tbuckley/cabot-search huggingface dataset:
A Gene Locus for Steroid-Resistant Nephrotic Syndrome with Deafness Maps to Chromosome 14q24.2
Authors: Rainer G Ruf, Matthias T F Wolf, Hans C Hennies, Barbara Lucke, Christina Zinn, Verena Varnholt, Anne Lichtenberger, Andreas Pasch, Anita Imm, Sonia Briese, Thomas Lennert, Arno Fuchshuber, Peter Nurnberg, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2003)

Steroid-resistant nephrotic syndrome (SRNS) leads to end-stage renal disease (ESRD) in childhood or young adulthood. Positional cloning for genes causing SRNS has opened the first insights into the understanding of its pathogenesis. This study reports a genome-wide search for linkage in a consanguineous Palestinian kindred with SRNS and deafness and detection of a region of homozygosity on chromosome 14q24.2. Multipoint analysis of 12 markers used for further fine mapping resulted in a LOD score Z(max) of 4.12 (theta = 0) for marker D14S1025 and a two-point LOD score of Z(max) = 3.46 (theta = 0) for marker D14S77. Lack of homozygosity defined D14S1065 and D14S273 as flanking markers to a 10.7 cM interval. The identification of the responsible gene will provide new insights into the molecular basis of nephrotic syndrome and sensorineural deafness.
<i>miR-146a</i> is a significant brake on autoimmunity, myeloproliferation, and cancer in mice
Authors: Mark P. Boldin, Konstantin D. Taganov, Dinesh S. Rao, Lili Yang, Jimmy L. Zhao, Manorama Kalwani, Yvette Garcia-Flores, Mui Luong, Asli Devrekanli, Jessica Xu, Guizhen Sun, Jia Tay, Peter S. Linsley, David Baltimore
Journal: The Journal of Experimental Medicine (2011)

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.
INFLUENCE OF DIETARY POTASSIUM AND SODIUM/POTASSIUM MOLAR RATIOS ON THE DEVELOPMENT OF SALT HYPERTENSION
Authors: Lewis K. Dahl, George Leitl, Martha Heine
Journal: The Journal of Experimental Medicine (1972)

Among genetically hypertension-prone rats, dietary sodium (chloride) was demonstrably hypertensinogenic and potassium (chloride) antihypertensinogenic. On diets containing the same NaCl but different KCl concentrations, mean blood pressure was greater in rats receiving less dietary potassium, i.e., diets with a higher Na/K molar ratio. On diets with different absolute concentrations of NaCl and KCl, but the same Na/K molar ratios, rats on the higher absolute NaCl intakes had the higher blood pressures. On diets with different absolute concentrations of NaCl and KCl, and different Na/K molar ratios, a group on a lower absolute NaCl intake but with a higher Na/K ratio could have more hypertension than a group on a higher absolute NaCl intake but with a lower Na/K ratio. At equivalent molar ratios, the respective effects of these two ions on blood pressure were dominated by that of sodium. It was concluded that the dietary Na/K molar ratio can be an important determinant for the severity, or even development, of salt-induced hypertension. The mechanism of the moderating effect of potassium on sodium-induced hypertension was unclear.
Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium
Authors: Amy Reynolds, Natalia Wharton, Alyson Parris, Esther Mitchell, Anastasia Sobolewski, Christy Kam, Loren Bigwood, Ahmed El Hadi, Andrea Münsterberg, Michael Lewis, Christopher Speakman, William Stebbings, Richard Wharton, Kevin Sargen, Richard Tighe, Crawford Jamieson, James Hernon, Sandeep Kapur, Naohide Oue, Wataru Yasui, Mark R Williams
Journal: Gut (2013)

<h3>Background</h3> A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. <h3>Objective</h3> To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. <h3>Design</h3> Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. <h3>Results</h3> Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. <h3>Conclusions</h3> Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population.
Microbial signatures in post-infectious irritable bowel syndrome – toward patient stratification for improved diagnostics and treatment
Authors: Jonna Jalanka, Anne Salonen, Susana Fuentes, Willem M de Vos
Journal: Gut Microbes (2015)

Irritable bowel syndrome (IBS) is a multifactorial and heterogeneous disorder estimated to affect over 10% of the Western population. A subset of the patients reports the start of the disease after an episode of gastroenteritis. The alterations in the intestinal microbiota of the post-infectious IBS (PI-IBS) patients were recently investigated in a British cohort and shown to differentiate from the healthy controls and resemble that of diarrhea-predominant IBS (IBS-D) patients. The altered 27 genus-like groups created a microbial signature, which could be used to objectively stratify patients and healthy controls. In this addendum, we combine the microbiota data derived from the British cohort with that of a recently reported Swedish PI-IBS cohort. Remarkably, robust and reproducible microbiota signatures were observed in these PI-IBS patients. We discuss these results with attention on the emerging role of microbiota in the classification, development and treatment of PI-IBS.
Phase II Trial of Autologous Tumor Vaccination, Anti-CD3-Activated Vaccine-Primed Lymphocytes, and Interleukin-2 in Stage IV Renal Cell Cancer
Authors: Alfred E. Chang, Qiao Li, Guihua Jiang, Donna M. Sayre, Thomas M. Braun, Bruce G. Redman
Journal: Journal of Clinical Oncology (2003)

