tbuckley/cabot-search huggingface dataset:
Influence of the New AJCC Breast Cancer Staging System on Sentinel Lymph Node Positivity and False-Negative Rates
Authors: David R McCready, Wei Sean Yong, Alexander K T Ng, Naomi Miller, Susan Done, Bruce Youngson
Journal: JNCI Journal of the National Cancer Institute (2004)

The sixth and newest edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer now defines axillary sentinel lymph nodes with micrometastatic deposits 0.2 mm in diameter or smaller as node-negative. The aim of this study was to determine how this new classification scheme would affect axillary sentinel lymph node positivity, false-negative rate, and overall accuracy of an inception cohort of 205 breast cancer patients undergoing definitive surgery that included sentinel lymph node biopsy plus level I/II axillary lymphadenectomy. Based on the previous AJCC system for staging breast cancer, in which all sentinel lymph node metastases were considered positive, the rate of nodal positivity in this cohort was 47%, the overall accuracy was 99%, and the false-negative rate was 2.1%. According to the new classification system, the rate of nodal positivity in this cohort was 39.5% and the overall accuracy was 98%. The false-negative rate rose to 4.9% because two patients with micrometastatic deposits 0.2 mm or smaller, which are considered node-negative in the new system, had macroscopically positive disease in non-sentinel lymph nodes found in the completion lymphadenectomy.
Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease
Authors: Ming Zhan, Irtaza M. Usman, Lin Sun, Yashpal S. Kanwar
Journal: Journal of the American Society of Nephrology (2014)

Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under high-glucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or d-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of d-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, d-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest d-glucarate as a potential therapeutic agent for the amelioration of DKD.
Thoracic ultrasound in the diagnosis of malignant pleural effusion
Authors: N R Qureshi, N M Rahman, F V Gleeson
Journal: Thorax (2008)

<h3>Background:</h3> Malignant pleural effusion (MPE) is a common clinical problem with described investigation pathways. While thoracic ultrasound (TUS) has been shown to be accurate in pleural fluid detection, its use in the diagnosis of malignant pleural disease has not been assessed. A study was undertaken to assess the diagnostic accuracy of TUS in differentiating malignant and benign pleural disease. <h3>Methods:</h3> 52 consecutive patients with suspected MPE underwent TUS and contrast-enhanced CT (CECT). TUS was used to assess pleural surfaces using previously published CT imaging criteria for malignancy, diaphragmatic thickness/nodularity, effusion size/nature and presence of hepatic metastasis (in right-sided effusions). A TUS diagnosis of malignant or benign disease was made blind to clinical data/other investigations by a second blinded operator using anonymised TUS video clips. The TUS diagnosis was compared with the definitive clinical diagnosis and in addition to the diagnosis found at CECT. <h3>Results:</h3> A definitive malignant diagnosis was based on histocytology (30/33; 91%) and clinical/CT follow-up (3/33; 9%). Benign diagnoses were based on negative histocytology and follow-up over 12 months in 19/19 patients. TUS correctly diagnosed malignancy in 26/33 patients (sensitivity 73%, specificity 100%, positive predictive value 100%, negative predictive value 79%) and benign disease in 19/19. Pleural thickening &gt;1 cm, pleural nodularity and diaphragmatic thickening &gt;7 mm were highly suggestive of malignant disease. <h3>Conclusion:</h3> TUS is useful in differentiating malignant from benign pleural disease in patients presenting with suspected MPE and may become an important adjunct in the diagnostic pathway.
Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction
Authors: Nazha Hamdani, Kalkidan G. Bishu, Marion von Frieling-Salewsky, Margaret M. Redfield, Wolfgang A. Linke
Journal: Cardiovascular Research (2012)

