tbuckley/cabot-search huggingface dataset:
The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer
Authors: T. Powles, I. Kayani, C. Blank, S. Chowdhury, S. Horenblas, J. Peters, J. Shamash, N. Sarwar, K. Boletti, A. Sadev, T. O'Brien, D. Berney, L. Beltran, J. Haanen, A. Bex
Journal: Annals of Oncology (2011)

The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated.Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC.Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%-35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien-Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90-4200) ml and 189 (70-420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6-15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy.Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.
Elevated blood markers 1 year before manifestation of malignant glioma
Authors: W. Gartner, A. Ilhan, D. Neziri, W. Base, M. Weissel, A. Wohrer, H. Heinzl, T. Waldhor, L. Wagner, M. Preusser
Journal: Neuro-Oncology (2010)

We detected distinct plasma concentration profiles of S100B, neuropeptide Y, and secretagogin in 3 of 191 patients enrolled in a previous study investigating brain-tissue–related markers in the blood of patients with atrial fibrillation. Intriguingly, 2 of these 3 patients, both of whom were without neurological symptoms at the time of blood sampling, were diagnosed with malignant glioma (MG) approximately 1 year later. To our knowledge, this is the first report indicating that distinct blood biomarker profiles may be detected long before clinical manifestation of MG.
Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury
Authors: Justin M. Belcher, Arun J. Sanyal, Aldo J. Peixoto, Mark A. Perazella, Joseph Lim, Heather Thiessen-Philbrook, Naheed Ansari, Steven G. Coca, Guadalupe Garcia-Tsao, Chirag R. Parikh
Journal: Hepatology (2013)

Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step-wise with the number of biomarkers above optimal diagnostic cutoffs. Conclusion : Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS. (Hepatology 2014;60:622–632)
Genetic Epidemiology of Major Depression: Review and Meta-Analysis
Authors: Patrick F. Sullivan, Michael C. Neale, Kenneth S. Kendler
Journal: American Journal of Psychiatry (2000)

The authors conducted a meta-analysis of relevant data from primary studies of the genetic epidemiology of major depression.The authors searched MEDLINE and the reference lists of previous review articles to identify relevant primary studies. On the basis of a review of family, adoption, and twin studies that met specific inclusion criteria, the authors derived quantitative summary statistics.Five family studies met the inclusion criteria. The odds ratios for proband (subjects with major depression or comparison subjects) versus first-degree relative status (affected or unaffected with major depression) were homogeneous across the five studies (Mantel-Haenszel odds ratio=2.84, 95% CI=2.31-3.49). No adoption study met the inclusion criteria, but the results of two of the three reports were consistent with genetic influences on liability to major depression. Five twin studies met the inclusion criteria, and their statistical summation suggested that familial aggregation was due to additive genetic effects (point estimate of heritability of liability=37%, 95% CI=31%-42%), with a minimal contribution of environmental effects common to siblings (point estimate=0%, 95% CI=0%-5%), and substantial individual-specific environmental effects/measurement error (point estimate=63%, 95% CI=58%-67%). The literature suggests that recurrence best predicts the familial aggregation of major depression.Major depression is a familial disorder, and its familiality mostly or entirely results from genetic influences. Environmental influences specific to an individual are also etiologically significant. Major depression is a complex disorder that does not result from either genetic or environmental influences alone but rather from both. These findings are notably consistent across samples and methods and are likely to be generally applicable.
Delayed time course of target lesion revascularization following saphenous vein graft angioplasty
Authors: M.K. Hong, R. Mehran, K.M. Kent, A.D. Pichard, L.F Satler, J.J. Popma, G.S. Mintz, H. Wu, T. Bucher, A. Greenberg, K. Morgan, T. Weaver, M.B. Leon
Journal: Journal of the American College of Cardiology (1998)
P275 Prevalence and Treatment of Active Asthma in Scotland Using the Prescribing Information System: Abstract P275 Table 1
Authors: MFC Steiner, G Devereux, SW Turner, J McLay, I Bishop, G Wyper
Journal: Thorax (2012)