Purpose: Previous preclinical and clinical studies have demonstrated that autologous tumor vaccines can induce relatively specific tumor-reactive T cells in draining lymph nodes. The adoptive transfer of these cells can result in tumor regression. Patients and Methods: Patients with stage IV renal cell cancer (RCC) were vaccinated with irradiated autologous tumor cells admixed with Calmette-Guérin bacillus. Approximately 7 days later, vaccine-primed lymph nodes (VPLNs) were harvested and the lymphoid cells secondarily activated with anti-CD3 monoclonal antibody and expanded in interleukin 2 (IL-2). The activated cells were subsequently infused intravenously along with the concomitant administration of bolus IL-2 (360,000 U/kg intravenously × 15 doses). Results: Thirty-nine patients were entered onto the study, of whom 34 completed an initial course of cell therapy consisting of a mean (SEM) number of 4.3 (2.2) × 10 10 VPLN cells. Among subjects who received cell therapy, there were nine responses (four complete responses [CRs] and five partial responses [PRs]), for an overall response rate of 27%. The durations of the CRs were &gt; 48, 45, &gt; 35, and 12 months, and the durations of the PRs were &gt; 63, 48, 15, 12, and 4 months. Cultured tumor cells were available to assess in vitro cytokine release of VPLN cells in 24 subjects. The median cytokine release ratio of interferon gamma (IFNγ) to IL-10 for responders and nonresponders was 992 and 5, respectively, which was significantly different (P = .047). Conclusion: The treatment protocol resulted in durable tumor responses in patients with advanced RCC. The ratio of IFNγ and IL-10 cytokines released in response to tumor by the VPLN cells was a significant correlate with tumor response.
Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis
Authors: Eric Yang, Adrienne Boire, Anika Agarwal, Nga Nguyen, Katie O'Callaghan, Powen Tu, Athan Kuliopulos, Lidija Covic
Journal: Cancer Research (2009)

Abstract Protease-activated receptor 1 (PAR1) is a G protein–coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide “pepducin,” P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer. [Cancer Res 2009;69(15):6223–31]
Prospective Long-Term Follow-Up of 44 Patients Who Received Cingulotomy for Treatment-Refractory Obsessive-Compulsive Disorder
Authors: Darin D. Dougherty, Lee Baer, G. Rees Cosgrove, Edwin H. Cassem, Bruce H. Price, Andrew A. Nierenberg, Michael A. Jenike, Scott L. Rauch
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Long-term outcome associated with cingulotomy for obsessive-compulsive disorder (OCD) was prospectively assessed. Findings are reported for 18 patients previously described in 1995 and for 26 new patients. METHOD: An open preoperative and follow-up assessment was conducted at multiple time points for 44 patients undergoing one or more cingulotomies for treatment-refractory OCD. The patients were assessed by using the Structured Clinical Interview for DSM-III-R preoperatively and with the Yale-Brown Obsessive Compulsive Scale, the Beck Depression Inventory, and the Sickness Impact Profile both preoperatively and at all follow-up assessments. The patients completed clinical global improvement scales at all follow-up assessments. RESULTS: At mean follow-up of 32 months after one or more cingulotomies, 14 patients (32%) met criteria for treatment response and six others (14%) were partial responders. Thus, 20 patients (45%) were at least partial responders at long-term follow-up after one or more cingulotomies. Few adverse effects were reported. CONCLUSIONS: Thirty-two percent to 45% of patients previously unresponsive to medication and behavioral treatments for OCD were at least partly improved after cingulotomy. Cingulotomy remains a viable treatment option for patients with severe treatment-refractory OCD.
The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses
Authors: Lifang Zhang, Jianhong Wu, Ming Tat Ling, Liang Zhao, Kong-Nan Zhao
Journal: Molecular Cancer (2015)