Heart failure (HF) with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Key alterations in HFpEF include increased left ventricular (LV) stiffness and abnormal relaxation. We hypothesized that myofilament protein phosphorylation and function are deranged in experimental HFpEF vs. normal myocardium. Such alterations may involve the giant elastic protein titin, which contributes decisively to LV stiffness. LV tissue samples were procured from normal dogs (CTRL) and old dogs with hypertension-induced LV hypertrophy and diastolic dysfunction (OHT/HFpEF). We quantified the expression and phosphorylation of myofilament proteins, including all-titin and site-specific titin phosphorylation, and assessed the expression/activity of major protein kinases (PKs) and phosphatases (PPs), myofilament calcium sensitivity (pCa50), and passive tension (Fpassive) of isolated permeabilized cardiomyocytes. In OHT vs. CTRL hearts, protein kinase-G (PKG) activity was decreased, whereas PKCα activity and PP1/PP2a expression were increased. Cardiac MyBPC, TnT, TnI and MLC2 were less phosphorylated and pCa50 was increased in OHT vs. CTRL. The titin N2BA (compliant) to N2B (stiff) isoform-expression ratio was lowered in OHT. Hypophosphorylation in OHT was detected for all-titin and at serines S4010/S4099 within titin-N2Bus, whereas S11878 within proline, glutamate, valine, and lysine (PEVK)-titin was hyperphosphorylated. Cardiomyocyte Fpassive was elevated in OHT, but could be normalized by PKG or PKA, but not PKCα, treatment. This patient-mimicking HFpEF model is characterized by titin stiffening through altered isoform composition and phosphorylation, both contributing to increased LV stiffness. Hypophosphorylation of myofilament proteins and increased calcium sensitivity suggest that functional impairment at the sarcomere level may be an early event in HFpEF.
Case against psychoanalysis in modern mental health services was unsubstantiated rhetoric
Authors: T. D. Simpson
Journal: BMJ (2012)

Salkovskis and Wolpert argue that psychoanalysis has no place in modern mental health services and make several damaging statements about its value.1 These include: that psychoanalysis resists the notion of outcome evaluation—“it makes no attempt to diagnose the patient’s condition, and does not recognise schizophrenia, or others with a genetic cause”; that “no attempt is made to find a cure”; and …
THE CULTURAL DIFFERENTIATION OF BETA HEMOLYTIC STREPTOCOCCI OF HUMAN AND BOVINE ORIGIN
Authors: J. Howard Brown
Journal: The Journal of Experimental Medicine (1920)

None of the procedures described serves by itself to differentiate streptococci of human and bovine origin with certainty, though each of them serves as a strong presumptive test. Most strains fall easily into the human or bovine group by all the tests. Eliminating these from consideration we have left certain irregular strains listed in Table VII. See PDF for Structure Taking all characters into consideration we are inclined to regard Strains J-E7, Cheese 1, and Cheese 2 as undoubtedly of bovine origin. Strain J-MJ also is representative of a group of streptococci which Jones has found in milk and which is being further studied by him. There remains Strain J-C65 which for the present must be regarded as of doubtful origin.
PAROTITIS ASSOCIATED WITH GLYCOSURIA AND ACIDOSIS
Authors: L. M. Routh
Journal: BMJ (1912)

WITH GLYCOSURiA. 'ULY 13,TI12.disease, lead poisoning, and so on.Harrogate has the advantage that treatment can be carried out in some cases as well in the winter as in the summer, and our sulplhur batlh, from its soothing effect in some cases of gouty eczema, etc., has earned the title of the Velvet Batlh.In 1626 Dr. Dean wrote concernino one of the first vells:It (dries up the too moist brain, and helps rheums, palsies, Gramps, etc.It is good againist inveterate headache, megrims, vortigo, epilepsy, convulsions, and the like, cold and moist diseases of the head.It cheers the spirits, strengthens the stomach, an(d promotes digestion.It's good in black an(d yellow jaundice anld hippo, as also in caclhexy an(d beginning dropsy, seeinlg it open-s obstructions and expels redundant serosities, etc.
The Molecular Biology of Cystic Fibrosis
Authors: T J Sferra, F S Collins
Journal: Annual Review of Medicine (1993)

