tbuckley/cabot-search huggingface dataset:
Sustained Delivery of VEGF Maintains Innervation and Promotes Reperfusion in Ischemic Skeletal Muscles Via NGF/GDNF Signaling
Authors: Dmitry Shvartsman, Hannah Storrie-White, Kangwon Lee, Cathal Kearney, Yevgeny Brudno, Nhi Ho, Christine Cezar, Corey McCann, Erin Anderson, John Koullias, Juan Carlos Tapia, Herman Vandenburgh, Jeff W Lichtman, David J Mooney
Journal: Molecular Therapy (2014)

Tissue reinnervation following trauma, disease, or transplantation often presents a significant challenge. Here, we show that the delivery of vascular endothelial growth factor (VEGF) from alginate hydrogels ameliorates loss of skeletal muscle innervation after ischemic injury by promoting both maintenance and regrowth of damaged axons in mice. Nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) mediated VEGF-induced axonal regeneration, and the expression of both is induced by VEGF presentation. Using both in vitro and in vivo modeling approaches, we demonstrate that the activity of NGF and GDNF regulates VEGF-driven angiogenesis, controlling endothelial cell sprouting and blood vessel maturation. Altogether, these studies produce evidence of new mechanisms of VEGF action, further broaden the understanding of the roles of NGF and GDNF in angiogenesis and axonal regeneration, and suggest approaches to improve axonal and ischemic tissue repair therapies. Tissue reinnervation following trauma, disease, or transplantation often presents a significant challenge. Here, we show that the delivery of vascular endothelial growth factor (VEGF) from alginate hydrogels ameliorates loss of skeletal muscle innervation after ischemic injury by promoting both maintenance and regrowth of damaged axons in mice. Nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) mediated VEGF-induced axonal regeneration, and the expression of both is induced by VEGF presentation. Using both in vitro and in vivo modeling approaches, we demonstrate that the activity of NGF and GDNF regulates VEGF-driven angiogenesis, controlling endothelial cell sprouting and blood vessel maturation. Altogether, these studies produce evidence of new mechanisms of VEGF action, further broaden the understanding of the roles of NGF and GDNF in angiogenesis and axonal regeneration, and suggest approaches to improve axonal and ischemic tissue repair therapies.
Proton Permeation Through the Myocardial Gap Junction
Authors: Massimiliano Zaniboni, Alessandra Rossini, Pawel Swietach, Nurindura Banger, Kenneth W. Spitzer, Richard D. Vaughan-Jones
Journal: Circulation Research (2003)

Although protons can directly or indirectly gate solute permeability of the myocardial gap junction, there is little information regarding their own permeation, despite their importance in the regulation of myocardial contractility and rhythm. By pipette-loading of acid into guinea pig isolated, ventricular myocyte pairs while imaging pH i confocally using SNARF fluorescence, we have observed that protons permeate the junctional region. Permeation is inhibited by glycyrrhetinic acid, an agent that also increases intercellular electrical resistance, suggesting H + permeation via gap junctions. The rate of spread of acid between cells appears to be limited by junctional permeation rather than by cytoplasmic diffusion. Mathematical analyses, combined with experiments using SNARF as a proton carrier, suggest that gap junctional H + transmission may be accomplished physiologically by the permeation of intrinsic “proton-porter” molecules. We propose that proton flux through gap junctions will contribute to the dissipation of regional acid loads within the myocardium. This represents a mechanism for the local control of myocardial pH i .
CONGENITAL OBSTRUCTION OF THE SMALL INTESTINE
Authors: WILLIAM E. LADD
Journal: JAMA (1933)

This paper is based on a study of sixty cases of congenital intestinal obstruction occurring in the Children's Hospital of Boston. Only those cases are included in which the obstruction was located in the small intestine and was due to one of two factors. Intrinsic obstruction is the interference in the continuity of the lumen of the intestine due to intraintestinal defects. Extrinsic obstruction is the interference in the function of the intestine by external pressure due to faulty rotation. Obstruction caused by bands which may or may not be of congenital origin and that, due to hernias and the vagaries of Meckel's diverticulum are not included. <h3>EMBRYOLOGY</h3> To understand these conditions one must consider the normal embryologic development of the intestine. Most of the embryologic events take place between the fifth and tenth weeks of fetal life. Prior to the fifth week of fetal life the intestine presents a
US Medical Researchers, the Nuremberg Doctors Trial, and the Nuremberg Code
Authors: Ruth R. Faden, Susan E. Lederer, Jonathan D. Moreno
Journal: JAMA (1996)