Infection with Human papillomaviruses (HPVs) leads to the development of a wide-range of cancers, accounting for 5% of all human cancers. A prominent example is cervical cancer, one of the leading causes of cancer death in women worldwide. It has been well established that tumor development and progression induced by HPV infection is driven by the sustained expression of two oncogenes E6 and E7. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways that may be equally important for transformation. Among these pathways, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling cascade plays a very important role in HPV-induced carcinogenesis by acting through multiple cellular and molecular events. In this review, we summarize the frequent amplification of PI3K/Akt/mTOR signals in HPV-induced cancers and discuss how HPV oncogenes E6/E7/E5 activate the PI3K/Akt/mTOR signalling pathway to modulate tumor initiation and progression and affect patient outcome. Improvement of our understanding of the mechanism by which the PI3K/Akt/mTOR signalling pathway contributes to the immortalization and carcinogenesis of HPV-transduced cells will assist in devising novel strategies for preventing and treating HPV-induced cancers.
Hemolysis of human erythrocytes is a new bioactivity of gangliosides.
Authors: K Horikawa, H Nakakuma, S Nagakura, M Kawakita, T Kagimoto, M Iwamori, Y Nagai, T Abe, K Takatsuki
Journal: The Journal of Experimental Medicine (1991)

Using sheep erythrocytes and liposomes, an inhibitory effect of gangliosides has been shown on the activation of the alternative pathway of complement. However, in studies using human erythrocytes, we found that gangliosides had hemolytic activity that was possibly mediated through activation of the alternative pathway. Pretreatment of human erythrocytes obtained from healthy volunteers or paroxysmal nocturnal hemoglobinuria (PNH) patients with a ganglioside mixture purified from human erythrocytes enhanced their susceptibility to homologous human complement, and resulted in dose-dependent hemolysis. The enhancement was more marked in PNH erythrocytes than control cells. Protease treatment of the ganglioside mixture did not change its hemolytic activity, but sialidase treatment abolished the activity. Among the major erythrocyte gangliosides, II3NeuAc-LacCer (GM3) was the most potent hemolytic agent. Gangliosides purified from bovine brain were also active, while neither nonsialylated glycosphingolipids, the ceramide moiety, or sialic acid alone were active. Sialic acid residues in the ganglioside molecules were essential to this activity, but the amount of the residue or the source of the gangliosides seemed not to be important. Several treatments inhibiting the alternative but not classical complement pathway markedly reduced the ganglioside hemolytic activity. This novel bioactivity of gangliosides was thus suggested to be mediated partly by activation of the alternative pathway.
Predictors of Early Discontinuation of Dual-Antiplatelet Therapy: Room for Improvement
Authors: Jennifer L. Jarvie, JoAnne M. Foody
Journal: Circulation (2010)

D rug-eluting stents (DES) have revolutionized the ap- proach to percutaneous coronary interventions and have substantially reduced restenosis compared with bare metal stents. 1,2Despite their advantages, DES are not without disadvantages.In particular, patients who receive DES remain at risk of a 1% to 2% incidence of stent thrombosis, which is often fatal. 3,4Dual-antiplatelet therapy (DAT) in the form of a thienopyridine and aspirin improves outcomes in patients who receive DES, 3,5 and early termination of DAT is associated with worse outcomes. 6Consequently, recommendations for the sirolimus-eluting stent and the paclitaxeleluting stent include a minimum of 12 months of uninterrupted thienopyridine therapy, while maintaining long-term aspirin therapy for the patients' underlying coronary disease. 7s such, early discontinuation of a thienopyridine should only be considered if bleeding risk substantially outweighs thrombotic risk or considered temporarily if a major invasive procedure is necessary.
Sick and Obstetric Nurses Bill
Authors: Alex. M. Weir
Journal: BMJ (1898)

Audi alteram partem."To the Editor. of THE LANOHT.SIRS,&mdash;I feel I am asking a great favour to be allowed to add a few words to the leading article on the above subject in your last issue, but our case is urgent, and therefore beg to be allowed to point out its urgency.Everybody must agree that the two classes needing representation are the dentists and the general practitioners, but I venture to think the former have the greater claim, and for the following reasons.
An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial
Authors: Irene J Higginson, Claudia Bausewein, Charles C Reilly, Wei Gao, Marjolein Gysels, Mendwas Dzingina, Paul McCrone, Sara Booth, Caroline J Jolley, John Moxham
Journal: The Lancet Respiratory Medicine (2014)

