tbuckley/cabot-search huggingface dataset:
α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes
Authors: Ana Luisa Kadekaro, Renny Kavanagh, Hiromi Kanto, Silva Terzieva, Jennifer Hauser, Nobuhiko Kobayashi, Sandy Schwemberger, James Cornelius, George Babcock, Howard G. Shertzer, Glynis Scott, Zalfa A. Abdel-Malek
Journal: Cancer Research (2005)

Abstract UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors α-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that α-melanocortin and endothelin-1 rescued human melanocytes from UV radiation–induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of α-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with α-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with α-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis.
Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010
Authors: Marcus A. Bachhuber, Brendan Saloner, Chinazo O. Cunningham, Colleen L. Barry
Journal: JAMA Internal Medicine (2014)

Opioid analgesic overdose mortality continues to rise in the United States, driven by increases in prescribing for chronic pain. Because chronic pain is a major indication for medical cannabis, laws that establish access to medical cannabis may change overdose mortality related to opioid analgesics in states that have enacted them.
Phase II Study of Rituximab Plus Three Cycles of CHOP and Involved-Field Radiotherapy for Patients With Limited-Stage Aggressive B-Cell Lymphoma: Southwest Oncology Group Study 0014
Authors: Daniel O. Persky, Joseph M. Unger, Catherine M. Spier, Baldassarre Stea, Michael LeBlanc, Matthew J. McCarty, Lisa M. Rimsza, Richard I. Fisher, Thomas P. Miller
Journal: Journal of Clinical Oncology (2008)

Purpose To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT). Patients and Methods Southwest Oncology Group (SWOG) study S0014 enrolled patients with newly diagnosed, aggressive, CD20-expressing non-Hodgkin's lymphoma (NHL). Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index (nonbulky stage II disease, age &gt; 60 years, WHO performance status of 2, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days −7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46 Gy of IFRT. Results Sixty patients with aggressive NHL were eligible. With the median follow-up of 5.3 years, treatment resulted in a progression-free survival (PFS) of 93% at 2 years and 88% at 4 years. Overall survival (OS) was 95% at 2 years and 92% at 4 years. These results were compared with those from a historic group of patients treated without rituximab on S8736, demonstrating PFS of 78% and OS of 88% at 4 years. Conclusion In limited-stage DLBCL, the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy, with 2-year PFS of at least 84%, meriting further investigation. There is a pattern of continuing relapse with modest survival gains. We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma.
Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers
Authors: Mark Cobbold, Naeem Khan, Batoul Pourgheysari, Sudhir Tauro, Dorothy McDonald, Husam Osman, Mario Assenmacher, Lucinda Billingham, Colin Steward, Charles Crawley, Eduardo Olavarria, John Goldman, Ronjon Chakraverty, Premini Mahendra, Charles Craddock, Paul A.H. Moss
Journal: The Journal of Experimental Medicine (2005)

Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8+ T cells from the blood of stem cell transplant donors using staining with HLA–peptide tetramers followed by selection with magnetic beads. CMV-specific CD8+ cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 × 103/kg with a purity of 98% of all T cells. CMV-specific CD8+ T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy.
TOTAL WATER AND CHLORIDE CONTENT OF DEHYDRATED RATS
Authors: T. G. H. Drake, C. F. McKhann, J. L. Gamble
Journal: The Journal of Experimental Medicine (1930)

