tbuckley/cabot-search huggingface dataset:
Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy
Authors: David M. Nathan, John B. Buse, Mayer B. Davidson, Robert J. Heine, Rury R. Holman, Robert Sherwin, Bernard Zinman
Journal: Diabetes Care (2006)

The epidemic of type 2 diabetes in the latter part of the 20th and in the early 21st century, and the recognition that achieving specific glycemic goals can substantially reduce morbidity, have made the effective treatment of hyperglycemia a top priority (1–3). While the management of hyperglycemia, the hallmark metabolic abnormality associated with type 2 diabetes, has historically had center stage in the treatment of diabetes, therapies directed at other coincident features, such as dyslipidemia, hypertension, hypercoagulability, obesity, and insulin resistance, have also been a major focus of research and therapy. Maintaining glycemic levels as close to the nondiabetic range as possible has been demonstrated to have a powerful beneficial impact on diabetes-specific complications, including retinopathy, nephropathy, and neuropathy in the setting of type 1 diabetes (4,5); in type 2 diabetes, more intensive treatment strategies have likewise been demonstrated to reduce complications (6–8). Intensive glycemic management resulting in lower HbA1c (A1C) levels has also been shown to have a beneficial effect on cardiovascular disease (CVD) complications in type 1 diabetes (9,10); however, the role of intensive diabetes therapy on CVD in type 2 diabetes remains under active investigation (11,12). Some therapies directed at lowering glucose levels have additional benefits with regard to CVD risk factors, while others lower glucose without additional benefits.

The development of new classes of blood glucose–lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has increased the treatment options for type 2 diabetes. Whether used alone or in combination with other blood glucose–lowering interventions, the availability of the newer agents has provided an increased number of choices for practitioners and patients and heightened uncertainty regarding the most appropriate means of treating this widespread disease. Although numerous reviews on the …
The Statistics of the Samaritan Free Hospital
Authors: W. G. King
Journal: BMJ (1900)

<h3>Background:</h3> There were large disruptions to health care services after the onset of the COVID-19 pandemic. We sought to describe the extent to which pandemic-related changes in service delivery and access affected use of primary care for children overall and by equity strata in the 9 months after pandemic onset in Manitoba and Ontario. <h3>Methods:</h3> We performed a population-based study of children aged 17 years or less with provincial health insurance in Ontario or Manitoba before and during the COVID-19 pandemic (Jan. 1, 2017–Nov. 28, 2020). We calculated the weekly rates of in-person and virtual primary care well-child and sick visits, overall and by age group, neighbourhood material deprivation level, rurality and immigrant status, and assessed changes in visit rates after COVID-19 restrictions were imposed compared to expected baseline rates calculated for the 3 years before pandemic onset. <h3>Results:</h3> Among almost 3 million children in Ontario and more than 300 000 children in Manitoba, primary care visit rates declined to 0.80 (95% confidence interval [CI] 0.77–0.82) of expected in Ontario and 0.82 (95% CI 0.79–0.84) of expected in Manitoba in the 9 months after the onset of the pandemic. Virtual visits accounted for 53% and 29% of visits in Ontario and Manitoba, respectively. The largest monthly decreases in visits occurred in April 2020. Although visit rates increased slowly after April 2020, they had not returned to prerestriction levels by November 2020 in either province. Children aged more than 1 year to 12 years experienced the greatest decrease in visits, especially for well-child care. Compared to prepandemic levels, visit rates were lowest among rural Manitobans, urban Ontarians and Ontarians in low-income neighbourhoods. <h3>Interpretation:</h3> During the study period, the pandemic contributed to rapid, immediate and inequitable decreases in primary care use, with some recovery and a substantial shift to virtual care. Postpandemic planning must consider the need for catch-up visits, and the long-term impacts warrant further study.
High-dose chemotherapy for ovarian carcinoma: Long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: J.A. Ledermann, R. Herd, D. Maraninchi, P. Viens, M. Buclon, T. Philip, H. Cure, J.-P. Lotz, F. Chauvin, P. Ferrante, G. Rosti
Journal: Annals of Oncology (2001)
Reply to “Testing for association between MeCP2 and the brahma-associated SWI/SNF chromatin-remodeling complex”
Authors: KN Harikrishnan, Sharmistha Pal, Michael Yarski, Emma K Baker, Maggie Z Chow, Michelle G de Silva, Jun Okabe, Li Wang, Peter L Jones, Saïd Sif, Assam El-Osta
Journal: Nature Genetics (2006)
CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis
Authors: Qiang Ding, Yumi Miyazaki, Koichiro Tsukasa, Shyuichiro Matsubara, Makoto Yoshimitsu, Sonshin Takao
Journal: Molecular Cancer (2014)

