tbuckley/cabot-search huggingface dataset:
Whole-Exome Sequencing Reveals IKBKB As a Cause of Combined Immunodeficiency
Authors: Talal Mousallem, Jialong Yang, Thomas J. Urban, Hongxia Wang, Roberta E. Parrott, Joseph L. Roberts, Rebecca H. Buckley, Xiaoping Zhong, David B. Goldstein
Journal: Journal of Allergy and Clinical Immunology (2014)
Favorable Prognostic Impact in Loss of <i>TP53</i> and <i>PIK3CA</i> Mutations after Neoadjuvant Chemotherapy in Breast Cancer
Authors: Yi-Zhou Jiang, Ke-Da Yu, Jing Bao, Wen-Ting Peng, Zhi-Ming Shao
Journal: Cancer Research (2014)

Abstract We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre- and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P &amp;lt; 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller–Payne score (P = 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival. Cancer Res; 74(13); 3399–407. ©2014 AACR.
The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity.
Authors: M J Berendt, R J North, D P Kirstein
Journal: The Journal of Experimental Medicine (1978)

It was shown that of four syngeneic, murine tumors investigated, only those that evoked the generation of a state of concomitant anti-tumor immunity were susceptible to endotoxin-induced regression. Moreover, the temporal relationship between the generation of concomitant immunity and the onset of susceptibility to endotoxin-induced regression points to the likely possibility that tumor regression depends on the preceding acquisition of the specifically-sensitized, effector T cells that express concomitant immunity. It is suggested that endotoxin-induced hemorrhagic necrosis which invariably precedes tumor regression serves to create conditions inside the tumor that are conducive to the entry and the functioning of effector T cells. It is also suggested that tumor necrosis factor causes hemorrhagic necrosis rather than tumor regression.
Are interferon- release assays useful for diagnosing active tuberculosis in a high-burden setting?
Authors: D.I. Ling, M. Pai, V. Davids, L. Brunet, L. Lenders, R. Meldau, G. Calligaro, B. Allwood, R. van Zyl-Smit, J. Peter, E. Bateman, R. Dawson, K. Dheda
Journal: European Respiratory Journal (2011)

Although interferon-γ release assays (IGRAs) are intended for diagnosing latent tuberculosis (TB), we hypothesised that in a high-burden setting: 1) the magnitude of the response when using IGRAs can distinguish active TB from other diagnoses; 2) IGRAs may aid in the diagnosis of smear-negative TB; and 3) IGRAs could be useful as rule-out tests for active TB. We evaluated the accuracy of two IGRAs (QuantiFERON®-TB Gold In-tube (QFT-GIT) and T-SPOT®. TB ) in 395 patients (27% HIV-infected) with suspected TB in Cape Town, South Africa. IGRA sensitivity and specificity (95% CI) were 76% (68–83%) and 42% (36–49%) for QFT-GIT and 84% (77–90%) and 47% (40–53%) for T-SPOT®. TB , respectively. Although interferon-γ responses were significantly higher in the TB versus non-TB groups (p&lt;0.0001), varying the cut-offs did not improve discriminatory ability. In culture-negative patients, depending on whether those with clinically diagnosed TB were included or excluded from the analysis, the negative predictive value (NPV) of QFT-GIT, T-SPOT®. TB and chest radiograph in smear-negative patients varied between 85 and 89, 87 and 92, and 98% (for chest radiograph), respectively. Overall accuracy was independent of HIV status and CD4 count. In a high-burden setting, IGRAs alone do not have value as rule-in or -out tests for active TB. In smear-negative patients, chest radiography had better NPV even in HIV-infected patients.
Action of Diazoxide on Skeletal Muscle Vascular Resistance
Authors: WM. JOHN POWELL, RICHARD M. GREEN, RICHARD B. WHITING, CHARLES A. SANDERS
Journal: Circulation Research (1971)