The circumstances present in upper intestinal obstruction which may be expected to reduce the water content of the body are fasting with water deprivation and a continued loss of secretions into the stomach. According to the data obtained from the above described experiments with rats, loss of body water during the first third of the survival period following pyloric obstruction is more than half accounted for by fasting with water deprivation. This body water is accompanied by a parallel loss of solids and may be regarded as a waste product of the consumption of body fat, glycogen, and protoplasm. Its loss does not disturb the per cent water content of the body tissues. The water lost into the stomach is responsible for an actual excess of water reduction over consumption of solids. Except in the case of the skin and blood, this excess loss of water is extremely small and produces a reduction of the per cent water content of tissues which is so slight as to permit the surmise that the water loss here derives entirely from the interstitial fluid of the tissues and that no dehydration of tissue cells occurs. The data are, however, not directly informative on this point. The total loss of body water during 12 hours following pyloric obstruction was found to be 12.6 per cent of the water content of a control animal. More than one-quarter (28.3 per cent) of the total body content of chloride ion was found to be lost and was entirely accounted for by the amount of chloride found in the gastric contents. Nearly half of the chloride loss derives from the skin. Data are presented which demonstrate that lower intestinal obstruction causes slight, if any, depletion of the water content of the body.
Non-clinical influences on clinical decision-making: a major challenge to evidence-based practice
Authors: FM Hajjaj, MS Salek, MKA Basra, AY Finlay
Journal: Journal of the Royal Society of Medicine (2010)

This article reviews an aspect of daily clinical practice which is of critical importance in virtually every clinical consultation, but which is seldom formally considered. Non-clinical influences on clinical decision-making profoundly affect medical decisions. These influences include patient-related factors such as socioeconomic status, quality of life and patient's expectations and wishes, physician-related factors such as personal characteristics and interaction with their professional community, and features of clinical practice such as private versus public practice as well as local management policies. This review brings together the different strands of knowledge concerning non-clinical influences on clinical decision-making. This aspect of decision-making may be the biggest obstacle to the reality of practising evidence-based medicine. It needs to be understood in order to develop clinical strategies that will facilitate the practice of evidence-based medicine.
Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial
Authors: Francis Ka Leung Chan, Vincent Wai Sun Wong, Bing Yee Suen, Justin Che Yuen Wu, Jessica Yuet Ling Ching, Lawrence Cheung Tsui Hung, Aric Josun Hui, Vincent King Sun Leung, Vivian Wing Yan Lee, Larry Hin Lai, Grace Lai Hung Wong, Dorothy Kai Lai Chow, Ka Fa To, Wai Keung Leung, Philip Wai Yan Chiu, Yuk Tong Lee, James Yun Wong Lau, Henry Lik Yuen Chan, Enders Kwok Wai Ng, Joseph Jao Yiu Sung
Journal: The Lancet (2007)
Two Faces of Chondroitin Sulfate Proteoglycan in Spinal Cord Repair: A Role in Microglia/Macrophage Activation
Authors: Asya Rolls, Ravid Shechter, Anat London, Yifat Segev, Jasmin Jacob-Hirsch, Ninette Amariglio, Gidon Rechavi, Michal Schwartz
Journal: PLoS Medicine (2008)

Chondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study.We inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-alpha) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells.Our results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.
Efficacy and Safety of Technosphere Inhaled Insulin Compared With Technosphere Powder Placebo in Insulin-Naive Type 2 Diabetes Suboptimally Controlled With Oral Agents
Authors: Julio Rosenstock, Richard Bergenstal, Ralph A. DeFronzo, Irl B. Hirsch, David Klonoff, Anders H. Boss, David Kramer, Richard Petrucci, Wen Yu, Brian Levy
Journal: Diabetes Care (2008)

This double-blind, placebo-controlled, randomized, multicenter, parallel-group study compared the efficacy, safety, and tolerability of Technosphere insulin with Technosphere powder as placebo in insulin-naive type 2 diabetic patients whose diabetes was suboptimally controlled with oral antidiabetic agents.Patients (n = 126) were randomly assigned to 12 weeks of therapy with Technosphere insulin or Technosphere powder after lifestyle education on nutrition, exercise, and instructions on inhaler use. The primary efficacy outcome was change in A1C from baseline to study end, and the secondary efficacy outcome was area under the curve for postprandial glucose levels during a meal test at treatment weeks 4, 8, and 12.A1C reduction from a mean baseline of 7.9% was greater with Technosphere insulin than with Technosphere powder (-0.72 vs. -0.30%; P = 0.003). Postprandial glucose excursions were reduced by 56% with Technosphere insulin compared with baseline, and maximal postprandial glucose levels were reduced by 43% compared with Technosphere powder. Incidences of hypoglycemia, hyperglycemia, cough, and other adverse events were low in both groups. Body weight was unchanged in both groups.Technosphere insulin was well tolerated and demonstrated significant improvement in glycemic control with clinically meaningful reductions in A1C levels and postprandial glucose concentrations after 12 weeks of treatment.
Inhibition of Membrane-Type 1 Matrix Metalloproteinase at Cell-Matrix Adhesions
Authors: Takahisa Takino, Hiromi Saeki, Hisashi Miyamori, Tomoya Kudo, Hiroshi Sato
Journal: Cancer Research (2007)

