tbuckley/cabot-search huggingface dataset:
Effect of 8-methoxypsoralen plus UVA (PUVA) on lymphocyte transformation and T cells in psoriatic patients
Authors: JORMA E. FRANKI, JUSSI ESKOLA, VAINO K. HOPSU-HAVU
Journal: British Journal of Dermatology (1979)

The peripheral blood lympochytes of the psoriatic patients studied initially showed a normal response to phytohaemagglutinin (PHA) and to purified protein derivative of turberculin (PPD) in a microculture using whole blood, but a lower than normal response to a high concentration of concanavalin A (Con A). The initial level of E-rosette-forming T cells in psoriatic patients (51.3%) was significantly lower than that in healthy controls (66.7%). A single exposure to 8-methoxypsoralen (8-MOP) and UVA light (PUVA) did not suppress the lymphocyte responses to PHA, Con A or PPD, rather the responses showed a tendency to be slightly increased. Similarly, no changes in the mitogen responses of peripheral blood lymphocytes were recorded during or after 12 weeks PUVA therapy for psoriasis. The lymphocytes still showed a weaker than normal response to a high concentration of Con A. However, the percentage of E-rosette-forming T cells in the peripheral blood increased from 51.3% to 62.8% after 12 weeks PUVA therapy. The low initial level of E-rosette-forming T cells was found to correlate more closely with the activity than with the extent of the disease. The increase found in the E-rosette-forming cells during PUVA therapy did not correlate with the improvement of the psoriatic lesions. The low response of peripheral blood lymphocytes of psoriatic patients to a high concentration of Con A correlated with the age of the patients but not with the activity or extent of the disease.
Vitamin D Biology Revealed Through the Study of Knockout and Transgenic Mouse Models
Authors: Sylvia Christakos, Tanya Seth, Jennifer Hirsch, Angela Porta, Anargyros Moulas, Puneet Dhawan
Journal: Annual Review of Nutrition (2013)

Early studies identifying vitamin D as an antirachitic factor led to studies in vitamin D-deficient models that resulted in a basic understanding of the mechanism of action of vitamin D. Recent studies using genetically modified mice have provided important new insight into the physiological role of vitamin D at target tissues and the functional significance of vitamin D target proteins, as well as the functional significance of proteins involved in the transport and metabolism of vitamin D. Studies using these mice have played an increasingly important role in elucidating the mechanisms involved in the control of calcium homeostasis and have provided evidence for a role of vitamin D in extraskeletal health.
Neonatal Congenital Malignant Melanoma With Lymph Node Metastasis
Authors: Shannon Tierney McElearney, Lynn T. Dengel, Ann Byron Robertson Vaughters, James W. Patterson, Eugene D. McGahren, Craig L. Slingluff
Journal: Journal of Clinical Oncology (2009)

A Caucasian baby girl presented at birth with a dark, irregular, raised skin lesion measuring approximately 2 cm in diameter on the medial aspect of her right leg (Fig 1). There was no history of melanoma in her family and no evidence of melanoma in her mother. At two weeks of age, she underwent an incisional biopsy of the lesion at a community hospital. Histologic review showed a superficial spreading invasive malignant melanoma with Breslow thickness greater than 2.5 mm, with a positive deep margin. There was angiolymphatic invasion but no definite ulceration. She was referred to our institution, where clinical exam revealed an otherwise healthy newborn girl, a black lesion on the right leg with a central scar measuring 1.5 cm in diameter. There were small palpable inguinal nodes in each groin, possibly more prominent on the right but not clinically suspicious. One week later, a wide local excision was performed with a 1 cm margin (Fig 1) and a full thickness skin graft. Lymphoscintigraphy revealed a sentinel node in the right groin, and a sentinel lymph node biopsy was performed. Her final pathology revealed an atypical malignant melanoma arising in a nevus with congenital features with Breslow thickness of 2.58 mm and Clark’s level V (Fig 2A). Margins were widely clear. The lesion was consistent with a primary melanoma, rather than metastatic disease from maternal origin. The sentinel node was positive for metastatic melanoma, with mitotic figures (Fig 2B) and S100 staining (Fig 2C). She underwent staging studies including CT scans of her head, chest, abdomen and pelvis as well as a bone scan. These were negative for metastatic disease. One month later, completion right inguinal lymph node dissection was performed, yielding five lymph nodes without metastatic disease. Her postoperative course was complicated by a wound abscess in the right groin that was drained operatively and healed well. Her final staging, at the age of 9 weeks, was therefore Stage IIIA (T3aN1aM0). No additional treatment was performed. She has been followed to her current age of 32 months without evidence of recurrence by clinical exam, serial chest radiographs, and annual CT scans of the abdomen and pelvis. She has had an excisional biopsy of a suspicious skin lesion from her lower abdomen at age 22 months that was an atypical nevus. She has normal function of her right lower extremity without lymphedema and is healthy and developmentally appropriate (Fig 3).
Lack of Rb and p53 Delays Cerebellar Development and Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification of <i>N-Myc</i> and <i>Ptch2</i>
Authors: Olga Shakhova, Carly Leung, Erwin van Montfort, Anton Berns, Silvia Marino
Journal: Cancer Research (2006)