Cystic fibrosis afflicts many children and, as the life expectancy for patients with this disease steadily increases, many adults as well. The identification and characterization of the gene responsible for this disorder provide a basis for understanding the pathophysiology of cystic fibrosis. Basic science advances are rapidly being integrated into the diagnostic and therapeutic regimens used by physicians in the care of patients with this disease.
The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: implications for necrosis initiation
Authors: Laura Bianchi, Beate Gerstbrein, Christian Frøkjær-Jensen, Dewey C Royal, Gargi Mukherjee, Mary Anne Royal, Jian Xue, William R Schafer, Monica Driscoll
Journal: Nature Neuroscience (2004)
Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins.
Authors: P W Sanders, B B Booker, J B Bishop, H C Cheung
Journal: Journal of Clinical Investigation (1990)

Proteinaceous cast formation in the distal nephron of the kidney from low molecular weight proteinuria is a significant, but poorly characterized, cause of renal failure. To study this phenomenon, we: (a) microperfused the loop segment (LS) of rats in vivo with artificial tubule fluid (ATF) containing four different low molecular weight proteins, 0.01-50 mg/ml, to detect alterations in LS function, and (b) examined the interaction between several proteins and Tamm-Horsfall glycoprotein (THP) in vitro with turbidity and dynamic light-scattering measurements. Perfusion of the LS for less than 2 min with cast-forming proteins (Bence Jones protein [BJP3] and myoglobin) decreased chloride absorption and elevated early distal tubule fluid (ED) [Cl-], compared with results obtained with control perfusions that used ATF alone. BJP3 decreased chloride absorption in a concentration-dependent fashion. Perfusion with non-cast-forming proteins (albumin and BJP1) enhanced chloride absorption and decreased ED [Cl-]. In vitro, proteins that had isoelectric points (pI) greater than 5.1 aggregated with THP. Aggregation was enhanced with increasing [NaCl] or [CaCl2]. Albumin (pI 4.8) and beta-lactoglobulin (pI 5.1) did not coprecipitate. The molecular size of THP alone increased when [NaCl] greater than 80 mM. Thus, cast-forming proteins aggregated with THP in vitro and caused in vivo LS dysfunction, which elevated ED [Cl-], facilitating aggregation. In contrast, non-cast-forming proteins either did not interact with THP or lowered ED [Cl-], which did not provide an environment for aggregation. Altered LS function and interaction of some proteins with THP were related to different physicochemical properties of the proteins and independently contributed to the formation of proteinaceous casts in the kidney.
Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial
Authors: Aliaksandr Skrahin, Raija K Ahmed, Giovanni Ferrara, Lalit Rane, Thomas Poiret, Yanina Isaikina, Alena Skrahina, Alimuddin Zumla, Markus J Maeurer
Journal: The Lancet Respiratory Medicine (2014)
Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration and Proliferation Depend on a Nitric Oxide–Mediated Decrease in Protein Kinase Cδ Activity
Authors: Yukitaka Shizukuda, Shaoqing Tang, Ryoji Yokota, J. Anthony Ware
Journal: Circulation Research (1999)

Abstract —Vascular endothelial growth factor (VEGF) promotes angiogenesis and endothelial cell (EC) migration and proliferation by affecting intracellular mediators, only some of which are known, distal to its receptors. Protein kinase C (PKC) participates in the function of VEGF, but the role of individual PKC isoenzymes is unknown. In this study, we tested the importance of the activity of specific PKC isoenzymes in human EC migration and proliferation in response to VEGF. PKCδ specific activity was depressed by the addition of VEGF (by 41±8% [P&lt;0.05] at 24 hours) in human umbilical vein ECs (HUVECs) and in a HUVEC-derived EC line, ECV, without changing the total amount of either protein or mRNA encoding PKCδ. Neither basic fibroblast growth factor (FGF-2) nor serum altered PKCδ specific activity. The VEGF-induced decrease of PKCδ activity, which began at 8 hours after stimulation, was strongly blocked by pretreatment with the nitric oxide (NO) synthase inhibitor N G -monomethyl- l -arginine in HUVECs; NO release peaked within 2 hours after stimulation. An exogenous NO donor, sodium nitroprusside, also decreased PKCδ activity. The inhibition by N G -monomethyl- l -arginine of VEGF-induced HUVEC migration and proliferation, but not that induced by FGF-2 or serum, suggested that the decrease in PKCδ via NO pathway is required for VEGF-induced EC migration and proliferation. Overexpression of PKCδ in ECV cells specifically prevented EC response to VEGF but not to FGF-2 or serum. Thus, we conclude that suppression of PKCδ activity via a NO synthase mechanism is required for VEGF-induced EC migration and proliferation, but not for that induced by FGF-2 or serum.
20-MST and PWC170 validity in non-Caucasian children in the UK.
Authors: C Mahoney
Journal: British Journal of Sports Medicine (1992)