Pancreatic cancer is a lethal disease due to the high incidence of metastasis at the time of detection. CD133 expression in clinical pancreatic cancer correlates with poor prognosis and metastasis. However, the molecular mechanism of CD133-regulated metastasis remains unclear. In recent years, epithelial-mesenchymal transition (EMT) has been linked to cancer invasion and metastasis. In the present study we investigated the role of CD133 in pancreatic cancer metastasis and its potential regulatory network. A highly migratory pancreatic cancer cell line, Capan1M9, was established previously. After shRNA was stable transducted to knock down CD133 in Capan1M9 cells, gene expression was profiled by DNA microarray. Orthotopic, splenic and intravenous transplantation mouse models were set up to examine the tumorigenesis and metastatic capabilities of these cells. In further experiments, real-time RT-PCR, Western blot and co-immunoprecipitate were conducted to evaluate the interactions of CD133, Slug, N-cadherin, ERK1/2 and SRC. We found that CD133+ human pancreatic cancer cells were prone to generating metastatic nodules in in vivo models using immunodeficient mice. In contrast, CD133 knockdown suppressed cancer invasion and metastasis in vivo. Gene profiling analysis suggested that CD133 modulated mesenchymal characteristics including the expression of EMT-related genes, such as Slug and N-cadherin. These genes were down-regulated following CD133 knockdown. Moreover, CD133 expression could be modulated by the extracellular signal-regulated kinase (ERK)1/2 and SRC signaling pathways. The binding of CD133 to ERK1/2 and SRC acts as an indispensable mediator of N-cadherin expression. These results demonstrate that CD133 plays a critical role in facilitating the EMT regulatory loop, specifically by upregulating N-cadherin expression, leading to the invasion and metastasis of pancreatic cancer cells. Our study provides a novel insight into the function of CD133 in the EMT program and a better understanding of the mechanism underlying the involvement of CD133 in pancreatic cancer metastasis.
Widespread long-term gene transfer to mouse skeletal muscles and heart.
Authors: L D Stratford-Perricaudet, I Makeh, M Perricaudet, P Briand
Journal: Journal of Clinical Investigation (1992)

Successful treatment of muscular disorders awaits an adapted gene delivery protocol. The clinically applicable technique used for hematopoietic cells which is centered around implantation of retrovirally modified cells may not prove sufficient for a reversal of phenotype when muscle diseases are concerned. We report here efficient, long-term in vivo gene transfer throughout mouse skeletal and cardiac muscles after intravenous administration of a recombinant adenovirus. This simple, direct procedure raises the possibility that muscular degenerative diseases might one day be treatable by gene therapy.
Vasectomy and health. Results from a large cohort study
Authors: F. J. Massey
Journal: JAMA (1984)

In this historical cohort study we identified, located, and, if living, interviewed 10,590 vasectomized men from four cities, along with a paired neighborhood control for each. The times between procedure data and interview or death ranged from under one to 41 years, with median equal to 7.9 years and with 2,318 pairs having ten or more years of follow-up. Participant reports of diseases or conditions that might possibly be related to vasectomy through an immunopathological mechanism were validated by direct contact with physicians and review of medical records. Results of this study do not support the suggestions of immunopathological consequences of vasectomy within the period of follow-up. Except for epididymitis-orchitis, the incidence of diseases for vasectomized men was similar or lower than for their paired controls.
Formation of normal desmin intermediate filaments in mouse hepatic stellate cells requires vimentin
Authors: Albert Geerts, Camilla Eliasson, Toshiro Niki, Annemie Wielant, Freja Vaeyens, Milos Pekny
Journal: Hepatology (2001)

Increased desmin synthesis and formation of desmin–containing intermediate filaments (IFs) is one of the hallmarks of transdifferentiation of hepatic stellate cells into myofibroblast–like cells. These desmin–enriched myofibroblast–like cells are the major sources of fibrotic extracellular matrix in chronically diseased liver. Myofibroblast–like cells are also involved in the contraction of sinusoids, which leads to increased intrahepatic pressure and portal hypertension. To address the requirements for the formation of desmin–containing IFs both in quiescent and in transdifferentiated stellate cells, we used mice deficient for glial fibrillary acidic protein (GFAP) and/or vimentin, which are additional IF proteins present in stellate cells. In this study, we show that desmin cannot form full–length bundles of IFs in the absence of both GFAP and vimentin. Quiescent and transdifferentiated GFAP -/- vim -/- stellate cells are devoid of normal bundles of IFs. Instead, they exhibit only residual IF bundles restricted to subcortical cytoplasm, although these cells contain equal desmin mRNA and protein levels as wild–type cells. The absence of vimentin alone restricts formation of desmin–containing IF bundles to the perinuclear region, while both the distal processes in quiescent stellate cells and the subcortical zone in myofibroblast–like cells remain free of desmin–containing IF bundles. The absence of GFAP alone does not interfere with the formation of desmin–containing IFs. Thus, to form normal IFs in stellate cells, desmin is required to partnerize with vimentin. In addition, these mouse models will prove to be instrumental in addressing the role of IFs in the process of stellate cell transdifferentiation.
Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro.
Authors: C W Smith, S D Marlin, R Rothlein, C Toman, D C Anderson
Journal: Journal of Clinical Investigation (1989)