Abstract Medulloblastomas are among the most common malignant brain tumors in childhood. They typically arise from neoplastic transformation of granule cell precursors in the cerebellum via deregulation of molecular pathways involved in normal cerebellar development. In a mouse model, we show here that impairment of the balance between proliferation and differentiation of granule cell precursors in the external granular layer of the developing cerebellum predisposes but is not sufficient to induce neoplastic transformation of these progenitor cells. Using array-based chromosomal comparative genomic hybridization, we show that genetic instability resulting from inactivation of the p53 pathway together with deregulation of proliferation induced by Rb loss eventually leads to neoplastic transformation of these cells by acquiring additional genetic mutations, mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss influences molecular mechanisms that cannot be mimicked by the loss of either p19ARF, p21, or ATM. (Cancer Res 2006; 66(10): 5190-200)
CDC recommends immediate HIV drugs after exposure
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

New guidelines from the US Centers for Disease Control and Prevention (CDC) call for antiretroviral drugs to be given to people who may have been exposed to HIV through sexual intercourse, injection of drugs, or injury. They recommend treatment with highly active antiretrovirals beginning within 72 hours of exposure and continuing for 28 days ( MMWR Morbidity and Mortality Weekly Report (Recommendations and Reports) 2005;54(RR02):1-20).

The guidelines say that antiretroviral drugs reduced the rate of transmission of HIV after exposure to the virus in animal studies, in trials looking at prevention of perinatal transmission, in studies of health workers who received prophylactic treatment after exposure at work, and in observational studies.

They say that there is an early window of opportunity to interrupt …
The induction of cytokines by polycation containing microspheres by a complement dependent mechanism
Authors: Anne Mari Rokstad, Ole-Lars Brekke, Bjørg Steinkjer, Liv Ryan, Gabriela Kolláriková, Berit L. Strand, Gudmund Skjåk-Bræk, John D. Lambris, Igor Lacík, Tom Eirik Mollnes, Terje Espevik
Journal: Biomaterials (2012)
Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection
Authors: Wayne W. Hancock, Bao Lu, Wei Gao, Vilmos Csizmadia, Kerrie Faia, Jennifer A. King, Stephen T. Smiley, Mai Ling, Norma P. Gerard, Craig Gerard
Journal: The Journal of Experimental Medicine (2000)

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein–coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-γ–inducible protein of 10 kD (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T cell α chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3−/−) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3−/− allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR+/+ mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.
The number needed to treat provides additional insight on the performance of detection points of asthma exacerbations in self-management plans
Authors: Persijn J Honkoop, Jacob K Sont
Journal: Thorax (2013)

