tbuckley/cabot-search huggingface dataset:
Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic–pituitary–adrenal axis
Authors: Theodore P. Braun, Xinxia Zhu, Marek Szumowski, Gregory D. Scott, Aaron J. Grossberg, Peter R. Levasseur, Kathryn Graham, Sheehan Khan, Sambasivarao Damaraju, William F. Colmers, Vickie E. Baracos, Daniel L. Marks
Journal: The Journal of Experimental Medicine (2011)

Skeletal muscle catabolism is a co-morbidity of many chronic diseases and is the result of systemic inflammation. Although direct inflammatory cytokine action on muscle promotes atrophy, nonmuscle sites of action for inflammatory mediators are less well described. We demonstrate that central nervous system (CNS)–delimited interleukin 1β (IL-1β) signaling alone can evoke a catabolic program in muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic–pituitary–adrenal (HPA) axis activation, as CNS IL-1β–induced atrophy is abrogated by adrenalectomy. Furthermore, we identified a glucocorticoid-responsive gene expression pattern conserved in models of acute and chronic inflammatory muscle atrophy. In contrast with studies suggesting that the direct action of inflammatory cytokines on muscle is sufficient to induce catabolism, adrenalectomy also blocks the atrophy program in response to systemic inflammation, demonstrating that glucocorticoids are requisite for this process. Additionally, circulating levels of glucocorticoids equivalent to those produced under inflammatory conditions are sufficient to cause profound muscle wasting. Together, these data suggest that a significant component of inflammation-induced muscle catabolism occurs indirectly via a relay in the CNS.
Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials
Authors: Keren Skalsky, Dafna Yahav, Jihad Bishara, Silvio Pitlik, Leonard Leibovici, Mical Paul
Journal: BMJ (2008)

Acid and alkaline phosphatases, esterases, and β-glucuronidase were studied histochemically in the colon of a patient with familial polyposis in whom malignant changes had occurred. The acid hydrolases were found to be localized mainly in the supranuclear region of the cells of the epithelium of the normal mucosa. In the polyp epithelium these enzymes were found mainly in the basal areas of the epithelium at the junction between the latter and the lamina propria. In the cancer cells enzyme activity was decreased and distributed randomly. Alkaline phosphatase was present only in the capillaries in the normal and the polypmucosa. In the cancer tissue this enzyme was found in the capillaries, the smooth muscle cells, and the invading cells of epithelial origin.
Evaluation of Early Diagnostic Services for the Elderly
Authors: C. P. Lowther, R. D. M. MacLeod, J. Williamson
Journal: BMJ (1970)

Medical examination was offered to a group of "high risk" old people who were not necessarily patients or known to their family doctors, but with the agreement of these family doctors. Two clinics set up for this purpose have been running for several years, and the results of examination and follow-up of 300 consecutive patients are reported.Major conditions were found in two-thirds of patients producing functional impairment in most of these.Recommendations as to therapy and management were carried out in 161 of 194 patients but not in the remainder.Clear evidence of improvement was found in half of the patients who carried out recommendations, and this improvement was attributable to earlier diagnosis than would have been achieved without these clinics in 42% of cases.Including all patients examined, the proportion helped by early diagnosis at 18 to 30 months' follow-up was 23%.It is concluded that the offer of a routine examination to high risk groups is of benefit to old people and a form of medical practice which should be widely adopted.
Treating the Developing Brain: Implications from Human Imaging and Mouse Genetics
Authors: B.J. Casey, Siobhan S. Pattwell, Charles E. Glatt, Francis S. Lee
Journal: Annual Review of Medicine (2012)

A fundamental issue in psychiatric medicine is the lack of empirical evidence indicating when, during development, a treatment will be most effective for a patient. We review behavioral and brain changes that occur across development, focusing on the period of adolescence, when there is a peak in diagnosis of many psychiatric disorders. We use anxiety disorders as an example because of their high prevalence in youth (affecting as many as 1 in 10). Basic forms of fear learning, which are at the core of anxiety disorders and are the targets of behavioral therapeutics, are examined as a function of age. We also discuss how fear learning has been genetically modulated in mice and humans. Based on these findings, we provide future directions for determining the efficacy of innovative therapies and preventive strategies for anxiety disorders as a function of age and potential genetic effects inferred from mice and humans.
Association Between Asthma-Related Emergency Department Visits, Tree Pollen, Pollution and Humidity In The Bronx, 2001 - 2008
Authors: Jennifer Toh, Mili Shum, Gabriele De Vos, Tulsi Desai, Priyank Patel, Sunit Jariwala, David L. Rosenstreich
Journal: Journal of Allergy and Clinical Immunology (2014)
Impaired liver regeneration and increased oval cell numbers following T cell–mediated hepatitis
Authors: Ian N. Hines, Michael Kremer, Fuyumi Isayama, Ashley W. Perry, Richard J. Milton, April L. Black, Christy L. Byrd, Michael D. Wheeler
Journal: Hepatology (2007)

