tbuckley/cabot-search huggingface dataset:
Role of Podocyte B7-1 in Diabetic Nephropathy
Authors: Paolo Fiorina, Andrea Vergani, Roberto Bassi, Monika A. Niewczas, Mehmet M. Altintas, Marcus G. Pezzolesi, Francesca D’Addio, Melissa Chin, Sara Tezza, Moufida Ben Nasr, Deborah Mattinzoli, Masami Ikehata, Domenico Corradi, Valerie Schumacher, Lisa Buvall, Chih-Chuan Yu, Jer-Ming Chang, Stefano La Rosa, Giovanna Finzi, Anna Solini, Flavio Vincenti, Maria Pia Rastaldi, Jochen Reiser, Andrzej S. Krolewski, Peter H. Mundel, Mohamed H. Sayegh
Journal: Journal of the American Society of Nephrology (2014)

Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase–dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy.
Involved-Field Radiation Therapy for Inoperable Non–Small-Cell Lung Cancer
Authors: Kenneth E. Rosenzweig, Sonal Sura, Andrew Jackson, Ellen Yorke
Journal: Journal of Clinical Oncology (2007)

Dose escalation has been shown to improve local control in non-small-cell lung cancer (NSCLC) treated with definitive radiation therapy, but with increased complications. We implemented the use of involved-field radiotherapy (IFRT) in an effort to reduce toxicity while treating the gross tumor to higher doses. This analysis reports failure rates in uninvolved nodal regions with the use of IFRT.A total of 524 patients with NSCLC treated with three-dimensional conformal radiotherapy at Memorial Sloan-Kettering Cancer Center between 1991 and 2005 were reviewed. Only lymph node regions initially involved with tumor by either biopsy or radiographic criteria were included in the clinical target volume. Elective nodal failure (ENF) was defined as a recurrence in an initially uninvolved lymph node in the absence of local failure.Only 32 patients (6.1%) with ENF were identified. The 2-year actuarial rates of elective nodal control and primary tumor control were 92.4% and 51%, respectively, with a median follow-up of 41 months in survivors. In patients who achieved local disease control, the 2-year elective nodal control rate was 91%. The median time to ENF was 6 months (range, 0 to 56 months). Many patients experienced treatment failure in multiple lymph node regions simultaneously.The use of IFRT did not cause a significant amount of failure in lymph node regions not included in the tumor volume. Therefore, IFRT remains an acceptable method of treatment that allows for dose escalation while minimizing toxicity.
Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation
Authors: O M Sieber
Journal: Gut (2006)

Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5', 3', and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein.We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5' Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes ("third hits") in some polyps. We found that the "third hit" probably initiated tumorigenesis. Somatic mutation spectra were similar in 5' and 3' mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, "third hits" were more common. Most "third hits" left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele.We propose that mutations, such as nt4661insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need "three hits" however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele.
Acute Lung Changes in Rheumatoid Arthritis
Authors: E. R. Beck, B. I. Hoffbrand
Journal: Annals of the Rheumatic Diseases (1966)

Much has been written about the'controversial subject of respiratory system involvement in rheuma- toid arthritis since the paper of Eliman and Ball (1948).It is now generally accepted that certain respiratory conditions, although more or less un- common, are true manifestations of rheumatoid disease.These are rheumatoid nodules occurring in pleura and lungs (Robertson and Brinkman, 1961) and nodular fibrosis associated with co-existing pneumoconiosis (Caplan 1953, 1959); also pleurisy and pleural effusions (Horler and Thomson, 1959; Ward, 1961) and diffuse interstitial pulmonary fibrosis (Lee and Brain, 1962; Brannan, Good, Divertie, and Baggenstoss, 1964) may occur in rheumatoid disease without any other aetiology.Although mention is made in the last two papers of acute pneumonia-like illnesses at the onset or during exacerbations of the chronic pulmonary disease, little attention has been paid to acute lung changes in rheumatoid arthritis.In patients with rheumatoid arthritis there are obvious difficulties in excluding associated or purely coincidental causes of acute pulmonary lesions and in attributing such changes to the rheumatoid process itself.We report here three cases of rheumatoid arthritis with acute lung lesions believed to be manifestations of rheumatoid disease as they occurred in association with the recognized rheumatoid phenomena of pleurisy and pericarditis (Tarpley, 1961; Wilkinson, 1962).The diagnostic criteria for rheumatoid arthritis are those of the American Rheumatism Association (Ropes, Bennett, Cobb, Jacox, and Jessar, 1959).Case Reports Case 1, a 46-year-old waitress, presented in 1959 with a history of precordial pain, anorexia, night sweats, and breathlessness on climbing stairs for one week, without cough or sputum.She gave a history of rheumatoid arthritis affecting the hands, elbows, wrists, knees, and shoulders since her late teens, for which she took aspirin.
Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer
Authors: Judy A King, Fang Tan, Flaubert Mbeunkui, Zachariah Chambers, Sarah Cantrell, Hairu Chen, Diego Alvarez, Lalita A Shevde, Solomon F Ofori-Acquah
Journal: Molecular Cancer (2010)