With interest we have read the paper of Kupczyk et al .1 It is an important contribution to the current understanding of the course and early detection of asthma exacerbations, especially with the advent of internet-based self-management programmes using daily or weekly monitoring.2 In the current research the authors found that the combination of a 20% decrease in peak expiratory flow (PEF) on 2 consecutive days or a 20% increase in day symptoms on 2 consecutive days optimally detects an exacerbation with …
E2F1 renders prostate cancer cell resistant to ICAM-1 mediated antitumor immunity by NF-κB modulation
Authors: Zijia Ren, Wenyao Kang, Lihua Wang, Baoliang Sun, Jiajia Ma, Chaogu Zheng, Jie Sun, Zhigang Tian, Xiaoyi Yang, Weihua Xiao
Journal: Molecular Cancer (2014)

E2F1 is the gatekeeper of the cell cycle controlling an analogous balance between proliferation and cell death. E2F1 expression is elevated in advanced prostate cancer. However, it is still unclear that the roles and mechanisms of E2F1 on prostate cancers. Targeted knockdown by interferon RNA was applied on two prostate cancer and Hela cell lines to examine the inverse correlation expression of E2F1 and ICAM-1. ICAM-1 promoter reporter and ChIP assays were used for analysis of the molecular basis of transcriptional regulation of E2F1 on ICAM-1. Co-IP assays were employed for testing the protein interaction between E2F1 and NF-κB. Tumor xenograft mice model with E2F1 and ICAM-1-knockdown prostate cancer cells were used to investigate the effects of E2F1 and ICAM-1 on antitumor immunity. E2F1 knockdown by a specific short hairpin RNA increased gene transcription and protein expression of ICAM-1. By using wild type and a series of mutant ICAM-1 promoter luciferase constructs, the NF-κB binding sites were found to be important for E2F1 regulation of ICAM-1 promoter. Targeted knockdown of E2F1 did not affect expression and phosphorylation of NF-κB and IκBα, but facilitated NF-κB binding to the ICAM-1 promoter, subsequently induced ICAM-1 transcription and production in prostate carcinoma cells. Furthermore, knockdown of E2F1 inhibited tumor growth of prostate cancer in vivo through increasing the susceptibility of tumor cells to ICAM-1-mediated anti-tumor immunity including enhancement of monocyte adhesion, leucocytes infiltration, as well as cytotoxicity against tumor cells. E2F1 knockdown inhibited prostate tumor growth in vitro and in vivo through sensitizing tumor cells to ICAM-1 mediated anti-immunity by NF-κB modulation, highlighting the potential of E2F1 as a therapeutic target.
Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation
Authors: Didrik Paus, Tri Giang Phan, Tyani D. Chan, Sandra Gardam, Antony Basten, Robert Brink
Journal: The Journal of Experimental Medicine (2006)

B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.
Is There Added Value to Adding ARB to ACE Inhibitors in the Management of CKD?
Authors: Debbie L. Cohen, Raymond R. Townsend
Journal: Journal of the American Society of Nephrology (2008)

Antagonism of the rennin-angiotensin-aldosterone-system (RAAS) decreases BP and reduces proteinuria in chronic kidney disease. BP is decreased approximately 5 mmHg when angiotensin II blockers are added to angiotensin-converting enzyme (ACE) inhibitors and is less than typically seen when other agents are added to existing ACE inhibitor regimens. Dual RAAS blockade results in additional reduction in proteinuria. Clinically insignificant increases in hyperkalemia and modest decreases in GFR occur. Data regarding long-term preservation of renal function are lacking. We suggest dual RAAS blockade be used in patients with chronic kidney disease with residual proteinuria on maximal ACE inhibitor or angiotensin II blocker therapy, anticipating additional data with ongoing trials.
Setting benchmark revision rates for total hip replacement: analysis of registry evidence
Authors: N.-B. Kandala, M. Connock, R. Pulikottil-Jacob, P. Sutcliffe, M. J. Crowther, A. Grove, H. Mistry, A. Clarke
Journal: BMJ (2015)