<h3>Background</h3> Many studies of the clinical epidemiology of asthma that have used routinely collected drug prescription or dispensing data have been limited to samples assumed to be representative of the national population from which they are drawn. Our aim was to describe asthma prevalence and treatment in children and young adults using the Prescribing Information System (PIS), a national prescribing and dispensing database for Scotland. <h3>Methods</h3> For more than 95% of the dispensed prescriptions in primary care between December 2009 and November 2011 a valid patient identifier was available and the database includes some socio-demographical characteristics (age-group, sex, SIMD) of the patients. Data were also linked to hospital admission data. The analysis was limited to patients aged up to 44 years to reduce contamination by COPD. Data We identified 358,804 patients with 2,809,563 dispensed prescriptions for inhaled therapies used for asthma; equating to a prevalence of 11.4% of the 3,139,356 people aged 0–44 registered with a GP in Scotland. The age specific prevalence rates are detailed in the table. However, 95,207 patients had only one or two dispensed prescriptions for short-acting beta2-agonists (SABA) and no other inhaled therapies in the two years; we consider these patients to be unlikely to have active asthma (table). Additionally, 1,041 cases on inhaled therapy had hospital admission(s) with a diagnosis of COPD (ICD10: J40-J44) and are excluded from further analysis. 6,056 (2.3%) of people collecting inhaled therapy (&gt;2 SABA) had at least one hospital admission with a primary diagnosis of asthma. 18.4% of patients collected SABA only, 46.8% collected SABA + inhaled corticosteroids (ICS), 0.1% (371) collected SABA +long acting beta2 agonist (LABA) only, 13.6% collected SABA +combined ICS/LABA preparation, 2.1% collected SABA + ICS +LABA, 1.7% collected ICS/LABA only, leukotriene receptor antagonists (LTRA) were collected by 8.1% and long acting antimuscarinic agents (LAMA) were collected by 1.0%. <h3>Conclusion</h3> This current and whole population database indicates that the prevalence of asthma is approximately 10% in young adults and 15% in children living in Scotland but prevalence of active asthma is approximately 8% in adults and 10% in children.
Intracellular targeting of antigens internalized by membrane immunoglobulin in B lymphocytes.
Authors: R N Mitchell, K A Barnes, S A Grupp, M Sanchez, Z Misulovin, M C Nussenzweig, A K Abbas
Journal: The Journal of Experimental Medicine (1995)

An important function of membrane immunoglobulin (mIg), the B cell antigen receptor, is to endocytose limiting quantities of antigen for efficient presentation to class II-restricted T cells. We have used a panel of mIg mutants to analyze the mechanism of mIg-mediated antigen presentation, and specifically to explore the ability of mIg to target internalized antigen to intracellular processing compartments. Transfected mIgs carrying substitutions for the transmembrane Tyr587 residue fail to efficiently present specifically bound antigen. However, these mutants internalize antigen normally, and their defect cannot be attributed to a lack of mIg-associated Ig alpha/Ig beta molecules. A novel functional assay for detecting antigenic peptides in subcellular fractions shows that wild-type mIg transfectants generate class II-peptide complexes intracellularly, whereas only free antigenic peptides are detectable in the mutant mIg transfectants. Furthermore, an antigen competition assay reveals that antigen internalized by the mutant mIgs fails to enter the intracellular processing compartment accessed by wild-type mIg. Therefore, mIg specifically targets bound and endocytosed antigen to the intracellular compartment where processed peptides associate with class II molecules, and the transmembrane Tyr587 residue plays an obligatory role in this process. Targeting of internalized antigen may be mediated by receptor-associated chaperones, and may be a general mechanism for optimizing the presentation of specifically bound and endocytosed antigens in b lymphocytes and other antigen-presenting cells.
Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?
Authors: Dhananjay Gupta, Jack L. Leahy
Journal: Journal of Clinical Investigation (2014)

A hallmark of type 2 diabetes is the reduction of pancreatic islet β cell mass through induction of apoptosis and lack of regeneration. In most patients, β cell dysfunction is associated with the presence of extracellular amyloid plaques adjacent to β cells and intracellular toxic oligomers that are comprised of islet amyloid polypeptide (IAPP). In this issue of the JCI, three independent research groups reveal that a functional autophagy system normally prevents the accumulation of toxic IAPP oligomers in human IAPP-expressing murine models. Furthermore, mice expressing human IAPP but deficient for β cell autophagy through genetic deletion of the autophagy initiator ATG7 developed β cell apoptosis and overt diabetes. Together, these studies indicate that autophagy protects β cells from the accumulation of toxic IAPP oligomers and suggest that enhancing autophagy may be a novel target for prevention of type 2 diabetes.
Intrinsic chemoresistance to gemcitabine is associated with constitutive and laminin-induced phosphorylation of FAK in pancreatic cancer cell lines
Authors: Wu Huanwen, Liang Zhiyong, Shi Xiaohua, Ren Xinyu, Wang Kai, Liu Tonghua
Journal: Molecular Cancer (2009)

