory behind the obesity prevention movement. It then explains how government at all levels is empowered to develop obesity prevention policy. Finally, it explores eight attributes of a promising state or local obesity prevention policy and sets the obesity prevention movement in the context of a larger movement to promote healthy communities and prevent chronic disease.
Glutathione <b> <i>S</i> </b>-Transferase Polymorphisms and Survival in Primary Malignant Glioma
Authors: M. Fatih Okcu, Mano Selvan, Li-E Wang, Linda Stout, Rodrigo Erana, Gladstone Airewele, Phyllis Adatto, Kenneth Hess, Francis Ali-Osman, Morris Groves, Alfred W. K. Yung, Victor A. Levin, Qingyi Wei, Melissa Bondy
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this research was to investigate the relationship between glutathione S-transferase (GST) polymorphisms and survival, and chemotherapy-related toxicity in 278 glioma patients. Experimental Design: We determined genetic variants for GSTM1, GSTT1, and GSTP1 enzymes by PCR and restriction fragment length polymorphisms. We conducted Kaplan-Meier and Cox-proportional hazard analyses to examine whether the GST polymorphisms are related to overall survival, and logistic regression analysis to explore whether the GST polymorphisms are associated with toxicity. Results: For patients with anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, and anaplastic ependymoma (n = 78), patients with GSTP1*A/*A-M1 null genotype survived longer than did the rest of the group (median survival “not achieved,” and 41 months, respectively; P = 0.06). Among patients treated with nitrosoureas (n = 108), those with GSTP1*A/*A and GSTM1 null genotype were 5.7 times (95% confidence interval, 0.9–37.4) more likely to experience an adverse event secondary to chemotherapy, compared with the others. Conclusions: In patients with anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, combination of germ-line GSTP1*A/*A and GSTM1 null genotype confers a survival advantage. Patients with this genotype also have an increased risk of adverse events secondary to chemotherapy that primarily comprised nitrosourea alkylating agents.
From Chronic Feed-Induced Intestinal Inflammation to Adenocarcinoma with Metastases in Salmonid Fish
Authors: Ole B. Dale, Brit Tørud, Agnar Kvellestad, Hanna S. Koppang, Erling O. Koppang
Journal: Cancer Research (2009)

Neoplasms in fish normally show poor abilities for metastasis, and there are no reports on intestinal cancer with metastasis to other organs. In aquaculture production, carnivorous salmonids in Northern Europe receive commercial feeds with plant ingredients. Such contents have been shown to cause chronic intestinal inflammation. Inflammation provokes carcinogenesis in the human gut, and here, we report a similar pathologic progression in salmonids. Nine commercially farmed groups of Atlantic salmon and rainbow trout (n = 39,160) and one experimental positive group (n = 789) fed the same commercial feed and two negative control groups (n = 3009) were investigated for the occurrence of intestinal tumors and metastases. Exposure period, gender, and sexual maturation were registered. Autopsy revealed an overall intestinal tumor occurrence of 10.62%, of which liver metastasis varied from 0% to 11.35% between the groups. Intestinal cancer prevalence increased from 0.50% to 14.81% during 4 months of feeding in the experimental group. A significant gender effect was registered in the commercially farmed groups but not in the experimental group. Histologic examination showed adenocarcinomas evolving through progressive epithelial dysplasia associated with severe chronic inflammation. One intestinal tumor was registered in one individual in the negative control groups. This is the first report on feed-induced intestinal carcinogenesis and metastasizing adenocarcinomas in fish fed an approved commercial diet. The pathogenesis was associated with a certain commercial diet provoking the inflammation-dysplasia-carcinoma sequence. The histologic progression was analogous to that of human colorectal cancer associated with inflammatory bowel disease.
Bcl11a is essential for lymphoid development and negatively regulates p53
Authors: Yong Yu, Juexuan Wang, Walid Khaled, Shannon Burke, Peng Li, Xiongfeng Chen, Wei Yang, Nancy A. Jenkins, Neal G. Copeland, Shujun Zhang, Pentao Liu
Journal: The Journal of Experimental Medicine (2012)

Transcription factors play important roles in lymphopoiesis. We have previously demonstrated that Bcl11a is essential for normal lymphocyte development in the mouse embryo. We report here that, in the adult mouse, Bcl11a is expressed in most hematopoietic cells and is highly enriched in B cells, early T cell progenitors, common lymphoid progenitors (CLPs), and hematopoietic stem cells (HSCs). In the adult mouse, Bcl11a deletion causes apoptosis in early B cells and CLPs and completely abolishes the lymphoid development potential of HSCs to B, T, and NK cells. Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a. Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities. Overexpression of Bcl2 and Mdm2, or p53 deficiency, rescues both lethality and proliferative defects in Bcl11a-deficient early B cells and enables the mutant CLPs to differentiate to lymphocytes. Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities. Deletion of Bcl11a may represent a new approach for generating a mouse model that completely lacks an adaptive immune system.