Abstract Background Activated leukocyte cell adhesion molecule (ALCAM) is implicated in the prognosis of multiple cancers with low level expression associated with metastasis and early death in breast cancer. Despite this significance, mechanisms that regulate ALCAM gene expression and ALCAM's role in adhesion of pre-metastatic circulating tumor cells have not been defined. We studied ALCAM expression in 20 tumor cell lines by real-time PCR, western blot and immunochemistry. Epigenetic alterations of the ALCAM promoter were assessed using methylation-specific PCR and bisulfite sequencing. ALCAM's role in adhesion of tumor cells to the vascular wall was studied in isolated perfused lungs. Results A common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiple cis -active elements including a functional p65 NF-κB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters. Conclusion Our data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer.
Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation
Authors: Marc-Werner Dobenecker, Jong Kyong Kim, Jonas Marcello, Terry C. Fang, Rab Prinjha, Remy Bosselut, Alexander Tarakhovsky
Journal: The Journal of Experimental Medicine (2015)

The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment.
A pair of memorable patients
Authors: Ben Challacombe
Journal: BMJ (2008)

In my time spent with the renal transplant team I have seen many examples of the immense kindness one person can show to another, but our unit recently performed a live, unrelated transplant that was particularly memorable. The kidney donor and recipient were great friends who had played jazz together for many years. I was involved in the hand-assisted laparoscopic donor nephrectomy, which proceeded without complication under consultant supervision. 

A couple of days later …
Diabetes Mellitus and Risk of Colorectal Cancer in the Singapore Chinese Health Study
Authors: Adeline Seow, Jian-Min Yuan, Woon-Puay Koh, Hin-Peng Lee, Mimi C. Yu
Journal: JNCI Journal of the National Cancer Institute (2006)

The incidence of colorectal cancer is highest in populations that consume an energy-dense diet, have low intakes of vegetables and fruit, or lead a sedentary lifestyle. These factors may influence colorectal carcinogenesis via insulin pathways. We examined whether diabetes mellitus was associated with colorectal cancer in Singapore Chinese, whose body type and lifestyle profiles are distinct from those of Western populations. Between April 1993 and December 1998, 63,257 Singapore Chinese men and women aged 45 to 74 years were enrolled in a prospective study of diet and cancer. Each subject provided dietary, medical, and lifestyle information through an in-person interview. As of December 31, 2002, 636 incident colorectal cancer cases had been diagnosed. A history of physician-diagnosed diabetes was statistically significantly associated with colorectal cancer risk in both men (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.2 to 2.1) and women (RR = 1.4, 95% CI = 1.0 to 1.9). In stratified analyses, this association remained statistically significant among the subset of diabetics with high total calorie intake and low physical activity levels. Our results support the hypothesis that hyperinsulinemia may play a role in colorectal carcinogenesis, even in a relatively lean population.
The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons
Authors: Xi Lu, Jeong Sook Kim-Han, Steve Harmon, Shelly E Sakiyama-Elbert, Karen L O'Malley
Journal: Molecular Neurodegeneration (2014)

6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment.
Dynamic changes in gene expression during human early embryo development: from fundamental aspects to clinical applications
Authors: S. Assou, I. Boumela, D. Haouzi, T. Anahory, H. Dechaud, J. De Vos, S. Hamamah
Journal: Human Reproduction Update (2010)

BACKGROUNDThe first week of human embryonic development comprises a series of events that change highly specialized germ cells into undifferentiated human embryonic stem cells (hESCs) that display an extraordinarily broad developmental potential. The understanding of these events is crucial to the improvement of the success rate of in vitro fertilization. With the emergence of new technologies such as Omics, the gene expression profiling of human oocytes, embryos and hESCs has been performed and generated a flood of data related to the molecular signature of early embryo development.
Prevention Conference VI: Diabetes and Cardiovascular Disease
Authors: Rita F. Redberg, Philip Greenland, Valentin Fuster, Kalevi Pyörälä, Steven N. Blair, Aaron R. Folsom, Anne B. Newman, Daniel H. O’Leary, Trevor J. Orchard, Bruce Psaty, J. Sanford Schwartz, Rodman Starke, Peter W.F. Wilson
Journal: Circulation (2002)

Writing Group addressed whether the high risk associated with diabetes can be averted by detection of subclinical or early cardiovascular disease (CVD) that would enable earlier focused intervention.This article will discuss current data and recommendations for risk assessment of CVD in persons with diabetes.The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
Developmental determinants in non-communicable chronic diseases and ageing
Authors: J Bousquet, J M Anto, K Berkouk, P Gergen, J Pinto Antunes, P Augé, T Camuzat, J Bringer, J Mercier, N Best, R Bourret, M Akdis, S H Arshad, A Bedbrook, C Berr, A Bush, G Cavalli, M A Charles, F Clavel-Chapelon, M Gillman, D R Gold, M Goldberg, J W Holloway, P Iozzo, S Jacquemin, C Jeandel, F Kauffmann, T Keil, G H Koppelman, S Krauss-Etschmann, D Kuh, S Lehmann, K C Lodrup Carlsen, D Maier, M Méchali, E Melén, J P Moatti, I Momas, P Nérin, D S Postma, K Ritchie, J M Robine, B Samolinski, V Siroux, P E Slagboom, H A Smit, J Sunyer, R Valenta, P Van de Perre, J M Verdier, M Vrijheid, M Wickman, P Yiallouros, M Zins
Journal: Thorax (2015)