The adherence of human neutrophils to human umbilical vein endothelial cells (HUVEC) is partially dependent on the CD11/CD18 family of glycoproteins on the neutrophil and ICAM-1 on the HUVEC. The CD18 heterodimer involved in this adherence was evaluated in vitro using subunit-specific monoclonal antibodies (MAbs). The adherence of unstimulated neutrophils to IL-1-stimulated HUVEC was significantly inhibited by anti-CD11a but not CD11b MAbs, while the adherence of fMLP-stimulated neutrophils was significantly inhibited by both anti-CD11a and -CD11b. Anti-CD11a, but not anti-CD11b MAbs, reduced the adherence of unstimulated neutrophils on purified ICAM-1 to the same low level untreated neutrophils exhibited on a control protein, glycophorin. Stimulation with fMLP significantly increased neutrophil attachment to purified ICAM-1, but not to the control protein. Anti-CD11b MAbs reduced this chemotactically augmented adherence to that of unstimulated neutrophils, and in combination with anti-CD11a MAbs reduced adherence to that on the control protein. The results in this report indicate that unstimulated neutrophils exhibit LFA-1-dependent attachment to ICAM-1, and chemotactic stimulation enhances the attachment of human neutrophils to ICAM-1 by a Mac-1-dependent process.
Letter: Oestrogens as a cause of endometrial carcinoma.
Authors: R E Oakey, R A Hawkins
Journal: BMJ (1976)

The authors refer to a previous article. Estrone sulphate is the most abundant form of estrogen so far discovered in peripheral plasma. At midcycle, its concentration is about 5 times that of estradiol-17beta and 15 times that of estrone. Therefore, it would be expected that estrone sulphate would have been recommended rather than the other compounds in considering the possible carcinogenic effect. Exposure to estrone sulphate continues after ovariectomy when the concentration of each estrogen is reduced. In vivo estriol is formed from these estrogens by an irreversible process. Selection of an estrogen for therapy is complicated by the fact that estron sulphate has little affinity for estrogen receptors of the uterus, at least in the rabbit and sheep. Estrogen sulphate is unlikely to exert estrogenic activity in the uterus without hydrolysis to estrone.
Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression
Authors: Susetta Finotto, George T. De Sanctis, Hans A. Lehr, Udo Herz, Michael Buerke, Mechthild Schipp, Brigitte Bartsch, Raja Atreya, Edgar Schmitt, Peter R. Galle, Harald Renz, Markus F. Neurath
Journal: The Journal of Experimental Medicine (2001)

Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4–producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate–labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.
Interleukin-1β Causes Acute Lung Injury via αvβ5 and αvβ6 Integrin–Dependent Mechanisms
Authors: Michael T. Ganter, Jérémie Roux, Byron Miyazawa, Marybeth Howard, James A. Frank, George Su, Dean Sheppard, Shelia M. Violette, Paul H. Weinreb, Gerald S. Horan, Michael A. Matthay, Jean-François Pittet
Journal: Circulation Research (2008)

Interleukin (IL)-1β has previously been shown to be among the most biologically active cytokines in the lungs of patients with acute lung injury (ALI). Furthermore, there is experimental evidence that lung vascular permeability increases after short-term exposure to IL-1 protein, although the exact mechanism is unknown. Therefore, the objective of this study was to determine the mechanisms of IL-1β–mediated increase in lung vascular permeability and pulmonary edema following transient overexpression of this cytokine in the lungs by adenoviral gene transfer. Lung vascular permeability increased with intrapulmonary IL-1β production with a maximal effect 7 days after instillation of the adenovirus. Furthermore, inhibition of the αvβ6 integrin and/or transforming growth factor-β attenuated the IL-1β–induced ALI. The results of in vitro studies indicated that IL-1β caused the activation of transforming growth factor-β via RhoA/αvβ6 integrin–dependent mechanisms and the inhibition of the αvβ6 integrin and/or transforming growth factor-β signaling completely blocked the IL-1β–mediated protein permeability across alveolar epithelial cell monolayers. In addition, IL-1β increased protein permeability across lung endothelial cell monolayers via RhoA- and αvβ5 integrin–dependent mechanisms. The final series of in vivo experiments demonstrated that pretreatment with blocking antibodies to both the αvβ5 and αvβ6 integrins had an additive protective effect against IL-1β–induced ALI. In summary, these results demonstrate a critical role for the αvβ5/β6 integrins in mediating the IL-1β–induced ALI and indicate that these integrins could be a potentially attractive therapeutic target in ALI.
Unmasking of cryptic natural killer (NK) cell recognition sites on chronic lymphocytic leukemia lymphocytes
Authors: Daniel L. Spitz, Dorothea Zucker‐Franklin, Zeenat F. Nabi
Journal: American Journal of Hematology (1988)

