Miracle-dz/UniFAR-FTUs huggingface dataset:
The IASLC Lung Cancer Staging Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours

Introduction: The seventh edition of the TNM Classification of Malignant Tumors is due to be published early in 2009. In preparation for this, the International Association for the Study of Lung Cancer established its Lung Cancer Staging Project in 1998. The recommendations of this committee for changes to the T, N, and M descriptors have been published. This report contains the proposals for the new stage groupings. Methods: Data were contributed from 46 sources in more than 19 countries. Adequate data were available on 67,725 cases of non-small cell lung cancer treated by all modalities of care between 1990 and 2000. The recommendations for changes to the T, N, and M descriptors were incorporated into TNM subsets. Candidate stage groupings were developed on a training subset and tested in a validation subset. Results: The suggestions include additional cutoffs for tumor size, with tumors >7 cm moving from T2 to T3; reassigning the category given to additional pulmonary nodules in some locations; and reclassifying pleural effusion as an M descriptor. In addition, it is suggested that T2b N0 M0 cases be moved from stage IB to stage IIA, T2a N1 M0 cases from stage IIB to stage IIA, and T4 N0–1 M0 cases from stage IIIB to stage IIIA. Conclusions: Such changes, if accepted, will involve a reassessment of existing treatment algorithms. However, they are based on an intensive and validated analysis of the largest database to date. The proposed changes would improve the alignment of TNM stage with prognosis and, in certain subsets, with treatment.
Changes in the gastrointestinal microbiota of children with acute lymphoblastic leukaemia and its association with antibiotics in the short term

Purpose. To detect the alteration of gut bacteria in children with ALL and analyse the impact of short‐term‐use of antibiotics on the changes caused by ALL. Methodology. We collected faecal samples from both children with ALL and healthy children. According to their medication history with antibiotics, we classified the samples into ALL+ATBx, ALL, CON+ATBx and CON groups. Next‐generation sequencing was performed to identify the gut bacteria according to the MiSeq platform. The Shannon index, Simpson index, Chao index and Ace index were used to represent the alpha diversity of gut bacteria. The beta diversity was estimated using the principles of co‐ordinate analysis and non‐metric multi‐dimensional scaling. The taxon composition and presence of biomarkers were then determined through bioinformatics. Results. With regard to alpha diversity, the Shannon index and Simpson index differed significantly between the ALL and CON groups, as well as the CON+ATBx and CON groups, but not the ALL+ATBx and CON+ATBx groups. With regard to beta diversity, the ALL and CON separated clearly into clusters, as did ALL+ATBx and CON+ATBx. There were differences in composition among the four groups at different taxonomy hierarchies. More bacteria showed an obvious difference between the paired groups ALL and CON than did for the paired groups ALL+ATBx and CON+ATBx. The area under the receiver operating characteristic curves for Bacteroidales and Enterococcaceae used to predict ALL were 0.735 and 0.724, respectively. Conclusion. ALL induced structural changes of the gut microbiota, with the alpha diversity being significantly weakened by antibiotics, but not beta diversity. Bacteroidales and Enterococcaceae can be referred to as biomarkers for ALL.
Control of rat GluR6 glutamate receptor open probability by protein kinase A and calcineurin