The validity was investigated of 20-MST (20 Metre Endurance Shuttle Run Test) and PWC170 (Physical Working Capacity) field tests with laboratory-measured peak oxygen uptake (VO2peak) in a multiracial UK population of 12-year olds: 103 subjects completed the 20-MST and 96 of these completed the PWC170. To assess validity, a laboratory treadmill test was completed by ten boys and ten girls who had performed both field tests. VO2peak was 43.8 ml kg-1 min-1 for boys and 38.5 ml kg-1 min-1 for girls. Pearson product-moment correlation showed 20-MST to be a reliable measure of cardiorespiratory fitness (r = 0.83, boys; r = 0.76, girls, P less than 0.03), while correlations with PWC170 were lower (r = 0.64, boys; r = 0.54, girls) and not significant. The 20-MST was consistent in retest (n = 20) - reliability coefficients r = 0.73, boys; r = 0.88, girls; P less than 0.01. The results suggest 20-MST is a valid, measure of fitness in this population when compared with VO2peak. PWC170 is less valid, possibly due to cultural and social backgrounds. The cycle test was inappropriate in this population, especially for girls unaccustomed to exercise and cycling. The 20-MST test is recommended for large groups of children when facilities are limited. It requires limited skill or habituation and is relatively non-invasive.
A Summary of the ADVANCE Trial
Authors: Simon R. Heller
Journal: Diabetes Care (2009)

The publication of the U.K. Prospective Diabetes Study (UKPDS) in 1998 helped to shape the management of type 2 diabetes in recent years (1). The study demonstrated several points. First, sulfonylureas are as safe as insulin in controlling blood glucose. Second, metformin reduced cardiovascular disease in an overweight subgroup. Third, the same benefit of glycemic control in reducing microvascular disease (previously noted in type 1 diabetes) is applied equally to patients with type 2 diabetes. A separation in A1C of ∼1% in the UKPDS reduced the risk of microvascular disease (largely diabetic retinopathy) by ∼25%. This reflected the data from the Diabetes Control and Complications Trial, where a separation in A1C of 2% in intensive and standard groups led to a reduction in microvascular disease of ∼50% (2).

A fourth demonstration was that there was no significant reduction in macrovascular disease but a trend toward fewer myocardial infarctions with more intensive glucose control. Fifth, using the current treatment of the time (first-generation sulfonylureas, human ultratard insulin, or metformin), it proved impossible to maintain glucose control, which tended to deteriorate throughout the study. It is now generally believed that the progressive fall in endogenous insulin production as β-cell numbers decline makes it difficult, if not impossible, to maintain tight control using standard treatment. Sixth, the UKPDS also showed that in those patients with hypertension, lowering blood pressure (BP) to moderate levels with either captopril or atenolol could reduce microvascular disease (3).

In a subsequent study, the UKPDS investigators presented the rates of both micro- and macrovascular disease according to the achieved levels of A1C during the study (4). They showed a linear relationship between A1C and both groups of complications. The implication of the article was that if glycemic control could be tightened below the levels achieved in the UKPDS, then it might be possible to reduce rates, not only of microvascular complications, but also cardiovascular disease as well.

The aim of the glucose arm of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (5) was to build on the information gained by the UKPDS and to answer the question as to whether intensifying glucose control to achieve an A1C of <6.5% would provide additional benefit in reducing the risk of both micro- and macrovascular disease.