Abstract Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion and metastasis. We previously reported that extracellular matrix degradation by MT1-MMP regulates cell migration via modulating sustained integrin-mediated signals. In this study, MT1-MMP–expressing cells were plated onto fibronectin-coated plates and monitored for cell-matrix adhesion formation and fibronectin degradation. The fibronectin was degraded and removed in line with the cell migration track. The migrating cells showed a polarized morphology and were in contact with the edge of fibronectin through the leading edge, in which cell-matrix adhesions are concentrated. Expression of MT1-MMP targeted to cell-matrix adhesions by fusing with the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK) promoted the initial fibronectin lysis at the cell periphery immediately after adhesion. These results suggest that fibronectin is degraded by MT1-MMP located at cell-matrix adhesions, which are concentrated at the leading edge of the migrating cells. To inhibit MT1-MMP at cell-matrix adhesion, the dominant negative form of MT1-MMP (MT1-Pex) was targeted to the cell-matrix adhesion by fusing with the FAT domain (MT1-Pex-FAT). MT1-Pex-FAT accumulated at cell-matrix adhesions and inhibited fibronectin degradation as well as FAK phosphorylation more effectively than parental MT1-Pex. MT1-Pex-FAT was also shown to suppress the invasion of tumor cells into three-dimensional collagen gel more strongly than MT1-Pex. These results suggest that MT1-MMP–mediated extracellular matrix lysis at cell-matrix adhesions induces the establishment of cell polarity, which facilitates cell-matrix adhesion turnover and subsequent cell migration. This model highlights the role of MT1-MMP at the leading edge of migrating cells. [Cancer Res 2007;67(24):11621–9]
Microsphere Measurement of Intrarenal Circulation of the Dog
Authors: LAWRENCE M. SLOTKOFF, ALEXANDER LOGAN, PEDRO JOSE, JOHN D'AVELLA, GILBERT M. EISNER
Journal: Circulation Research (1971)

Distribution of cortical blood flow was measured in the dog by a technique based on radionuclide-labeled microspheres. Initially it was necessary to test possible pitfalls of this technique. Completeness of trapping in the kidney, the effect on renal function, and the notion that microsphere distribution reflects blood flow distribution in the kidney cortex were studied. Renal vein blood contained less than 0.2% of the microspheres (16.8µ diameter) found in the renal artery after an aortic injection. No impairment of C PAH (control 167±4; postinjection 179±31 ml/min), C In (control 39.3%6; postinjection 37.6±2 ml/min), and T m glucose (control 90.8±13; postinjection 102±24) was found using doses adequate to measure renal blood flow (5 mg/injection x 4 injections). After 4 injections of 50 mg each significant impairment of renal function was observed. Intrarenal blood flow distribution was determined during hemorrhagic hypotension. 169 Yb-labeled microspheres were injected into the root of the aorta before, and 85 Sr-labeled microspheres after, acute hemorrhage. Radioactivity was measured in the outer two thirds and inner one third of kidney slices. Tissue blood flow was calculated and expressed as the ratio of outer cortex to inner cortex counts. Renal blood flow was redistributed to the inner cortex after hemorrhage (ratio before, 3.00; after 1.30, P &lt; 0.01). Finally, the results of this technique were compared to a widely used method of measuring intrarenal blood flow distribution, 133 Xe washout. The first component of the washout technique correlated fairly well with total cortical flow but it was not possible to match the second component with any single anatomical area of the kidney. Limitations of the 133 Xe washout are discussed.
Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic β-cell line, MIN6
Authors: Fumi Sawada, Toyoshi Inoguchi, Hirotaka Tsubouchi, Shuji Sasaki, Masakazu Fujii, Yasutaka Maeda, Hidetaka Morinaga, Masatoshi Nomura, Kunihisa Kobayashi, Ryoichi Takayanagi
Journal: Metabolism (2008)
Transitional B cells are the target of negative selection in the B cell compartment.
Authors: R Carsetti, G Köhler, M C Lamers
Journal: The Journal of Experimental Medicine (1995)