Abstract Background One of the major reasons for poor prognosis of pancreatic cancer is its high resistance to currently available chemotherapeutic agents. In recent years, focal adhesion kinase (FAK), a central molecule in extracellular matrix (ECM)/integrin-mediated signaling, has been thought to be a key determinant of chemoresistance in cancer cells. In this study, we aimed to determine the roles of FAK phosphorylation in the intrinsic chemoresistance of pancreatic cancer cell lines. Results Our results showed that, the level of constitutive phosphorylation of FAK at Tyr397 correlated with the extent of intrinsic resistance to Gemcitabine (Gem) in four pancreatic cancer cell lines. Moreover, in Panc-1 cells, which had high expression of pFAK, specific inhibition of constitutive FAK phosphorylation by either RNAi or FRNK overexpression decreased the phosphorylation of Akt, reduced the levels of survivin expression and Bad phosphorylation at Ser136 and increased Gem-induced cytotoxicity and apoptosis. However, in AsPC-1 cells with a low level of pFAK, neither FAK RNAi nor FRNK overexpression affected Gem-induced cell apoptosis. We further found that laminin (LN) induced FAK and Akt phosphorylation in a time-dependent manner, increased the levels of survivin and pBad (pS136) and decreased Gem-induced cytotoxicity and apoptosis in AsPC-1 cells; Specific inhibition of LN-induced FAK phosphorylation by either FAK RNAi or FRNK overexpression suppressed the effects of LN on AsPC-1 cells. Moreover, inhibition of constitutive FAK phosphorylation in Panc-1 cells and LN-induced FAK phosphorylation in AsPC-1 cells by a novel and more specific FAK phosphorylation inhibitor PF-573,228 showed similar results with those of FAK phosphorylation inhibition by FAK RNAi or FRNK overexpression. Conclusions In conclusion, our research demonstrates for the first time that both constitutive and LN-induced FAK phosphorylation contribute to increased intrinsic chemoresistance to Gem in pancreatic cancer cell lines and these effects are partly due to the regulation of Akt and Bad phosphorylation and survivin expression. Development of selective FAK phosphorylation inhibitors may be a promising way to enhance chemosensitivity in pancreatic cancer.
Is the process of urinary urea concentration responsible for a high glomerular filtration rate?
Authors: L Bankir, M Ahloulay, N Bouby, M M Trinh-Trang-Tan, F Machet, B Lacour, P Jungers
Journal: Journal of the American Society of Nephrology (1993)

For subjects on a normal diet, urea is the major urinary solute and is markedly concentrated in the urine compared with in the plasma. Because urea is not known to undergo active secretion, its excretion rests on filtration lessened to a variable extent by tubular reabsorption. It is well established that the efficiency of urea excretion drops with increasing urinary concentration and decreasing urinary flow rate (from approximately 60% of filtered load, above 2 mL/min, to approximately 20% below 0.5 mL/min) because the prolonged transit time in the distal nephron favors passive urea reabsorption. Thus, a higher urinary concentration is achieved at the expense of a reduced efficiency of urea excretion. Recent experimental observations suggest that GFR could actually increase in parallel with the urinary concentrating activity, thus ensuring a normal urea excretion in the face of a high, concentration-dependent urea reabsorption, with only a moderate increase in plasma urea. A possible mechanism is proposed that could explain how the vasopressin-induced intrarenal recycling of urea (which contributes to improvement in urinary concentration), but not an exogenous urea administration, could indirectly depress the tubuloglomerular feedback and hence increase GFR. An increased concentration of an osmotically active solute in the thick ascending limb of Henle's loop (such as urea and, in some cases, glucose) could enable a lower NaCl concentration to be achieved at the macula densa by reducing the osmotically driven water leakage in this nephron segment. This mechanism could explain the hyperfiltration seen in various pathophysiologic situations such as chronic vasopressin infusion, high protein intake, severe burns, and diabetes mellitus. Whatever the mechanism, if the need to excrete relatively high amounts of urea in a concentrated urine leads to a sustained elevation of GFR, the price to pay for this water economy is higher than generally assumed. It is not limited to the energy spent in the sodium reabsorption providing the "single effect" for the urinary concentrating process. It also includes the consequences on the glomerular filter of sustained high pressure and flow and the energy spent in reabsorbing the extra load of solutes filtered. In chronic renal failure, the ability to form hypertonic urine declines but is nevertheless well preserved with respect to declining GFR, thus imposing on remnant nephrons an additional permanent stimulus for hyperfiltration.(ABSTRACT TRUNCATED AT 400 WORDS)
Combined heterozygous loss of <i>Ebf1</i> and <i>Pax5</i> allows for T-lineage conversion of B cell progenitors
Authors: Jonas Ungerbäck, Josefine Åhsberg, Tobias Strid, Rajesh Somasundaram, Mikael Sigvardsson
Journal: The Journal of Experimental Medicine (2015)