The regeneration of liver tissue following transplantation is often complicated by inflammation and tissue damage induced by a number of factors, including ischemia and reperfusion injury and immune reactions to the donor tissue. The purpose of the current study is to characterize the effects of T cell–mediated hepatitis induced by concanavalin A (ConA) on the regenerative response in vivo. Liver regeneration following a partial (70%) hepatectomy (pHx) was associated with elevations in serum enzymes and the induction of key cell cycle proteins (cyclin D, cyclin E, and Stat3) and hepatocyte proliferation. The induction of T cell–mediated hepatitis 4 days before pHx increased serum enzymes 48 hours after pHx, reduced early cyclin D expression and Stat3 activation, and suppressed hepatocyte proliferation. This inhibition of proliferation was also associated with increased expression of p21, the activation of Smad2, the induction of transforming growth factor beta and interferon gamma expression, and reduced hepatic interleukin 6 production. Moreover, the ConA pretreatment increased the numbers of separate oval cell-like CD117+ cells and hematopoietic-like Sca-1+ cell populations 48 hours following pHx. The depletion of natural killer (NK) cells, an important component of the innate immune response, did not affect liver injury or ConA-induced impairment of hepatocyte proliferation but did increase the numbers of both CD117-positive and Sca-1–positive cell populations. Finally, splenocytes isolated from ConA-pretreated mice exerted cytotoxicity toward autologous bone marrow cells in an NK cell–dependent manner. Conclusion: T cell–mediated hepatitis alters early cytokine responses, reduces hepatocellular regeneration, and induces NK cell–sensitive oval cell and hematopoietic-like cell expansion following pHx. (HEPATOLOGY 2007;46:229–241.)
Measurements of Tumor Cell Autophagy Predict Invasiveness, Resistance to Chemotherapy, and Survival in Melanoma
Authors: Xiao-Hong Ma, Shengfu Piao, Dan Wang, Quentin W. Mcafee, Katherine L. Nathanson, Julian J. Lum, Lin Z. Li, Ravi K. Amaravadi
Journal: Clinical Cancer Research (2011)

Autophagy consists of lysosome-dependent degradation of cytoplasmic contents sequestered by autophagic vesicles (AV). The role of autophagy in determining tumor aggressiveness and response to therapy in melanoma was investigated in this study.Autophagy was measured in tumor biopsies obtained from metastatic melanoma patients enrolled on a phase II trial of temozolomide and sorafenib and correlated to clinical outcome. These results were compared with autophagy measurements in aggressive and indolent melanoma cells grown in two- and three-dimensional (3D) culture and as xenograft tumors. The effects of autophagy inhibition with either hydroxychloroquine or inducible shRNA (short hairpin RNA) against the autophagy gene ATG5 were assessed in three-dimensional spheroids.Patients whose tumors had a high autophagic index were less likely to respond to treatment and had a shorter survival compared with those with a low autophagic index. Differences in autophagy were less evident in aggressive and indolent melanoma cells grown in monolayer culture. In contrast, autophagy was increased in aggressive compared with indolent melanoma xenograft tumors. This difference was recapitulated when aggressive and indolent melanoma cells were grown as spheroids. Autophagy inhibition with either hydroxychloroquine or inducible shRNA against ATG5 resulted in cell death in aggressive melanoma spheroids, and significantly augmented temozolomide-induced cell death.Autophagy is a potential prognostic factor and therapeutic target in melanoma. Three dimensional culture mimics the tumor microenvironment better than monolayer culture and is an appropriate model for studying therapeutic combinations involving autophagy modulators. Autophagy inhibition should be tested clinically in patients with melanoma.
EGFR-Activating Mutations Correlate with a Fanconi Anemia–like Cellular Phenotype That Includes PARP Inhibitor Sensitivity
Authors: Heike N. Pfäffle, Meng Wang, Liliana Gheorghiu, Natalie Ferraiolo, Patricia Greninger, Kerstin Borgmann, Jeffrey Settleman, Cyril H. Benes, Lecia V. Sequist, Lee Zou, Henning Willers
Journal: Cancer Research (2013)

In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2-M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer.
Polymerase chain reaction in the diagnosis of onychomycosis: a large, single-institute study
Authors: C.E. Litz, R.Z. Cavagnolo
Journal: British Journal of Dermatology (2010)