B lymphocytes recognize antigen through membrane-bound antigen-receptors, membrane IgM and IgD (mIgM and mIgD). Binding to foreign antigens initiates a cascade of biochemical events that lead to activation and differentiation. In contrast, binding to self-antigens leads to death or to inactivation. It is commonly believed that the B cells acquire the ability to discriminate between self and nonself in the early phases of development. We report here that immature B cells, which have just emerged from the mIgMneg, B220pos pool, are not deleted upon binding of self-antigen. In vivo, developing B cells become sensitive to tolerance induction in a relatively late window of differentiation, when they are in transition from the immature (HSAbright, B220dull) to the mature (HSAdull, B220bright) stage. In the transitional B cells, early markers of differentiation such as Pgp1 (CD44) and ThB reach the highest level of expression, while the expression of CD23 and mIgD, late markers of differentiation, and expression of class II MHC, progressively increases. Most of the transitional B cells, but only few of the mature and of the immature B cells, express the fas antigen, while mature B cells, but not immature and transitional B cells, express bcl-2 protein. mIgM is present in low amounts in immature B cells, reaches the highest level of expression in transitional B cells and is down-regulated in mature resting B cells, where it is coexpressed with mIgD. The high expression of mIgM, the presence of the fas antigen and the absence of bcl-2 protein is compatible with the high sensitivity of transitional B cells to negative selection. In vitro, immature B cells die rapidly by apoptosis after cross-linking of mIgM. This result, combined with the resistance of immature B cells to elimination in vivo, suggests that early in development the stroma cell microenvironment modulates signals transduced through mIgM. The functional and phenotypic division of IgMpos bone marrow B cells in three compartments not only allows to define the target population of physiological processes like negative selection, but will also be a helpful tool for an accurate description of possible developmental blocks in mutant mice.
Slug Promotes Survival during Metastasis through Suppression of Puma-Mediated Apoptosis
Authors: Seaho Kim, Jiahong Yao, Kimita Suyama, Xia Qian, Bin-Zhi Qian, Sanmay Bandyopadhyay, Olivier Loudig, Carlos De Leon-Rodriguez, Zhen Ni Zhou, Jeffrey Segall, Fernando Macian, Larry Norton, Rachel B. Hazan
Journal: Cancer Research (2014)

Tumor cells must overcome apoptosis to survive throughout metastatic dissemination and distal organ colonization. Here, we show in the Polyoma Middle T mammary tumor model that N-cadherin (Cdh2) expression causes Slug (Snai2) upregulation, which in turn promotes carcinoma cell survival. Slug was dramatically upregulated in metastases relative to primary tumors. Consistent with a role in metastasis, Slug knockdown in carcinoma cells suppressed lung colonization by decreasing cell survival at metastatic sites, but had no effect on tumor cell invasion or extravasation. In support of this idea, Slug inhibition by shRNA sensitized tumor cells to apoptosis by DNA damage, resulting in caspase-3 and PARP cleavage. The prosurvival effect of Slug was found to be caused by direct repression of the proapoptotic gene, Puma (Bbc3), by Slug. Consistent with a pivotal role for a Slug-Puma axis in metastasis, inhibition of Puma by RNA interference in Slug-knockdown cells rescued lung colonization, whereas Puma overexpression in control tumor cells suppressed lung metastasis. The survival function of the Slug-Puma axis was confirmed in human breast cancer cells, where Slug knockdown increased Puma expression and inhibited lung colonization. This study demonstrates a pivotal role for Slug in carcinoma cell survival, implying that disruption of the Slug-Puma axis may impinge on the survival of metastatic cells.