ADVANCE also asked questions about BP lowering in patients with type 2 diabetes. The aims of the BP arm were to establish whether routine provision of BP-lowering therapy produced additional benefits in terms of macro- and microvascular disease, irrespective of baseline BP, and added to the benefits produced by other cardiovascular preventive therapies, including ACE inhibitors.
Evaluating Topological Conflict in Centipede Phylogeny Using Transcriptomic Data Sets
Authors: Rosa Fernández, Christopher E. Laumer, Varpu Vahtera, Silvia Libro, Stefan Kaluziak, Prashant P. Sharma, Alicia R. Pérez-Porro, Gregory D. Edgecombe, Gonzalo Giribet
Journal: Molecular Biology and Evolution (2014)

Relationships between the five extant orders of centipedes have been considered solved based on morphology. Phylogenies based on samples of up to a few dozen genes have largely been congruent with the morphological tree apart from an alternative placement of one order, the relictual Craterostigmomorpha, consisting of two species in Tasmania and New Zealand. To address this incongruence, novel transcriptomic data were generated to sample all five orders of centipedes and also used as a test case for studying gene-tree incongruence. Maximum likelihood and Bayesian mixture model analyses of a data set composed of 1,934 orthologs with 45% missing data, as well as the 389 orthologs in the least saturated, stationary quartile, retrieve strong support for a sister-group relationship between Craterostigmomorpha and all other pleurostigmophoran centipedes, of which the latter group is newly named Amalpighiata. The Amalpighiata hypothesis, which shows little gene-tree incongruence and is robust to the influence of among-taxon compositional heterogeneity, implies convergent evolution in several morphological and behavioral characters traditionally used in centipede phylogenetics, such as maternal brood care, but accords with patterns of first appearances in the fossil record.
<sup>18</sup>F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging
Authors: Min Yang, Haokao Gao, Yaru Zhou, Ying Ma, Qimeng Quan, Lixin Lang, Kai Chen, Gang Niu, Yongjun Yan, Xiaoyuan Chen
Journal: Theranostics (2011)

Radiolabeled bombesin analogs are promising probes for cancer imaging of gastrin-releasing peptide receptor (GRPR). In this study, we developed (18)F-labeled GRPR agonists and antagonists for positron emission tomography (PET) imaging of prostate cancer. GRPR antagonists ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH(2)CH(3)) and MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH(2)CH(3)), and agonists AGBBN (Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) and MAGBBN (Gly-Gly-Gly-Arg-Asp-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) were radiolabeled with (18)F via 4-nitrophenyl 2-(18)F-fluoropropionate. The in vitro receptor binding, cell uptake, and efflux properties of the radiotracers were studied on PC-3 cells. An in vivo PET study was performed on mice bearing PC-3 tumors. Direct (18)F-labeling of known GRPR antagonist ATBBN and agonist AGBBN did not result in good tumor targeting or appropriate pharmacokinetics. Modification was made by introducing a highly hydrophilic linker Gly-Gly-Gly-Arg-Asp-Asn. Higher receptor binding affinity, much higher cell uptake and slower washout were observed for the agonist (18)F-FP-MAGBBN over the antagonist (18)F-FP-MATBBN. Both tracers showed good tumor/background contrast, with the agonist (18)F-FP-MAGBBN having significantly higher tumor uptake than the antagonist (18)F-FP-MATBBN (P < 0.01). In conclusion, Gly-Gly-Gly-Arg-Asp-Asn linker significantly improved the pharmacokinetics of the otherwise hydrophobic BBN radiotracers. (18)F-labeled BBN peptide agonists may be the probes of choice for prostate cancer imaging due to their relatively high tumor uptake and retention as compared with the antagonist counterparts.
Proteomic Patterns of Preinvasive Bronchial Lesions
Authors: S. M. Jamshedur Rahman, Yu Shyr, Pinar B. Yildiz, Adriana L. Gonzalez, Huiming Li, Xueqiong Zhang, Pierre Chaurand, Kiyoshi Yanagisawa, Bonnie S. Slovis, Robert F. Miller, Mathew Ninan, York E. Miller, Wilbur A. Franklin, Richard M. Caprioli, David P. Carbone, Pierre P. Massion
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

A proteomics approach is warranted to further elucidate the molecular steps involved in lung tumor development. We asked whether we could classify preinvasive lesions of airway epithelium according to their proteomic profile.