tbuckley/cabot-search huggingface dataset:
Tuning mTOR activity for immune balance
Authors: Kai Yang, Hongbo Chi
Journal: Journal of Clinical Investigation (2013)

The mTOR pathway orchestrates diverse physiological processes, including T cell functions and fate decisions; however, the regulation of mTOR-dependent T cell differentiation remains elusive. In this issue, Park et al. examine the role of TSC1, an mTOR signaling regulator, in T cell differentiation and the balance between T cell–mediated immunity and tolerance. They found that enhanced mTOR activity in Tsc1-deficient T cells promotes Th1 and Th17 differentiation, leading to increased intestinal inflammation in murine colitis. Tsc1-deficient Tregs had impaired suppressive activity in inflammatory conditions. These defects were associated with the acquisition of effector-like phenotypes and could be further exacerbated by concomitant loss of transcription factor Foxo3. This study highlights that TSC1-mediated control of mTOR activity impinges on the balance between immunity and tolerance by dictating effector and regulatory T cell responses.
ISOLATION OF NEW LYMPHOTROPIC RETROVIRUS FROM TWO SIBLINGS WITH HAEMOPHILIA B, ONE WITH AIDS
Authors: E. Vilmer, C. Rouzioux, F. Vezinet Brun, A. Fischer, J.C. Chermann, F. Barre-Sinoussi, C. Gazengel, C. Dauguet, P. Manigne, C. Griscelli, L. Montagnier
Journal: The Lancet (1984)
Compartmentation of G Protein-Coupled Signaling Pathways in Cardiac Myocytes
Authors: Susan F Steinberg, Laurence L Brunton
Journal: The Annual Review of Pharmacology and Toxicology (2001)

There is a large body of functional data that supports the existence of subcellular compartmentation of the components of cyclic AMP action in the heart. Data from isolated perfused hearts and from purified ventricular myocytes imply a fixed and hormone-specific spatial relationship amongst components of cyclic AMP synthesis, response, and degradation. Available data demonstrate that within a cardiac myocyte, not all cyclic AMP gains access to all cyclic AMP-dependent protein kinase (PKA), that not all PKA interacts with all possible cellular substrates of PKA, and that only a subset of the myocyte's phosphodiesterases (PDEs) may degrade cyclic AMP after a given synthetic stimulus. Molecular mechanisms contributing to compartmentation are being discovered: localization of receptors, G proteins, and adenylyl cyclases in caveolar versus noncaveolar regions of the sarcolemma; localization of PKA by A-kinase anchoring proteins; localization of PKA substrates, PDE isoforms, and phosphoprotein phosphatases in discrete subcellular regions; and differential regulation of multiple isoforms of adenylyl cyclase, phosphoprotein phosphatase, and PDE in distinct subcellular compartments.
ON THE TREATMENT OF PNEUMONIA: A Series of 67 Cases with 2 Deaths
Authors: D. E. Dickson
Journal: BMJ (1918)

IMUDIOAL JOUUA& 427Influence on Streptococcal Infection.It was generally noticed during the period in which the Leclainclhe and VallWe serum was given preventively thlat, except in gas gangrene, the cases seemed to run a straiglhtforward course, witlhout severe streptococcal infections, and thiat secondary operations on this score were infrequent.Among 15 cases of streptococcal septicaemia which occurred in patients admitted during this period, only four had received preventive doses of Leclainclhe and Vallhe serum.Seven patients who had all been treated with fairly large doses of Leclainche and Vallee serum recovered. CLASS III.Believing that the Leclainclie and Vallee serumn mialgt bave an inhibiting action on the streptococcus, in a tlhird series of cases (57, witlh 36 fractures) 10 c.cm. of Leclainche and Vall4e serum were added to the initial dose of 30 acm. of mdlange serum.Although in ten of these cases gangrene was already present in the form of cellulitis or abscess, in only one did massive gas gangrene develop-namely, after ligature of the external.iliacartery, fifteen days after the preventive dose of nmlange had been given.CASE XI.J. was wounded on September 2nd, at 4 p.m., a bullet per- forating the left thigh and pubic ramus, fracturing the femur and pelvis, and reaching the pelvic peritoneal cavity.At 9 p.m. on September 3rd the bullet was removed by laparotomy, the pelvis drained, and the thigh wound excised
Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235
Authors: Pieter J.A. Eichhorn, Magüi Gili, Maurizio Scaltriti, Violeta Serra, Marta Guzman, Wouter Nijkamp, Roderick L. Beijersbergen, Vanesa Valero, Joan Seoane, René Bernards, José Baselga
Journal: Cancer Research (2008)