Tests commonly used in the diagnosis of onychomycosis include potassium hydroxide (KOH) preparation, histopathological examination with periodic acid-Schiff stain (PAS) and culture. These tests are either time-consuming or require specially trained personnel. A recently developed polymerase chain reaction (PCR) assay has the potential to provide a quick, inexpensive, operator-independent diagnosis of onychomycosis.To determine the range of fungal species detected by the PCR technique and to compare this technique with KOH, PAS and culture on patient specimens.A total of 176 dermatophytic and nondermatophytic fungal culture isolates were tested by PCR. Five hundred and fifty nail specimens from 550 patients with suspected onychomycosis were split and tested concurrently with PCR, PAS, KOH and culture.PCR was positive in 65 out of 66 dermatophyte culture isolates and negative in all 110 nondermatophyte and yeast isolates. Overall, PAS, PCR, KOH and culture were positive in 54%, 37%, 40% and 22% of specimens, respectively. Fifty-two per cent were positive for KOH and PCR.PCR is a specific, relatively sensitive test for onychomycosis. When used in conjunction with KOH, PCR can produce positivity rates similar to those with PAS alone.
A phase II study of 9-aminocamptothecin in advanced non-small-cell lung cancer
Authors: E.E. Vokes, R.H. Ansari, G.A. Masters, P.C. Hoffman, A. Klepsch, M.J. Ratain, D.F. Sciortino, T.E. Lad, S. Krauss, P.A.S. Fishkin, H.M. Golomb
Journal: Annals of Oncology (1998)
TCF7L2 Variants Associate with CKD Progression and Renal Function in Population-Based Cohorts
Authors: Anna Ko[Combining Diaeresis]ttgen, Shih-Jen Hwang, Evadnie Rampersaud, Josef Coresh, Kari E. North, James S. Pankow, James B. Meigs, Jose C. Florez, Afshin Parsa, Daniel Levy, Eric Boerwinkle, Alan R. Shuldiner, Caroline S. Fox, W.H. Linda Kao
Journal: Journal of the American Society of Nephrology (2008)

Genetic variants may increase susceptibility to both diabetes and kidney disease. Whether known diabetes-associated variants in the transcription factor 7–like 2 (TCF7L2) gene are associated with chronic kidney disease (CKD) progression and markers of kidney function is unknown. Participants of the Atherosclerosis Risk in Communities Study (ARIC; n = 11,061 self-identified white and n = 4014 black), Framingham Heart Offspring Cohort (FHS; n = 2468), and Heredity and Phenotype Intervention Heart Study (HAPI; n = 861) were genotyped at five (ARIC) and two (FHS) common TCF7L2 variants. The diabetes-conferring risk alleles at rs7903146 and rs7901695 were significantly associated with CKD progression among ARIC participants overall and among those without baseline diabetes. The overall adjusted hazard ratios per rs7903146 T allele were 1.17 (95% confidence interval [CI] 1.04 to 1.32) for white individuals and 1.20 (95% CI 1.03 to 1.41) for black individuals. Similarly, the overall hazard ratios per rs7901695 C allele were 1.19 (95% CI 1.06 to 1.34) for white individuals and 1.27 (95% CI 1.09 to 1.48) for black individuals. The FHS cohort supported these results: The rs7903146 T allele was significantly associated with lower estimated GFR (P = 0.01) and higher cystatin C (P = 0.004) in adjusted analyses overall and among those without diabetes. In the HAPI cohort, the rs7901695 C allele was significantly associated with lower estimated GFR in adjusted analyses (P = 0.049), as were several variants upstream and downstream of TCF7L2 (P < 0.003). No identified variant in the ARIC or FHS cohorts was associated with albuminuria. In conclusion, several population-based samples suggest that variants in the TCF7L2 gene are associated with reduced kidney function or CKD progression, overall and specifically among participants without diabetes.
CCR2 modulates inflammatory and metabolic effects of high-fat feeding
Authors: S. P. Weisberg
Journal: Journal of Clinical Investigation (2006)

The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.
Cell Therapy for Modification of the Myocardial Electrophysiological Substrate
Authors: Lior Yankelson, Yair Feld, Tal Bressler-Stramer, Ilanit Itzhaki, Irit Huber, Amira Gepstein, Doron Aronson, Shimon Marom, Lior Gepstein
Journal: Circulation (2008)