Controversy exists as to whether arteriolar dilation after diazoxide (DZ) administration is due to a prolonged vascular effect that outlasts the presence of circulating levels of DZ or to equilibrium of arteriolar sites with circulating DZ. To resolve this question, the direct effects of DZ on the vascular resistance (VR) of the isolated blood-perfused (constant-flow) gracilis muscle were evaluated in 44 anesthetized dogs. Intra-arterial infusions of DZ resulted in falls in vascular resistance (-35.9±5.5 SEM %) which returned to control levels after the infusions, thus indicating that irreversible binding to arterioles or a prolonged arteriolar effect independent of plasma levels of the drug did not obtain. Decreases (- 16% to -35%) in VR could also be achieved by premixing DZ in the blood perfusion reservoir at concentrations between 40 and 100 mg/L (which may be achieved clinically); thus albumin binding does not abolish the activity of DZ. Decreases in VR by DZ were not related to stimulation of beta-adrenergic receptors, alteration in Na + or K + balance, or changes in venous levels of glucose, lactate, pO 2 , pCO 2 , or pH. When norepinephrine and angiotensin II were infused during diazoxide infusions their vasoconstrictor response was attenuated. Thus DZ has a direct effect in lowering VR which is independent of measurable changes in gracilis muscle metabolism. Moreover, the VR effect of DZ is not dependent on a prolonged arteriolar effect independent of plasma concentrations of the drug.
Cell-free Tumor DNA in Blood Plasma As a Marker for Circulating Tumor Cells in Prostate Cancer
Authors: Heidi Schwarzenbach, Catherine Alix-Panabières, Imke Müller, Nicolas Letang, Jean-Pierre Vendrell, Xavier Rebillard, Klaus Pantel
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Circulating cell-free DNA in the blood of cancer patients harbors tumor-specific aberrations. Here, we investigated whether this DNA might also reflect the presence of circulating tumor cells (CTC). Experimental Design: To identify the source of cell-free DNA in blood, plasma derived from 81 patients with prostate cancer was examined for CTCs and cell-free DNA. An epithelial immunospot assay was applied for detection of CTCs, and a PCR-based fluorescence microsatellite analysis with a panel of 14 polymorphic markers was used for detection of allelic imbalances (AI). Results: The plasma DNA levels significantly correlated with the diagnosis subgroups of localized (stage M0, n = 69) and metastasized prostate cancer (stage M1, n = 12; P = 0.03) and with the tumor stage of these patients (P &amp;lt; 0.005). AI was found on cell-free DNA in plasma from 45.0% and 58.5% of M0 and M1 patients, respectively. Detection of CTCs showed that 71.0% or 92.0% of the M0 and M1 patients harbored 1 to 40 CTCs in their blood, respectively. The occurrence of CTCs correlated with tumor stage (P &amp;lt; 0.03) and increasing Gleason scores (P = 0.04). Notably, significant associations of the number of CTCs with the AI frequencies at the markers D8S137 (P = 0.03), D9S171 (P = 0.04), and D17S855 (P = 0.02) encoding the cytoskeletal protein dematin, the inhibitor of the cyclin-dependent kinase CDKN2/p16 and BRCA1, respectively, were observed. Conclusions: These findings show, for the first time, a relationship between the occurrence of CTCs and circulating tumor-associated DNA in blood, which, therefore, might become a valuable new source for monitoring metastatic progression in cancer patients.
Chromosome 4 hyperploidy represents an early genetic aberration in premalignant Barrett's oesophagus
Authors: S H Doak
Journal: Gut (2003)