Abstract The sensitivity of chronic lymphocytic leukemia (CLL) lymphocytes to attack by natural killer (NK) cells has remained questionable. To clarify this issue, freshly isolated lymphocytes of 37 patients with B‐CLL, five with WDLL and two with HCL, were tested with a standard cytotoxicity assay with NK cells from normal donors. All these targets were resistant to cytolysis by the effectors. Freeze‐fracture analysis of CLL cell plasma membranes revealed that they have a larger number of intramembranous particles (IMP) associated with the external leaflet (E‐face) than have normal lymphocytes. Unlike other neoplastic cells, exposure of CLL lymphocytes to phorbol esters or treatment with neuraminidase did not render them vulnerable to attack by NK cells, nor did 5 days of culture have an effect. Incubation of CLL lymphocytes with anti‐lg‐μ (24–72 hr) or with 0.1% pepsin (15 min) resulted in 15% and 27% cytolysis, respectively. B‐lymphocytes from the blood of healthy donors were not killed when treated similarly: These data establish that freshly isolated B‐CLL lymphocytes are resistant to NK cytolysis but that in contrast to normal B‐cells, they possess cryptic NK‐recognition structures, which may be uncovered by surface modulation.
Analysis of the structure of empty and peptide-loaded major histocompatibility complex molecules at the cell surface.
Authors: B Catipović, G Talluri, J Oh, T Wei, X M Su, T E Johansen, M Edidin, J P Schneck
Journal: The Journal of Experimental Medicine (1994)

We compared the conformation of empty and peptide-loaded class I major histocompatibility complex (MHC) molecules at the cell surface. Molecular conformations were analyzed by fluorescence resonance energy transfer (FRET) between fluorescent-labeled Fab fragments bound to the alpha 2 domain of the MHC heavy chain and fluorescent-labeled Fab fragments bound to beta 2-microglobulin. No FRET was found between Fab fragments bound to empty H-2Kb, but FRET was detected when empty H-2Kb molecules were loaded with peptide. The magnitude of FRET depended on the sequence of the peptide used. The results imply that empty H-2Kb molecules are in a relatively extended conformation, and that this conformation becomes more compact when peptide is bound. These changes, which are reflected in peptide-dependent binding of monoclonal antibodies, affect the surfaces of MHC molecules available for contact with T cell receptors and hence may influence T cell-receptor recognition of MHC molecules.
Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ
Authors: Udo Rudloff, Lindsay M. Jacks, Jessica I. Goldberg, Christine A. Wynveen, Edi Brogi, Sujata Patil, Kimberly J. Van Zee
Journal: Journal of Clinical Oncology (2010)

Purpose While the mortality associated with ductal carcinoma in situ (DCIS) is minimal, the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) is relatively high. Radiation therapy (RT) and antiestrogen agents reduce the risk of IBTR and are considered standard treatment options after BCS. However, they have never been proven to improve survival, and in themselves carry rare but serious risks. Individualized estimation of IBTR risk would assist in decision making regarding the various treatment options for women with DCIS. Patients and Methods From 1991 to 2006, 1,868 consecutive patients treated with BCS for DCIS were identified. A multivariate Cox proportional hazards model was constructed using the 1,681 in whom data were complete. Ten clinical, pathologic, and treatment variables were built into a nomogram estimating probability of IBTR at 5 and 10 years after BCS. The model was validated for discrimination and calibration using bootstrap resampling. Results The DCIS nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated good calibration and discrimination, with a concordance index of 0.704 (bootstrap corrected, 0.688) and a concordance probability estimate of 0.686. Factors with the greatest influence on risk of IBTR in the model included adjuvant RT or endocrine therapy, age, margin status, number of excisions, and treatment time period. Conclusion The DCIS nomogram integrates 10 clinicopathologic variables to provide an individualized risk estimate of IBTR in a woman with DCIS treated with BCS. This tool may assist in individual decision making regarding various treatment options and help avoid over- and undertreatment of noninvasive breast cancer.