Abstract Small molecule inhibitors of HER2 are clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, we performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumor suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we show that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that phosphatidylinositol 3-kinase (PI3K)–induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance, which can be effectively reversed by NVP-BEZ235. [Cancer Res 2008;68(22):9221–30]
Nitric Oxide Synthase Isoforms and Glomerular Hyperfiltration in Early Diabetic Nephropathy
Authors: ROLAND VEELKEN, KARL F. HILGERS, ANDREA HARTNER, ALEXANDER HAAS, KIRSTEN P. BO[Combining Diaeresis]HMER, R. BERND STERZEL
Journal: Journal of the American Society of Nephrology (2000)

Abstract. This study tested the hypothesis that nitric oxide (NO)-mediated renal vasodilation due to the activity of the inducible nitric oxide synthase (iNOS) contributes to glomerular hyperfiltration in diabetic rats. Two weeks after induction of diabetes mellitus by streptozotocin, mean arterial BP (MAP), GFR (inulin clearance), and renal plasma flow (RPF) (para-aminohippurate clearance) were measured in conscious instrumented rats. Diabetic rats had elevated GFR (3129 ± 309 μl/min versus 2297 ± 264 μl/min in untreated control rats, P &lt; 0.05) and RPF (10526 ± 679 μl/min versus 8005 ± 534 μl/min), which was prevented by chronic insulin treatment. Intravenous administration of 0.1 and 1 mg of L-imino-ethyl-lysine (L-NIL), an inhibitor of iNOS, did not affect MAP, GFR, or RPF, either in diabetic or control rats. A higher L-NIL dose (10 mg) increased MAP and decreased RPF in diabetic rats significantly ( n = 6, P &lt; 0.05), but not in controls ( n = 6). In addition, 0.1 mg of N G -nitro-L-arginine methyl ester (L-NAME), a nonselective blocker of NOS isoforms, decreased GFR (2389 ± 478 μl/min) and RPF (7691 ± 402 μl/min) in diabetic animals to control levels, while renal hemodynamics in normoglycemic rats were not altered. Higher L-NAME doses (1 and 10 mg) reduced GFR and RPF in diabetic and control rats to identical levels. In glomeruli isolated from diabetic and control rats, neither iNOS mRNA nor iNOS protein expression was detected. In contrast, increased protein levels of endothelial constitutive NOS (ecNOS) were found in glomeruli of diabetic rats compared with controls. By immunohistochemistry, ecNOS but not iNOS staining was observed in the endothelium of preglomerular vessels and in diabetic glomeruli. These results support the notion that increased NO availability due to greater abundance of ecNOS contributes to the pathogenesis of glomerular hyperfiltration in early experimental diabetic nephropathy. In contrast, we found no functional or molecular evidence for increased glomerular expression and activity of iNOS in diabetic rats.
PKC412 normalizes mutation‐related keratin filament disruption and hepatic injury in mice by promoting keratin–myosin binding
Authors: Raymond Kwan, Lu Chen, Koksun Looi, Guo‐Zhong Tao, Sujith V. Weerasinghe, Natasha T. Snider, Mary Anne Conti, Robert S. Adelstein, Qing Xie, M. Bishr Omary
Journal: Hepatology (2015)