Background— Traditional antiarrhythmic pharmacological therapies are limited by their global cardiac action, low efficacy, and significant proarrhythmic effects. We present a novel approach for the modification of the myocardial electrophysiological substrate using cell grafts genetically engineered to express specific ionic channels. Methods and Results— To test the aforementioned concept, we performed ex vivo, in vivo, and computer simulation studies to determine the ability of fibroblasts transfected to express the voltage-sensitive potassium channel Kv1.3 to modify the local myocardial excitable properties. Coculturing of the transfected fibroblasts with neonatal rat ventricular myocyte cultures resulted in a significant reduction (68%) in the spontaneous beating frequency of the cultures compared with baseline values and cocultures seeded with naive fibroblasts. In vivo grafting of the transfected fibroblasts in the rat ventricular myocardium significantly prolonged the local effective refractory period from an initial value of 84±8 ms (cycle length, 200 ms) to 154±13 ms ( P &lt;0.01). Margatoxin partially reversed this effect (effective refractory period, 117±8 ms; P &lt;0.01). In contrast, effective refractory period did not change in nontransplanted sites (86±7 ms) and was only mildly increased in the animals injected with wild-type fibroblasts (73±5 to 88±4 ms; P &lt;0.05). Similar effective refractory period prolongation also was found during slower pacing drives (cycle length, 350 to 500 ms) after transplantation of the potassium channels expressing fibroblasts (Kv1.3 and Kir2.1) in pigs. Computer modeling studies confirmed the in vivo results. Conclusions— Genetically engineered cell grafts, transfected to express potassium channels, can couple with host cardiomyocytes and alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness.
Psychiatric Disorders Among Bariatric Surgery Candidates: Relationship to Obesity and Functional Health Status
Authors: Melissa A. Kalarchian, Marsha D. Marcus, Michele D. Levine, Anita P. Courcoulas, Paul A. Pilkonis, Rebecca M. Ringham, Julia N. Soulakova, Lisa A. Weissfeld, Dana L. Rofey
Journal: American Journal of Psychiatry (2007)

Objective: The present study was designed to document psychiatric disorders among candidates for weight loss surgery and to examine the relationship of psychopathology to degree of obesity and functional health status. Method: The authors collected demographic and clinical information from 288 individuals seeking surgery. Assessments were administered independently of the preoperative screening and approval process. The study group was mostly female (83.3%) and white (88.2%). Mean body mass index (BMI) of the group was 52.2 kg/m 2 (SD=9.7), and the mean age was 46.2 years (SD=9.4). Results: Approximately 66% of the participants had a lifetime history of at least one axis I disorder, and 38% met diagnostic criteria at the time of preoperative evaluation. In addition, 29% met criteria for one or more axis II disorders. Axis I psychopathology, but not axis II, was positively related to BMI, and both axis I and axis II psychopathology were associated with lower scores on the Medical Outcomes Study 36-item Short-Form Health Survey. Conclusions: Current and past DSM-IV psychiatric disorders are prevalent among bariatric surgery candidates and are associated with greater obesity and lower functional health status, highlighting the need to understand potential implications for surgery preparation and outcome. Future work also will focus on the course of psychiatric disorder during the post-surgery period and its relationship to weight loss and maintenance.
Effect of PEG Pairing on the Efficiency of Cancer-Targeting Liposomes
Authors: Phei Er Saw, Jinho Park, Eunbeol Lee, Sukyung Ahn, Jinju Lee, Hyungjun Kim, Jinjoo Kim, Minsuk Choi, Omid C. Farokhzad, Sangyong Jon
Journal: Theranostics (2015)

Standardized poly(ethylene glycol)-modified (PEGylated) liposomes, which have been widely used in research as well as in pre-clinical and clinical studies, are typically constructed using PEG with a molecular weight of 2000 Da (PEG 2000 ).Targeting ligands are also generally conjugated using various functionalized PEG 2000 .However, although standardized protocols have routinely used PEG 2000 , it is not because this molecular weight PEG has been optimized to enhance tumor uptake of nanoparticles.Herein, we investigated the effect of various PEG lipid pairings-that is, PEG lipids for targeting-ligand conjugation and PEG lipids for achieving 'stealth' function-on in vitro cancer cell-and in vivo tumor-targeting efficacy.A class of high-affinity peptides (aptides) specific to extra domain B of fibronectin (APT EDB ) was used as a representative model for a cancer-targeting ligand.We synthesized a set of aptide-conjugated PEGylated phospholipids (APT EDB -PEG 2000 -DSPE and APT EDB -PEG 1000 -DSPE) and then paired them with methoxy-capped PEGylated phospholipids with diverse molecular weights (PEG 2000 , PEG 1000 , PEG 550 , and PEG 350 ) to construct various aptide-conjugated PEGylated liposomes.The liposomes with APT EDB -PEG 2000 /PEG 1000 and APT EDB -PEG 1000 /PEG 550 pairings had the highest uptake in EDB-positive cancer cells.Furthermore, in a U87MG xenograft model, APT EDB -PEG 2000 /PEG 1000 liposomes retarded tumor growth to the greatest extent, followed closely by APT EDB -PEG 1000 /PEG 550 liposomes.Among the PEGylated liposomes tested, pairs in which the methoxy-capped PEG length was about half that of the targeting ligand-displaying PEG exhibited the best performance, suggesting that PEG pairing is a key consideration in the design of drug-delivery vehicles.