To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19(+) progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de-differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5(+/-)Ebf1(+/-) pro-B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5(+/-)Ebf1(+/-) pro-B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation.
The Effect of Intensive Diabetes Treatment on Resting Heart Rate in Type 1 Diabetes
Authors: Andrew D. Paterson, Brandy N. Rutledge, Patricia A. Cleary, John M. Lachin, Richard S. Crow
Journal: Diabetes Care (2007)

OBJECTIVE—Cardiovascular disease is a major cause of morbidity and mortality in individuals with type 1 diabetes. Resting heart rate (RHR) is a risk factor for cardiovascular disease in the general population, and case-control studies have reported a higher RHR in individuals with type 1 diabetes. In individuals with type 1 diabetes, there is a positive correlation between A1C and RHR; however, no prospective studies have examined whether a causal relationship exists between A1C and RHR. We hypothesized that intensive diabetes treatment aimed to achieve normal A1C levels has an effect on RHR in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS—A total of 1,441 individuals with type 1 diabetes who participated in the Diabetes Control and Complications Trial (DCCT) had their RHR measured biennially by an electrocardiogram during the DCCT and annually for 10 years during the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. RESULTS—During the DCCT, intensive treatment was associated with lower mean RHR than conventional treatment, both in adolescents (69.0 vs. 72.0 bpm [95% CI 62.8–75.7 and 65.7–78.9, respectively], P = 0.013) and adults (66.8 vs. 68.2 [65.3–68.4 and 66.6–69.8, respectively], P = 0.0014). During follow-up in the EDIC, the difference in RHR between the treatment groups persisted for at least 10 years (P &amp;lt; 0.0001). CONCLUSIONS—Compared with conventional therapy, intensive diabetes management is associated with lower RHR in type 1 diabetes. The lower RHR with intensive therapy may explain, in part, its effect in reducing cardiovascular disease, recently demonstrated in type 1 diabetes.
Spatial and temporal distribution of airborne Bacillus thuringiensis var. kurstaki during an aerial spray program for gypsy moth eradication.
Authors: K Teschke, Y Chow, K Bartlett, A Ross, C van Netten
Journal: Environmental Health Perspectives (2001)

We measured airborne exposures to the biological insecticide Bacillus thuringiensis var. kurstaki (Btk) during an aerial spray program to eradicate gypsy moths on the west coast of Canada. We aimed to determine whether staying indoors during spraying reduced exposures, to determine the rate of temporal decay of airborne concentrations, and to determine whether drift occurred outside the spray zone. During spraying, the average culturable airborne Btk concentration measured outdoors within the spray zone was 739 colony-forming units (CFU)/m3 of air. Outdoor air concentrations decreased over time, quickly in an initial phase with a half time of 3.3 hr, and then more slowly over the following 9 days, with an overall half-time of about 2.4 days. Inside residences during spraying, average concentrations were initially 2-5 times lower than outdoors, but at 5-6 hr after spraying began, indoor concentrations exceeded those outdoors, with an average of 244 CFU/m3 vs. 77 CFU/m3 outdoors, suggesting that the initial benefits of remaining indoors during spraying may not persist as outside air moves indoors with normal daily activities. There was drift of culturable Btk throughout a 125- to 1,000-meter band outside the spray zone where measurements were made, a consequence of the fine aerosol sizes that remained airborne (count median diameters of 4.3 to 7.2 microm). Btk concentrations outside the spray zone were related to wind speed and direction, but not to distance from the spray zone.