Background Breathlessness is a common and distressing symptom, which increases in many diseases as they progress and is diffi cult to manage.We assessed the eff ectiveness of early palliative care integrated with respiratory services for patients with advanced disease and refractory breathlessness.Methods In this single-blind randomised trial, we enrolled consecutive adults with refractory breathlessness and advanced disease from three large teaching hospitals and via general practitioners in South London.We randomly allocated (1:1) patients to receive either a breathlessness support service or usual care.Randomisation was computer generated centrally by the independent Clinical Trials Unit in a 1:1 ratio, by minimisation to balance four potential confounders: cancer versus non-cancer, breathlessness severity, presence of an informal caregiver, and ethnicity.The breathlessness support service was a short-term, single point of access service integrating palliative care, respiratory medicine, physiotherapy, and occupational therapy.Research interviewers were masked as to which patients were in the treatment group.Our primary outcome was patient-reported breathlessness mastery, a quality of life domain in the Chronic Respiratory Disease Questionnaire, at 6 weeks.All analyses were by intention to treat.Survival was a safety endpoint.This trial is registered with ClinicalTrials.gov,number NCT01165034. FindingsBetween Oct 22, 2010 and Sept 28, 2012, 105 consenting patients were randomly assigned (53 to breathlessness support service and 52 to usual care).83 of 105 (78%) patients completed the assessment at week 6.Mastery in the breathlessness support service group improved compared with the control (mean diff erence 0•58, 95% CI 0•01-1•15, p=0•048; eff ect size 0•44).Sensitivity analysis found similar results.Survival rate from randomisation to 6 months was better in the breathlessness support service group than in the control group (50 of 53 [94%] vs 39 of 52 [75%]) and in overall survival (generalised Wilcoxon 3•90, p=0•048).Survival diff erences were signifi cant for patients with chronic obstructive pulmonary disease and interstitial lung disease but not cancer.Interpretation The breathlessness support service improved breathlessness mastery.Our fi ndings provide robust evidence to support the early integration of palliative care for patients with diseases other than cancer and breathlessness as well as those with cancer.The improvement in survival requires further investigation.
Cancer-Associated Loss-of-Function Mutations Implicate DAPK3 as a Tumor-Suppressing Kinase
Authors: John Brognard, You-Wei Zhang, Lorena A. Puto, Tony Hunter
Journal: Cancer Research (2011)

Abstract Cancer kinome sequencing studies have identified several protein kinases predicted to possess driver (i.e., causal) mutations. Using bioinformatic applications, we have pinpointed DAPK3 (ZIPK) as a novel cancer-associated kinase with functional mutations. Evaluation of nonsynonymous point mutations, discovered in DAPK3 in various tumors (T112M, D161N, and P216S), reveals that all three mutations decrease or abolish kinase activity. Furthermore, phenotypic assays indicate that the three mutations observed in cancer abrogate the function of the kinase to regulate both the cell cycle and cell survival. Coexpression of wild-type (WT) and cancer mutant kinases shows that the cancer mutants dominantly inhibit the function of the WT kinase. Reconstitution of a non–small cell lung cancer cell line that harbors an endogenous mutation in DAPK3 (P216S) with WT DAPK3 resulted in decreased cellular aggregation and increased sensitivity to chemotherapy. Our results suggest that DAPK3 is a tumor suppressor in which loss-of-function mutations promote increased cell survival, proliferation, cellular aggregation, and increased resistance to chemotherapy. Cancer Res; 71(8); 3152–61. ©2011 AACR.
Suppressors of Cytokine Signaling Regulate Angiotensin II-Activated Janus Kinase-Signal Transducers and Activators of Transcription Pathway in Renal Cells
Authors: Purificación Hernández-Vargas, Oscar López-Franco, Guillermo Sanjuán, Mónica Rupérez, Guadalupe Ortiz-Muñoz, Yusuke Suzuki, Pablo Aguado-Roncero, Gloria Pérez-Tejerizo, Julia Blanco, Jesús Egido, Marta Ruiz-Ortega, Carmen Gómez-Guerrero
Journal: Journal of the American Society of Nephrology (2005)

Suppressors of cytokine signaling (SOCS) family is constituted by cytokine-inducible proteins that modulate receptor signal transduction via tyrosine kinases, mainly the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Differential SOCS expression was noted in renal cells that were incubated with inflammatory stimuli, but the role of SOCS in the pathogenesis of renal diseases is not yet well defined. Because angiotensin II (Ang II) plays a key role in renal disease, SOCS proteins were studied as a novel mechanism involved in the negative regulation of Ang II-mediated processes. Systemic Ang II infusion for 3 d increased the renal mRNA expression of SOCS-3 and SOCS-1. SOCS protein synthesis was found in glomerular mesangial area and tubules. In cultured mesangial cells and tubular epithelial cells, Ang II induced a rapid and transient SOCS-3 and SOCS-1 expression in parallel with JAK2 and STAT1 activation. In both cell types, overexpression of SOCS proteins prevented the STAT activation in response to Ang II. SOCS expression observed in Ang II-infused rats and in Ang II-stimulated cells was significantly inhibited by treatment with AT1 but not AT2 receptor antagonist and was attenuated in mesangial cells from AT1a-deficient mice, demonstrating the implication of AT1 in those responses. In SOCS-3 knockdown studies, antisense oligonucleotides inhibited the expression of SOCS-3 and increased the Ang II-induced STAT activation and c-Fos/c-Jun expression, then resulting in a more severe renal damage. These results suggest that SOCS proteins may act as negative regulators of Ang II signaling in renal cells and implicate SOCS as important modulators of renal damage.