<b>Objective</b> To compare 10 year revision rates for frequently used types of primary total hip replacement to inform setting of a new benchmark rate in England and Wales that will be of international relevance. <b>Design</b> Retrospective cohort study. <b>Setting</b> National Joint Registry. <b>Participants</b> 239 000 patient records. <b>Main outcome measures</b> Revision rates for five frequently used types of total hip replacement that differed according to bearing surface and fixation mode, encompassing 62% of all primary total hip replacements in the National Joint Registry for England and Wales. Revision rates were compared using Kaplan-Meier and competing risks analyses, and five and 10 year rates were estimated using well fitting parametric models. <b>Results</b> Estimated revision rates at 10 years were 4% or below for four of the five types of total hip replacement investigated. Rates differed little according to Kaplan-Meier or competing risks analysis, but differences between prosthesis types were more substantial. Cemented prostheses with ceramic-on-polyethylene bearing surfaces had the lowest revision rates (1.88-2.11% at 10 years depending on the method used), and cementless prostheses with ceramic-on-ceramic bearing surfaces had the highest revision rates (3.93-4.33%). Men were more likely to receive revision of total hip replacement than were women, and this difference was statistically significant for four of the five prosthesis types. <b>Conclusions</b> Ten year revision rate estimates were all less than 5%, and in some instances considerably less. The results suggest that the current revision rate benchmark should be at least halved from 10% to less than 5% at 10 years. This has implications for benchmarks internationally.
Plasma Concentration of IGF-I Is Independently Associated With Insulin Sensitivity in Subjects With Different Degrees of Glucose Tolerance
Authors: Giorgio Sesti, Angela Sciacqua, Marina Cardellini, Maria Adelaide Marini, Raffaele Maio, Marco Vatrano, Elena Succurro, Renato Lauro, Massimo Federici, Francesco Perticone
Journal: Diabetes Care (2005)

OBJECTIVE—We studied the relationships between plasma IGF-I concentrations and insulin sensitivity in subjects with various degrees of glucose tolerance. RESEARCH DESIGN AND METHODS—A total of 357 nondiabetic subjects, 54 subjects with impaired glucose tolerance and 98 newly diagnosed type 2 diabetic subjects, were consecutively recruited, and anthropometric and biochemical characteristics were collected. RESULTS—IGF-I concentrations were negatively correlated with age, BMI, waist-to-hip ratio, triglyceride levels, and systolic and diastolic blood pressure. IGF-I concentrations were positively correlated with HDL cholesterol and homeostasis model assessment of insulin sensitivity (HOMA-S). The correlations remained significant after adjusting for sex, age, and BMI. Correlations for HOMA-S with these metabolic and anthropometric variables were of a similar degree and direction to those for IGF-I concentrations. Stepwise linear regression analysis in a model, which included well-known modulators of insulin sensitivity such as sex, age, BMI, glucose tolerance status, family history of diabetes, waist-to-hip ratio, systolic and diastolic blood pressure, HDL cholesterol, and triglyceride levels, revealed that IGF-I concentrations were independently associated with insulin sensitivity accounting for 10.8% of its variation (P &amp;lt; 0.0001). IGF-I concentrations were significantly lower in subjects with World Health Organization (WHO)-defined metabolic syndrome compared with subjects without metabolic syndrome (P &amp;lt; 0.0001). Logistic regression analysis showed that each unit increase in log-transformed IGF-I concentrations was associated with a 90.5% reduction in the risk of WHO-defined metabolic syndrome. CONCLUSIONS—These data indicate that IGF-I has the characteristics to be a marker for the insulin resistance syndrome. This suggests that low IGF-I levels may be a useful marker for identifying subjects at risk for cardiovascular disease.
Regulation of the Na+/Ca2+ exchanger (NCX) in the murine embryonic heart
Authors: M REPPEL, B FLEISCHMANN, H REUTER, P SASSE, H SCHUNKERT, J HESCHELER
Journal: Cardiovascular Research (2007)