The Advisory Committee on Human Radiation Experiments (ACHRE), established to review allegations of abuses of human subjects in federally sponsored radiation research, was charged with identifying appropriate standards to evaluate the ethics of cold war radiation experiments. One central question for ACHRE was to determine what role, if any, the Nuremberg Code played in the norms and practices of US medical researchers. Based on the evidence from ACHRE's Ethics Oral History Project and extensive archival research, we conclude that the Code, at the time it was promulgated, had little effect on mainstream medical researchers engaged in human subjects research. Although some clinical investigators raised questions about the conduct of research involving human beings, the medical profession did not pursue this issue until the 1960s.
Rejection — More Than the Eye Can See
Authors: Terry B. Strom
Journal: New England Journal of Medicine (2005)

In comparing current clinical outcomes in renal transplantation with those of 30 years ago,1 graft failure from immunologic factors and death from opportunistic infection in the first year after transplantation are no longer common clinical outcomes. The therapeutic regimens used today to prevent and treat rejection or infection among renal-transplant recipients bear only a small resemblance to those used 30 years ago.In contrast, the diagnostic strategies used to detect rejection and distinguish it from other causes of renal dysfunction have not budged during the past two decades. A rise in the level of serum creatinine suggests allograft dysfunction, but . . .
Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632
Authors: M Takamura
Journal: Hepatology (2001)

Intrahepatic metastasis is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). Cell motility mediated by Rho- and p160 Rho-associated coiledcoil forming protein kinase (p160ROCK) signaling pathways has recently been shown to play a critical role in intrahepatic metastasis in human HCC. Furthermore, the stable introduction of dominant-negative p160ROCK into Li7 cells resulted in a reduced metastatic rate in mice with severe combined immunodeficiency (SCID). To investigate whether the specific p160ROCK inhibitor, Y-27632, could also inhibit intrahepatic metastasis, the effect of Y-27632 on the cell motility and intrahepatic metastasis of Li7 was investigated. Y-27632 markedly blocked actin reorganization and motility of Li7 cells mediated by lysophosphatidic acid (LPA). Y-27632 was administered continuously into the peritoneal cavity using a micro-osmotic pump, together with orthotopic implantation of Li7 cells into the liver of SCID mice. Phosphate-buffered saline (PBS) alone was administered as the control. The incidence of mice with metastatic nodules decreased in the Y-27632-treated group. The primary tumor volume at the site of injection was smaller in the Y-27632-treated group compared with the control group, but the difference was not statistically significant. Histologically, control tumors showed infiltrative growth into the sinusoidal area at the tumor boundary, whereas Y-27632-treated tumors showed expansive growth and low invasiveness. These findings confirm the importance of the Rho/p160ROCK signaling pathway in intrahepatic metastasis of human HCC, and indicate that Y-27632 may be useful for the prevention of intrahepatic metastasis of human HCC.
Decision Analysis: Society and Individuals
Authors: Robert J. Yaes
Journal: JAMA (1991)

<h3>To the Editor.</h3> —In assuming that "society is nothing more than a collection of individuals,"<sup>1</sup>Eddy has misconstrued the conflict between individuals and society regarding new medical treatment modalities. Individual people live in societies because societies can provide services to them that they cannot provide for themselves. These services range from national defense to public sanitation. In order to provide these services, society has needs that are distinct from the needs of its individual members. Thus, society may need such things as MX missiles and sewage treatment plants, for which an individual would have little use. Medical care, of course, is one of the more important services that a society provides to its members. Eddy gets to the heart of the matter when he states, "there are no controlled clinical trials showing any benefit of high-dose chemotherapy with autologous bone marrow transplantation (HDC-ABMT)." He then goes on to<i>assume</i>
Angiotensinogen: a candidate gene involved in preeclampsia?
Authors: Reynir Arngrímsson, Smita Purandare, Michael Connor, James J Walker, Steingrímur Björnsson, Florent Soubrier, Yuri V. Kotelevtsev, Reynir T. Geirsson, Hölmgeir Björnsson
Journal: Nature Genetics (1993)
P1-12-07: Pharmacokinetics (PK) of Trastuzumab Emtansine and Paclitaxel or Docetaxel in Patients with HER2−Positive MBC Previously Treated with a Trastuzumab-Containing Regimen.
Authors: D Lu, S Modi, AD Elias, P Agarwal, J-H Yi, AE Guardino, BL Althaus, S Girish
Journal: Cancer Research (2011)