<b>Background and aims:</b> Characterisation of the underlying molecular mechanisms that promote Barrett's progression may ultimately lead to identification of potential predictive genetic markers that classify patients' malignant risk. In an attempt to understand these causative pathways, fluorescence in situ hybridisation (FISH) was used in this study to determine when specific genetic alterations arise during Barrett's associated neoplastic progression. <b>Methods:</b> Endoscopic cytology brushings were obtained from 28 patients with Barrett's metaplasia, 28 with dysplasia (20 low grade dysplasia (LGD) and eight with high grade dysplasia (HGD)), and seven with adenocarcinoma, together with paired control brushings from regions of normal proximal squamous cell epithelium. The exfoliated epithelial cells were washed and deposited onto slides. Probes specific for the centromeres of chromosomes 4, 8, 20, and Y, and locus specific probes for the tumour suppressor genes p16, p53, and Rb were subsequently hybridised. <b>Results:</b> Aneuploidy was found early in progression, with metaplastic tissues displaying increased copy numbers of chromosomes 4 and 8. Chromosome 4 hyperploidy was found in 89%, 90%, 88%, and 100% of metaplasias, LGD, HGD, adenocarcinomas, respectively, while chromosome 8 hyperploidy occurred in 71%, 75%, 100%, and 100% of patients with the respective staging. Loss of the p16 tumour suppressor gene also presented in metaplastic epithelium (7%) but most other genetic aberrations were only seen in HGD. <b>Conclusions:</b> Genetic instability arises well before dysplasia in Barrett's oesophagus, with chromosome 4 and 8 hyperploidy representing the earliest and most common alterations identified. As these aberrations are widespread at all the premalignant stages, there may be genes on chromosomes 4 and 8 that are involved in both the initiation and progression of Barrett's oesophagus.
Astrocyte elevated gene-1 is associated with metastasis in head and neck squamous cell carcinoma through p65 phosphorylation and upregulation of MMP1
Authors: Yi-Ping Wang, I-Ju Liu, Chiung-Pin Chiang, Han-Chung Wu
Journal: Molecular Cancer (2013)

Abstract Background The survival rate of head and neck squamous cell carcinoma (HNSCC) at advanced stage is poor, despite contemporary advances in treatment modalities. Recent studies have indicated that astrocyte elevated gene-1 (AEG-1), a single transmembrane protein without any known functional domains, is overexpressed in various malignancies and is implicated in both distant metastasis and poor survival. Results High expression of AEG-1 in HNSCC was positively correlated with regional lymph node metastasis and a poor 5-year survival rate. Knockdown of AEG-1 in HNSCC cell lines reduced their capacity for colony formation, migration and invasion. Furthermore, decreased tumor volume and metastatic foci were observed after knockdown of AEG-1 in subcutaneous xenografts and pulmonary metastasis assays in vivo , respectively. We also demonstrated that AEG-1 increased phosphorylation of the p65 subunit of NF-κB, and regulated the expression of MMP1 in HNSCC cells. Moreover, compromised phosphorylation of the p65 (RelA) subunit of NF-κB at serine 536 was observed upon silencing of AEG-1 in both HNSCC cell lines and clinical specimens. Conclusion High expression of AEG-1 is associated with lymph node metastasis and its potentially associated mechanism is investigated.
Avoidability of hospital deaths and association with hospital-wide mortality ratios: retrospective case record review and regression analysis
Authors: Helen Hogan, Rebecca Zipfel, Jenny Neuburger, Andrew Hutchings, Ara Darzi, Nick Black
Journal: BMJ (2015)