Objective The Na+/Ca2+ exchanger (NCX) is involved in embryonic heart development and function demonstrated by the abnormal myofibrillar organization, defects in heartbeat, and early embryonic death of NCX-null embryos. It was therefore the aim of our study to identify key functional regulators of the embryonic NCX. MethodsNCX current (INCX) density was measured as the Ni2+ (5 mM)-sensitive current applying the whole-cell patch-clamp technique in early (EDS, E10.5V) and late developmental stage (LDS, E16.5V) mouse ventricular cardiomyocytes. Results Compared to LDS, cardiomyocytes derived from EDS showed a significantly higher basal INCX density for the INCX forward (−120 mV: −4.1±1 pA/pF, n=15 versus −1.7±0.4, n=11, p<0.05) and reverse modes (+60 mV: 4.0±0.9 pA/pF, n=15 versus 1.8±0.4, n=11, p<0.05). There was 2–3-fold elevation of forward and reverse current in LDS on application of ATP-γ-S (2 mM) together with forskolin (1 μM) as well as intracellular application of the catalytic subunit of cAMP-dependent protein kinase (cPKA, 200 U/mL), cAMP (200 μM), phorbol 12-myristate-13-acetate (PMA), a direct activator of protein kinase C (PKC), and 8-Br-cGMP, a membrane permeable analog of cGMP. The specific PKC inhibitor Ro 31-8220 significantly reduced INCX by 70%. Co-application of 20 μM PKA inhibitor Fragment 14-22 (PKI), a specific inhibitor of PKA, and cAMP significantly reduced the exchanger activity by approx 60%. Despite these obvious effects in LDS we could not detect a significant impact of these compounds on INCX in EDS-derived cardiomyocytes. Application of the alkaline phosphatase to test for constitutive phosphorylation of NCX did not affect INCX density in LDS but led to an approx 80% reduction of INCX in EDS. Conclusion In EDS cardiomyocytes INCX density is upregulated, at least in part by the high phosphorylation of the exchanger protein. At LDS, embryonic cardiomyocytes showed a strong increase of INCX density upon stimulation by PKC- and PKA-dependent signalling pathways.
Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement
Authors: Sjoerd Rodenhuis, Dick J Richel, Elsken van der Wall, Jan H Schornagel, Joke W Baars, Caro CE Koning, Johannes L Peterse, Jacques H Borger, Willem J Nooijen, Roel Bakx, Otilia Dalesio, Emiel Rutgers
Journal: The Lancet (1998)
Endoscopic management of familial adenomatous polyposis in patients refusing colectomy
Authors: Hideki Ishikawa, Michihiro Mutoh, Takeo Iwama, Sadao Suzuki, Takashi Abe, Yoji Takeuchi, Tomiyo Nakamura, Yasumasa Ezoe, Gen Fujii, Keiji Wakabayashi, Takeshi Nakajima, Toshiyuki Sakai
Journal: Endoscopy (2015)

<b>Background and study aims: </b>Colectomy protects against colorectal cancer in familial adenomatous polyposis (FAP); however, some patients with FAP refuse surgery. The aim of this study was to evaluate the feasibility and safety of endoscopic management of these patients. <b>Patients and methods:</b> A retrospective review of medical records was performed to identify adult patients with FAP who refused colectomy and were managed by repeated colonoscopies to remove numerous polyps between 2001 and 2012. Polyps were removed by hot snare polypectomy or endoscopic mucosal resection. Polyps of < 10 mm in size and without endoscopic features suggesting cancer were discarded without histological examination; the remaining polyps were examined histologically. <b>Results: </b>Of the 95 eligible patients, five (5.3 %) were excluded. The remaining 90 patients (median age at first visit 29 years [range 16 – 68 years]; 46 males) were followed for a median of 5.1 years (interquartile range [IQR] 3.3 – 7.3 years). During this period, a total of 55 701 polyps were resected without adverse events such as bleeding or perforation. The median numbers of endoscopic treatment sessions and polyps removed per patient were 8 (IQR 6 – 11) and 475 (IQR 211 – 945), respectively. Five patients had noninvasive carcinoma (Category 4.2 according to the revised Vienna classification), detected within 10 months from the start of the follow-up period. All of these patients were treated endoscopically, without signs of recurrence during a median follow-up of 4.3 years (IQR 2.0 – 7.1 years). No invasive colorectal cancer was recorded during the study period. Two patients (2.2 %) underwent colectomy because the polyposis phenotype had changed to dense polyposis. <b>Conclusion:</b> Endoscopic management of FAP is feasible and safe in the medium term.