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.
Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors
Authors: M. G. Netea
Journal: Journal of Clinical Investigation (2006)

The fungal pathogen Candida albicans has a multilayered cell wall composed of an outer layer of proteins glycosylated with N- or O-linked mannosyl residues and an inner skeletal layer of beta-glucans and chitin. We demonstrate that cytokine production by human mononuclear cells or murine macrophages was markedly reduced when stimulated by C. albicans mutants defective in mannosylation. Recognition of mannosyl residues was mediated by mannose receptor binding to N-linked mannosyl residues and by TLR4 binding to O-linked mannosyl residues. Residual cytokine production was mediated by recognition of beta-glucan by the dectin-1/TLR2 receptor complex. C. albicans mutants with a cell wall defective in mannosyl residues were less virulent in experimental disseminated candidiasis and elicited reduced cytokine production in vivo. We concluded that recognition of C. albicans by monocytes/macrophages is mediated by 3 recognition systems of differing importance, each of which senses specific layers of the C. albicans cell wall.
The True and False Croup of French Pathologists
Authors: J. W. F. S. Shand
Journal: BMJ (1875)

The following case (also quoted by Gubler) occurred in I854 in Trousseau's service at the Hotel Dieu of Paris.I give only a sum- mary of the leading facts.The patient, a vaccinated subject, was attacked with confluent small-pox.During desquamation, she was seized with sudden and complete paralysis, and with less sensation in the lower extremities.The eruption, which was abundant, appeared on December 25th, and ran a normal course.On January 6th, she was convalescent, taking food, and able to leave her bed for two hours.On January 8th, she bad loss of sensation and motion of the lower extremities and abdominal muscles, extending on both sides up to the breasts.The left superior extremity was likewise paralysed from the finger to the middle of the humerus.There -was retention of urine.The respiration was very laborious and very rapid.On January i 6th, there was orthopncea, exceed ingly quick breathing, and acute pain wlheni pressure was made over the dorsal region of the verte- bral column.There were likewvise lancinating spontaneous pains in the cervical region.There was almost complete motor paralysis and absolute insensibility of the left arm.The anxesthesia of the trunk was mostly on the left side, where it existed as high up as the nipple.There was a total loss of voluntary motor power in both lower extre- mities, retention of urine, and incontinence of the fieces.On January i8th, the patient died.On that day, there was an apparent ameliora-
Loss of Heterozygosity for Chromosomes 1p and 16q Is an Adverse Prognostic Factor in Favorable-Histology Wilms Tumor: A Report From the National Wilms Tumor Study Group
Authors: Paul E. Grundy, Norman E. Breslow, Sierra Li, Elizabeth Perlman, J. Bruce Beckwith, Michael L. Ritchey, Robert C. Shamberger, Gerald M. Haase, Giulio J. D'Angio, Milton Donaldson, Max J. Coppes, Marcio Malogolowkin, Patricia Shearer, Patrick R.M. Thomas, Roger Macklis, Gail Tomlinson, Vicki Huff, Daniel M. Green
Journal: Journal of Clinical Oncology (2005)

To determine if tumor-specific loss of heterozygosity (LOH) for chromosomes 1p or 16q is associated with a poorer prognosis for children with favorable-histology (FH) Wilms tumor entered on the fifth National Wilms Tumor Study (NWTS-5).Between August 1995 and June 2002, 2,021 previously untreated children with FH or anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK) or malignant rhabdoid tumor of the kidney (RTK), were treated with stage- and histology-specific therapy. Their tumors were assayed for LOH for polymorphic DNA markers on chromosomes 1p and 16q. ResultsLOH for 1p or 16q was rarely observed in CCSK (n = 90) or RTK (n = 22). The relative risk (RR) of relapse for patients with FH stage I to IV tumors with LOH, stratified by stage, was 1.56 for LOH 1p (P = .01) and 1.49 for LOH 16q (P = .01), whereas the RR of death was 1.84 (P = .03) and 1.44 (P = .15), respectively. When the effects of LOH for both regions were considered jointly among patients with stage I to II FH disease, the risks of relapse and death were increased for LOH 1p only (RR = 2.2, P = .02 for relapse; RR = 4.0, P = .02 for death), for LOH 16q only (RR = 1.9, P = .01 and RR = 1.4, P = .60) and for LOH for both regions (RR = 2.9, P = .001 and RR = 4.3, P = .01) in comparison with patients with LOH at neither locus. The risks of relapse and death for patients with stage III to IV FH tumors were increased only with LOH for both regions (RR = 2.4, P = .01 and RR = 2.7, P = .04).Tumor-specific LOH for both chromosomes 1p and 16q identifies a subset of FH Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.