Keratins, among other cytoskeletal intermediate filament proteins, are mutated at a highly conserved arginine with consequent severe disease phenotypes due to disruption of keratin filament organization. We screened a kinase inhibitor library, using A549 cells that are transduced with a lentivirus keratin 18 (K18) construct, to identify compounds that normalize filament disruption due to K18 Arg90Cys mutation at the conserved arginine. High-throughput screening showed that PKC412, a multikinase inhibitor, ameliorated K18 Arg90Cys-mediated keratin filament disruption in cells and in the livers of previously described transgenic mice that overexpress K18 Arg90Cys. Furthermore, PKC412 protected cultured A549 cells that express mutant or wild-type K18 and mouse livers of the K18 Arg90Cys-overexpressing transgenic mice from Fas-induced apoptosis. Proteomic analysis of proteins that associated with keratins after exposure of K18-expressing A549 cells to PKC412 showed that nonmuscle myosin heavy chain-IIA (NMHC-IIA) partitions with the keratin fraction. The nonmuscle myosin-IIA (NM-IIA) association with keratins was confirmed by immune staining and by coimmunoprecipitation. The keratin-myosin association is myosin dephosphorylation-dependent; occurs with K8, the obligate K18 partner; is enhanced by PKC412 in cells and mouse liver; and is blocked by hyperphosphorylation conditions in cultured cells and mouse liver. Furthermore, NMHC-IIA knockdown inhibits PKC412-mediated normalization of K18 R90C filaments.The inhibitor PKC412 normalizes K18 Arg90Cys mutation-induced filament disruption and disorganization by enhancing keratin association with NM-IIA in a myosin dephosphorylation-regulated manner. Targeting of intermediate filament disorganization by compounds that alter keratin interaction with their associated proteins offers a potential novel therapeutic approach for keratin and possibly other intermediate filament protein-associated diseases.
Is initially metastatic breast carcinoma different from recurrent metastatic breast carcinoma?
Authors: O. Dizdar, S. Aksoy, K. Altundag
Journal: Annals of Oncology (2008)

We read with great interest the article by Largillier et al. [1.Largillier R. Ferrero J.M. Doyen J. Prognostic factors in 1038 women with metastatic breast cancer.Ann Oncol. 2008; 19: 2012-2019Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar] in which they analyzed prognostic factors in 1038 women with metastatic breast cancer. They did not show the importance of metastasis-free interval as a prognostic factor predicting survival from time of metastatic occurrence in their studies on contrary to other studies stating that early recurrence is an independent predictor of survival [2.Chang J. Clark G.M. Allred D.C. et al.Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor.Cancer. 2003; 97: 545-553Crossref PubMed Scopus (231) Google Scholar, 3.Insa A. Lluch A. Prosper F. et al.Prognostic factors predicting survival from first recurrence in patients with metastatic breast cancer: analysis of 439 patients.Breast Cancer Res Treat. 1999; 56: 67-78Crossref PubMed Scopus (151) Google Scholar, 4.Vogel C.L. Azevedo S. Hilsenbeck S. et al.Survival after first recurrence of breast cancer. The Miami experience.Cancer. 1992; 70: 129-135Crossref PubMed Scopus (77) Google Scholar]. There are two groups of metastatic breast cancer patients as recurrent metastatic breast carcinoma and initially metastatic breast carcinoma. Studies showed that initially metastatic breast carcinoma has an equivalent outcome in term of overall survival compared with recurrent metastatic breast carcinoma [5.Jimeno A. Amador M.L. González-Cortijo L. et al.Initially metastatic breast carcinoma has a distinct disease pattern but an equivalent outcome compared with recurrent metastatic breast carcinoma.Cancer. 2004; 100: 1833-1842Crossref PubMed Scopus (18) Google Scholar, 6.Saydam B.K. Goksel G. Korkmaz E. et al.Comparison of the clinical and pathological features between patients with recurrent metastatic breast carcinoma and patients with initially metastatic breast carcinoma.Saudi Med J. 2008; 29: 81-86PubMed Google Scholar]. Since patients with initially metastatic breast carcinoma are chemo- and hormone-naive patients, they are expected to respond to treatment more effectively than patients with recurrent breast cancer. Therefore, survival from time of metastatic occurrence should be better in initially metastatic breast carcinoma. Although definition and inclusion of these patients were not described in detail in Largillier et al. [1.Largillier R. Ferrero J.M. Doyen J. Prognostic factors in 1038 women with metastatic breast cancer.Ann Oncol. 2008; 19: 2012-2019Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar] study, these group of patients may affect the prediction of metastases-free interval as a significant prognostic factor if they were included into patient groups who have metastases-free interval <24 months.
Antitumor Activity of Human Papillomavirus Type 16 E7–Specific T Cells against Virally Infected Squamous Cell Carcinoma of the Head and Neck
Authors: Andreas Albers, Koji Abe, Jennifer Hunt, Jun Wang, Andres Lopez-Albaitero, Carsten Schaefer, William Gooding, Theresa L. Whiteside, Soldano Ferrone, Albert DeLeo, Robert L. Ferris
Journal: Cancer Research (2005)