<b>Objectives</b> To determine the proportion of avoidable deaths (due to acts of omission and commission) in acute hospital trusts in England and to determine the association with the trust’s hospital-wide standardised mortality ratio assessed using the two commonly used methods - the hospital standardised mortality ratio (HSMR) and the summary hospital level mortality indicator (SHMI). <b>Design</b> Retrospective case record review of deaths. <b>Setting</b> 34 English acute hospital trusts (10 in 2009 and 24 in 2012/13) randomly selected from across the spectrum of HSMR. <b>Main outcome measures</b> Avoidable death, defined as those with at least a 50% probability of avoidability in view of trained medical reviewers. Association of avoidable death proportion with the HSMR and the SHMI assessed using regression coefficients, to estimate the increase in avoidable death proportion for a one standard deviation increase in standardised mortality ratio. <b>Participants</b> 100 randomly selected hospital deaths from each trust. <b>Results</b> The proportion of avoidable deaths was 3.6% (95% confidence interval 3.0% to 4.3%). It was lower in 2012/13 (3.0%, 2.4% to 3.7%) than in 2009 (5.2%, 3.8% to 6.6%). This difference is subject to several factors, including reviewers’ greater awareness in 2012/13 of orders not to resuscitate, patients being perceived as sicker on admission, minor differences in review form questions, and cultural changes that might have discouraged reviewers from criticising other clinicians. There was a small but statistically non-significant association between HSMR and the proportion of avoidable deaths (regression coefficient 0.3, 95% confidence interval −0.2 to 0.7). The regression coefficient was similar for both time periods (0.1 and 0.3). This implies that a difference in HSMR of between 105 and 115 would be associated with an increase of only 0.3% (95% confidence interval −0.2% to 0.7%) in the proportion of avoidable deaths. A similar weak non-significant association was observed for SHMI (regression coefficient 0.3, 95% confidence interval −0.3 to 1.0). <b>Conclusions</b> The small proportion of deaths judged to be avoidable means that any metric based on mortality is unlikely to reflect the quality of a hospital. The lack of association between the proportion of avoidable deaths and hospital-wide SMRs partly reflects methodological shortcomings in both metrics. Instead, reviews of individual deaths should focus on identifying ways of improving the quality of care, whereas the use of standardised mortality ratios should be restricted to assessing the quality of care for conditions with high case fatality for which good quality clinical data exist.
Block of transient outward-type cloned cardiac K+ channel currents by quinidine.
Authors: A Yatani, M Wakamori, G Mikala, A Bahinski
Journal: Circulation Research (1993)

The antiarrhythmic drug quinidine has been shown to block several types of K+ channel currents in cardiac preparations including the transient outward current (Ito). To characterize the molecular mechanism of quinidine block, a cloned Ito-type cardiac K+ channel (RHK1) was expressed in Xenopus oocytes, and drug effects were examined on whole-cell and single-channel currents. Extracellular application of quinidine reduced whole-cell RHK1 current amplitude in a concentration-dependent manner. The block was voltage dependent, with an IC50 of 1.69 mM at 0 mV, and the value decreased to 875 microM at +60 mV. Quinidine significantly slowed the current inactivation time course during voltage-clamp pulses without changing the rate of activation or the steady-state inactivation. To test the channel-state dependence of quinidine block, the cells were "rested" in the presence of quinidine (500 microM) for 2 to 3 minutes before applying depolarizing pulses to +60 mV. During the first pulse, the current inactivation rate was slower than control, but the peak current was only reduced by less than 5%. Subsequent pulses reduced the peak current amplitude to approximately 50% of control. These results suggest that quinidine blocks the open channel and that the drug must first dissociate before the channel can close, thereby causing a crossover in current tracings. In measurements of single-channel current from cell-attached patches, open time was reduced by quinidine in a concentration-dependent manner. Single-channel current amplitude was not altered by quinidine. Application of quinidine to the intracellular side of inside-out patches had an effect similar to that obtained from cell-attached patches but at 10-fold lower concentrations. External quinidine may therefore have to pass into or through the cell membrane to reach its blocking site.
Computed Tomography Screening for Lung Cancer in a High-Risk Population: Update on Current Status
Authors: P. Russo, L. Paleari, P. Granone, A. Cesario, U. Pastorino
Journal: JNCI Journal of the National Cancer Institute (2008)

Lung cancers cause more deaths than any other form of cancer ( 1 ), and approximately 85% of them occur in current or former cigarette smokers ( 2 ).Two recent studies of computed tomography (CT) screening of lung cancer ( 3 , 4 ) have received worldwide press coverage of their discordant conclusions.The difference in the conclusions of the two studies reflected different opinions as to which outcome constitutes real evidence of the effectiveness of screening --the decline in the death rate, or the increase in survival time after diagnosis.
Closed posteromedial dislocation of the tibiotalar joint without fracture in a basketball player
Authors: M Uyar, A Tan, M Işler, E Cetinus
Journal: British Journal of Sports Medicine (2004)