Abstract Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab, DM1 (a potent cytotoxic tubulin polymerization inhibitor), and the stable MCC linker. Based on in vitro and preclinical data suggesting synergy in tumor cell cytotoxicity with T-DM1 + taxanes, these combinations are being tested in phase Ib studies. The assessment of risk for PK-based drug interaction (PK-DI) with these combinations is important. T-DM1 is expected to undergo proteolytic degradation with no significant involvement of cytochrome P450 isoenzymes (CYPs), and DM1 is metabolized mainly by CYP3A4 (and to a lesser extent by CYP3A5). Paclitaxel (P) and docetaxel (D) are metabolized primarily by CYP2C8 and CYP3A4, respectively. None of these drugs inhibits or induces CYPs at clinically relevant concentrations. Since DM1 and D are both metabolized by CYP3A4, PK-DI may occur. This is less likely with DM1 and P since they are primarily metabolized by different CYPs. Methods: The tolerability, PK, and dose-limiting toxicities of T-DM1 + P or D were investigated in 2 studies (TDM4652g and BP22572) of patients with HER2−positive MBC previously treated with a trastuzumab-containing regimen. For PK-DI analysis, both studies used a staggered dosing design in the first cycle, with same-day dosing in subsequent cycles. Study BP22572 was later amended to give both drugs on the same day in all cycles. Either P (65 mg/m2, n=11; 80 mg/m2, n=6) or D (60 mg/m2, n=12; 75 mg/m2, n=6) was combined with T-DM1 at various doses (2 mg/kg or 2.4 mg/kg q3w or 1.2 mg/kg qw for TDM4652g; 2.4 mg/kg or 3.6 mg/kg q3w for BP22572). PK of T-DM1, total trastuzumab (conjugated + unconjugated trastuzumab), DM1, P, and D were evaluated and compared with historical singleagent data and across cycles within the study, using population analysis and/or noncompartmental analysis (NCA), as data allowed. Preliminary safety and efficacy data for the historical T-DM1 singleagent studies were reported previously (Krop JCO 2010; Burris JCO 2010; Krop ESMO 2010). Results: The PK of P and D were similar from cycle 1 to cycle 2 for maximum concentration (Cmax), area under the concentration-time curve, halflife, clearance (CL) and steady-state volume of distribution, and were also similar to historical single-agent data. The Cmax of DM1 was &amp;lt;8 ng/mL in both studies, and the average Cmax values were similar to historical single-agent data. T-DM1 PK parameters for the combination studies are within the range of historical single-agent data (Table). Data from additional patients and doses in the combination studies will be presented. Conclusion: The risk of clinically relevant PK-DI between T-DM1 and P or D appears to be low. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-07.
381 Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes in living cells
Authors: D MORADPOUR, M EVANS, R GOSERT, Z YUAN, H BLUM, S GOFF, B LINDENBACH, C RICE
Journal: Hepatology (2003)

Genotype 1a is a most prevalent genotype of hepatitis C virus in North America yet HCV replication has been studied predominantly with genotype 1b subgenomic replicons under neomycin selection in Huh-7 cells. Development of 1a-related dicistronic replicons under neo selection proved difficult and required either “conditioned” Huh-7 cells and/or chimeric genomes harboring pre-engineered adaptive mutations. We report the construction of a novel dicistronic genotype 1a(H77C) replicon expressing the puromycin N-acetyltransferase (PAC) gene as a selectable marker that, without prior introduction of adaptive mutations, allows establishment of puromycin-resistant Huh-7 colonies after transfection of naïve Huh-7 cells. The large majority of HCV1a/PAC replicons did not reveal any adaptive mutations on short-term passage of Huh-7 cells. Continued passage led to mutations in the non-structural genes although these mutations did not significantly enhance replication of the original replicon. Transfection with total cellular RNA isolated from HCV1a/PAC replicon-containing cells led to a significant increase in colony-forming ability. The data identify PAC as an efficient selectable marker for studies of HCV replication, which may be useful with different genotypes in different host cell systems.
Training the Internist
Authors: STANLEY SLATER
Journal: Annals of Internal Medicine (1979)

Letters1 September 1979Training the InternistSTANLEY SLATER, M.D.STANLEY SLATER, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-91-3-491_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Despite — perhaps because of— Dr. Barondess' eminent position in the American College of Physicians, his paper in the March issue (1) should not stand without comment. The summary suggests opposition to providing training time in office gynecology, orthopedics, and other fields above what is currently part of training programs. Yet, on p. 414, he indicates that such training must be included in the residency training of the internist. I am not sure everyone would agree that the diagnosis of vaginitis, and its treatment, is any simpler than that of pneumonia or other uncomplicated infections treated on...Reference1. BARONDESS J. The training of the internist: with some messages from practice. Ann Intern Med. 1979; 90:412-7. LinkGoogle Scholar1. BARONDESS J. The training of the internist: with some messages from practice. Ann Intern Med. 1979; 90:412-7. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: 130 Louise Drive; Newport News, VA 23601 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByEmc, a negative HLH regulator with multiple functions in Drosophila development 1 September 1979Volume 91, Issue 3Page: 491-491KeywordsOrthopedicsPneumoniaResidency Issue Published: 1 September 1979 PDF DownloadLoading ...
Effective Surgical Adjuvant Therapy for High-Risk Rectal Carcinoma
Authors: J E Krook, C G Moertel, L L Gunderson, H S Wieand, R T Collins, R W Beart, T P Kubista, M A Poon, W C Meyers, J A Mailliard
Journal: New England Journal of Medicine (1991)

Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone.Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU).After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups.The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.
Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy?
Authors: G KOJDA, R HAMBRECHT
Journal: Cardiovascular Research (2005)

A lack of exercise training and/or regular physical activity is a known risk factor for cardiovascular disease. Exercise training induces marked vascular remodeling by increasing angiogenesis and arteriogenesis. These changes in the architecture of the vascular tree are likely associated with functional changes and improved organ blood flow. Physical forces such as shear stress, transmural pressure and cyclic stretch activate mechanotransduction mechanisms in endothelial and smooth muscle cells that are mediated by integrins and associated RhoA small GTPase. They stimulate various signal transduction pathways involving phosphorylation of kinases such as focal adhesion kinase, c-Src, Akt kinase, phosphatidylinositol 3-kinase, myosin light chain kinase and mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinase (ERK). These mechanisms result in upregulation of genes mediating antiatherogenic effects by promoting antiapoptotic and antiproliferative signals, by increasing vascular NO bioavailability and by changing calcium handling and the vascular myogenic response to pressure. Exercise-induced increase of vascular eNOS expression and of eNOS Ser-1177 phosphorylation is most likely an important and potentially vasoprotective effect of exercise training. The underlying mechanisms involve cell membrane proteins such as integrins and products of vascular oxidative stress such as hydrogen peroxide. Exercise-induced eNOS expression is transient and reversible and regulated by factors such as angiogenesis, arteriogenesis and antioxidative effects including upregulation of superoxide dismutases (SOD1, SOD3) and downregulation of NAD(P)H oxidase, which likely blunts the effects of oxidative stress. Based on these observations, it appears reasonable to assume that exercise training can be viewed as an effective antioxidant and antiatherogenic therapy.
Estrogen Therapy in Postmenopausal Women
Authors: Kristine Yaffe, George Sawaya, Ivan Lieberburg, Deborah Grady
Journal: JAMA (1998)

Several studies have suggested that estrogen replacement therapy in postmenopausal women improves cognition, prevents development of dementia, and improves the severity of dementia, while other studies have not found a benefit of estrogen use.To determine whether postmenopausal estrogen therapy improves cognition, prevents development of dementia, or improves dementia severity.We performed a literature search of studies published from January 1966 through June 1997, using MEDLINE, manually searched bibliographies of articles identified, and consulted experts.Studies that evaluated biological mechanisms of estrogen's effect on the central nervous system and studies that addressed the effect of estrogen on cognitive function or on dementia.We reviewed studies for methods, sources of bias, and outcomes and performed a meta-analysis of the 10 studies of postmenopausal estrogen use and risk of dementia using standard meta-analytic methods.Biochemical and neurophysiologic studies suggest several mechanisms by which estrogen may affect cognition: promotion of cholinergic and serotonergic activity in specific brain regions, maintenance of neural circuitry, favorable lipoprotein alterations, and prevention of cerebral ischemia. Five observational studies and 8 trials have addressed the effect of estrogen on cognitive function in nondemented postmenopausal women. Cognition seems to improve in perimenopausal women, possibly because menopausal symptoms improve, but there is no clear benefit in asymptomatic women. Ten observational studies have measured the effect of postmenopausal estrogen use on risk of developing dementia. Meta-analysis of these studies suggests a 29% decreased risk of developing dementia among estrogen users, but the findings of the studies are heterogeneous. Four trials of estrogen therapy in women with Alzheimer disease have been conducted and have had primarily positive results, but most have been small, of short duration, non-randomized, and uncontrolled.There are plausible biological mechanisms by which estrogen might lead to improved cognition, reduced risk for dementia, or improvement in the severity of dementia. Studies conducted in women, however, have substantial methodologic problems and have produced conflicting results. Large placebo-controlled trials are required to address estrogen's role in prevention and treatment of Alzheimer disease and other dementias. Given the known risks of estrogen therapy, we do not recommend estrogen for the prevention or treatment of Alzheimer disease or other dementias until adequate trials have been completed.