Abstract Human papillomavirus (HPV)–associated squamous cell carcinoma of the head and neck (SCCHN) seems to be a suitable target for cancer vaccination. HPV-encoded oncogenic proteins, such as E7, are promising tumor-specific antigens and are obligatory for tumor growth. Because few immunologic studies have analyzed the endogenous HPV-specific immune response in this subset of SCCHN patients, we studied T-cell frequencies against HPV-16 E711-20 or E786-93 in tumor-bearing, human leukocyte antigen (HLA)-A*0201+ SCCHN patients, whose tumors were either HPV-16+ or HPV-16−. In HPV-16+ SCCHN patients, frequencies of T cells against either peptide were significantly elevated (P &amp;lt; 0.005) compared with HPV-16− patients or healthy volunteers. Tetramer+ T cells showed evidence of terminally differentiated phenotype (CD45RA+CCR7−) and an elevated level of CD107a staining for degranulation. Despite detectable expression of the restricting HLA class I allele, HLA-A*0201-E711-20– or HLA-A*0201-E786-93–specific CTL obtained by in vitro stimulation of healthy donor peripheral blood mononuclear cells only recognize a naturally HPV-16-transformed, HLA-A*0201+ SCCHN cell line after pretreatment with IFN-γ. This cell line had little or no expression of LMP2, TAP1, and tapasin, critical components of the HLA class I antigen-processing machinery, which were up-regulated by IFN-γ treatment. Immunohistochemistry of HPV-16+ SCCHN tumors showed that these antigen-processing machinery components are down-regulated in tumors in vivo compared with adjacent normal squamous epithelium. Thus, immunity to HPV-16 E7 is associated with the presence of HPV-16 infection and presentation of E7-derived peptides on SCCHN cells, which show evidence of immune escape. These findings support further development of E7-specific immunotherapy and strategies for up-regulation of antigen-processing machinery components in HPV-associated SCCHN.
Intrarenal renin-angiotensin-sodium interdependent mechanism controlling postclamp renal artery pressure and renin release in the conscious dog with chronic one-kidney Goldblatt hypertension.
Authors: C R Ayers, R E Katholi, E D Vaughan, R M Carey, H M Kimbrough, M R Yancey, C L Morton
Journal: Circulation Research (1977)

We studied postclamp renal artery pressure and renin release in eight conscious dogs with one-kidney Goldblatt hypertension. On normal sodium intake, intrarenal blockade of angiotensin II with Sar1-Ala8-angiotension II (P-113, saralasin acetate) markedly decreased postclamp renal artery pressure and increased renin release during the first 5 days after renal artery constriction. We found that 10-14 days after renal artery constriction, the maintenance of postclamp renal artery pressure and negative feedback on renin release became markedly less dependent on angiotensin II, as shown by almost no change in postclamp renal pressure or renin release with intrarenal blockade of angiotensin II. At this stage of our study the dogs were given a sodium diet of less than 5 mEq/day and we found that within 5-10 days intrarenal blockade of angiotensin II once again markedly decreased postclamp renal artery pressure and increased renin release. These observations support the concept of an angiotensin II-sodium interdependent negative feedback mechanism for renin release.
Skeletal muscle metabolites and fibre types in patients with advanced chronic obstructive pulmonary disease (COPD), with and without chronic respiratory failure
Authors: P Jakobsson, L Jorfeldt, A Brundin
Journal: European Respiratory Journal (1990)