Acute ankle injury is one of the most common problems in sports medicine. Although most are ankle sprains, dislocations are occasionally seen. The case is presented of a closed posteromedial ankle dislocation without fracture which occurred during a basketball match. The literature is also reviewed.
The effect of connexin40 deficiency on ventricular conduction system function during development
Authors: Barbora Sankova, Jiri Benes, Eliska Krejci, Laurent Dupays, Magali Theveniau-Ruissy, Lucile Miquerol, David Sedmera
Journal: Cardiovascular Research (2012)

AimsThe aim of this study was to characterize ventricular activation patterns in normal and connexin40-deficient mice in order to dissect the role of connexin40 in developing the conduction system.
Phase II study of interim PET–CT-guided response-adapted therapy in advanced Hodgkin's lymphoma
Authors: P. Ganesan, R. Rajendranath, K. Kannan, V. Radhakrishnan, T.S. Ganesan, K. Udupa, K.M. Lakshmipathy, V. Mahajan, S. Sundersingh, S. Rajaraman, R. Krishnakumar, T.G. Sagar
Journal: Annals of Oncology (2015)
Indications for cryopreservation of ovarian tissue
Authors: J Donnez, S Bassil
Journal: Human Reproduction Update (1998)

For patients who are planning to have chemotherapy, radiotherapy or to undergo bilateral oophorectomy, loss of ovarian function will result in premature ovarian menopause and loss of fertility. For these women, although there is no successful method for the cryopreservation of human oocytes, ovarian tissue cryobanking is proposed with a view to its autotransplantation at a later date or the isolation and in-vitro maturation of oocytes. Embryo preservation is indeed not an option for single women and even for married women because delaying treatment for at least 2 months of in-vitro fertilization cycles is inappropriate and life-threatening. Following the success of animal experiments, there have been reports of ovarian cryopreservation for women having to receive chemotherapy and/or radiotherapy. We present four case reports of ovarian tissue cryobanking and review the consequences of chemotherapy and radiotherapy on gonadal function, as well as the indications for freezing ovarian tissue.
Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey scale and power Doppler ultrasonography
Authors: E Naredo
Journal: Annals of the Rheumatic Diseases (2004)

In a pilot study recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered to 12 neutropenic preterm infants to determine if neonatal neutropenia is secondary to decreased endogenous G-CSF production. Respiratory variables were monitored because of the possible link between inflammatory cells and hyaline membrane disease. All infants showed increased neutrophil counts. The only possible side effect observed was an exacerbation of thrombocytopenia.
Serum Insulin-Like Growth Factor-I Levels and Prostate Cancer Risk--Interpreting the Evidence
Authors: P. Cohen
Journal: JNCI Journal of the National Cancer Institute (1998)

with such a history that the luteal false-negative phenomenon was observed in the Canadian study. Are menstruating women who have never used oral contraceptives at an advantage for mammographic imaging? And if so, why? Furthermore, we still have no measure of within-woman cyclic changes. All that is needed is an observational study in which premenopausal volunteers would agree to have split mammographic screening in the same menstrual cycle: one breast imaged in the follicular phase and the other in the luteal phase, with the technique kept as constant as possible. But an even more important question has been waiting to be answered ever since Tabar et al. (6) published their first results from the Two-County Study in Sweden back in 1985 that showed excess breast cancer mortality in screened women aged 40‐49 years. This mortality paradox is clearly displayed in a recent updated overview of the Swedish randomized trials (7) and parallels similar observations in the 7-year results from the Canadian National Breast Screening Study (8). However, as the end of the 1990s approaches, we know that the mortality paradox extinguishes itself 7 or more years after screening is initiated. So now the question is not so much: Why was the paradox ever observed? It is rather: Why is the benefit from screening this age group so small relative to screening older women, and why is the benefit so delayed? Even today, after many years of follow-up, two of the Swedish studies (7), Ostergotland (part of the Two-County Study) and Stockholm, show equal breast cancer mortality in screened and unscreened groups aged 40‐49 years. Can we agree that the arbitrary cutoff, age 40‐49 years versus 50‐59 years, used in the analysis of screening trials is a crude proxy for a cutoff that separates mainly premenopausal women