Eighteen patients with advanced COPD, 8 with chronic respiratory failure (RF) and 10 without (nonRF, NRF) were investigated using spirometry, arterial blood gas analysis and biopsies taken from the quadriceps femorls muscle. The biopsies were analysed for ATP, creatine phosphate (CrP), creatine (Cr), lactate and glycogen content. Muscle fibre composition was also studied. Low concentrations of ATP, glycogen and CrP were found in the RF patients. Significant correlations were found between muscle metabolites and arterial blood gas values with the strongest correlation between muscle glycogen and arterial PO2 (r = 0.70; p less than 0.001). A very low percentage of "oxidative" type I muscle fibres was found in both groups. Possible mechanisms causing depletion of muscle metabolites are discussed.
A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the <i>KCNJ2</i> Gene
Authors: Silvia G. Priori, Sandeep V. Pandit, Ilaria Rivolta, Omer Berenfeld, Elena Ronchetti, Amit Dhamoon, Carlo Napolitano, Justus Anumonwo, Marina Raffaele di Barletta, Smitha Gudapakkam, Giuliano Bosi, Marco Stramba-Badiale, José Jalife
Journal: Circulation Research (2005)

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG ( I Kr ) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 ( I Ks ) channel. Here we identify a new variant, “SQT3”, which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 ( I K1 ) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I K1 than the wild-type ( P &lt;0.05) at potentials between −75 mV and −45 mV, with the peak current being shifted in the former with respect to the latter (WT, −75 mV; D172N, −65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I K1 greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients’ consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.
The effect of visible light and near-infrared radiation on constitutive pigment of patients with vitiligo
Authors: I. Seo, A. Baqer, N. Kollias
Journal: British Journal of Dermatology (2010)

Journal Article The effect of visible light and near‐infrared radiation on constitutive pigment of patients with vitiligo Get access I. Seo, I. Seo Models and Methods Department, Johnson and Johnson Consumer Companies, Skillman, NJ 08558‐9418, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar A. Baqer, A. Baqer Department of Dermatology, Al‐Sabah Hospital, Ministry of Public Health, Kuwait Search for other works by this author on: Oxford Academic Google Scholar N. Kollias N. Kollias Models and Methods Department, Johnson and Johnson Consumer Companies, Skillman, NJ 08558‐9418, U.S.A. Nikiforos Kollias. E‐mail: NKollia@its.jnj.com Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 163, Issue 1, 1 July 2010, Pages 211–213, https://doi.org/10.1111/j.1365-2133.2010.09761.x Published: 01 July 2010
Intraphylum Diversity and Complex Evolution of Cyanobacterial Aminoacyl-tRNA Synthetases
Authors: Ignacio Luque, María Loreto Riera-Alberola, Alfonso Andújar, Jesús A G Ochoa de Alda
Journal: Molecular Biology and Evolution (2008)

A comparative genomic analysis of 35 cyanobacterial strains has revealed that the gene complement of aminoacyl-tRNA synthetases (AARSs) and routes for aminoacyl-tRNA synthesis may differ among the species of this phylum. Several genes encoding AARS paralogues were identified in some genomes. In-depth phylogenetic analysis was done for each of these proteins to gain insight into their evolutionary history. GluRS, HisRS, ArgRS, ThrRS, CysRS, and Glu-Q-RS showed evidence of a complex evolutionary course as indicated by a number of inconsistencies with our reference tree for cyanobacterial phylogeny. In addition to sequence data, support for evolutionary hypotheses involving horizontal gene transfer or gene duplication events was obtained from other observations including biased sequence conservation, the presence of indels (insertions or deletions), or vestigial traces of ancestral redundant genes. We present evidences for a novel protein domain with two putative transmembrane helices recruited independently by distinct AARS in particular cyanobacteria.