1 We have used non‐stationary variance analysis to examine the single channel conductance and the probability of channel opening at the peak of the homomeric GluR6 response (Po,peak) to 100–200 ms application (10–90% exchange time, 0–3 ms) of glutamate onto excised membrane patches from transiently transfected human embryonic kidney cells (HEK 293). 2 Our determinations of both Po,peak and single channel conductance of simulated current responses are insensitive to system filtering, response rise time, desensitization rate and measured variation in our drug perfusion speed. Isolation of stochastic current fluctuations using the local mean response waveform minimizes problems associated with modest run‐down of response amplitude during the experiment. 3 The slope conductance calculated from the weighted mean unitary currents for the channels activated in response to glutamate application is 16 pS. Chord conductance between −40 and −80 mV is independent of agonist concentration. Conversion of the codon for glutamine621 to arginine (Q621R) by RNA editing reduces conductance by more than 35‐fold to less than 0.4 pS without changing response time course, desensitization, or Po,peak. 4 P o,peak is high at saturating glutamate concentrations (0.65 ± 0.23; mean ±s.d.) and varies with agonist concentration. The half‐maximally effective glutamate concentration (EC50) determined for Po,peak (0.2 mm; Hill slope = 0.6) is similar to that determined for the macroscopic peak current amplitude (0.5 mm; Hill slope = 1.0) in response to rapid agonist application. 5 Inclusion of the purified catalytic subunit of cAMP‐dependent protein kinase A (PKA) in the patch pipette increases Po,peak to 0.85 ± 0.12 and co‐transfection of cells with a cDNA encoding the catalytic subunit of PKA (Cα‐PKA) increases Po,peak to 0.94 ± 0.09. 6 Inclusion of purified calcineurin plus its coactivators 200 nm Ca2+ and calmodulin in the patch pipette decreases Po,peak to 0.48 ± 0.10. The calcineurin‐stimulated decrease of Po,peak in cells co‐transfected with Cα‐PKA is blocked by 800 nm deltamethrin, a calcineurin inhibitor. Calmodulin, 200 nm Ca2+ and deltamethrin have no effect on Po,peak in the absence of calcineurin. As predicted from its effects on Po,peak, inclusion of calcineurin in the patch pipette accelerates the run‐down of whole cell GluR6 responses in cells co‐transfected with Cα‐PKA. 7 The effects of both calcineurin and PKA on Po,peak for GluR6 receptors in excised patches occur without any detectable changes to response time course, desensitization, or chord conductance. 8 We conclude that the binding of glutamate to homomeric GluR6 receptors is associated with a high probability of channel opening, which is under the control of two signalling systems that are known to be co‐localized at the neuronal membrane: PKA (Po,peak near 1.0) and calcineurin (Po,peak near 0.5).
Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis

The aim of this study was to define the standardized incidence ratio (SIR) of malignancy and the potential risk factors of concomitant malignancies in patients with inflammatory myopathies, including clinically amyopathic dermatomyositis (CADM). A total of 145 patients diagnosed with either dermatomyositis/polymyositis (DM/PM) or CADM at our institute between 1984 and 2002 were enrolled in the study. The demographic, clinical and laboratory features of the patients at the time of DM/PM or CADM diagnosis were compared between patients with and without malignancies, respectively. Multivariate analysis by logistic regression was used to determine the independent risk factors for the development of malignancies in DM/PM patients. Malignancy was found in 17 of 70 patients with DM (24%), three of 15 patients with CADM (20%), and three of 51 patients with PM (6%). Gastric cancer (8/23) was the most common malignancy. Compared with general population, the SIR of malignancies was 13.8 (range 9.0–21.1). The patients who developed malignancies were older (61.5 vs. 51.1 years; P < 0.005), presented more often with dysphagia (61 vs. 15%; P < 0.0001) and were less likely to have the complication of interstitial lung disease (30 vs. 60%; P < 0.05). These features were independent predictive factors for developing malignancies in multiple logistic regression analysis. The results of our study confirm that CADM in addition to DM was associated with high rates of malignancy among our patient cohort.
Transient renin–angiotensin system stimulation in an early stage of life causes sustained hypertension in rats

Objectives Transient administration of inhibitors of the renin–angiotensin system (RAS) during the prehypertensive period in rats and humans leads to a long-lasting lowering of blood pressure (BP). Our aim was to unravel the critical period in which activation of the RAS induces chronic effects on BP and to determine the role of renal function and structure in this process. Methods Studies were performed in Cyp1a1-Ren2 rats, which harbor a construct for the production of mouse renin. This construct becomes activated when indole-3-carbinol (I3C) is added to the diet. Young (4 weeks old) and adult (30 weeks old) Cyp1a1-Ren2 rats were randomly assigned to either the I3C treatment group or the control group. Renin production was stimulated from week 4 to 8 in young and week 30 to 34 in adult rats. BP follow-up was performed via photoelectric/oscillometric tail cuff method and intra-arterial BP was determined at 4, 8, 12 and 20 weeks of age or 34 and 38 weeks of age. Additionally, renal vascular resistance, albuminuria, renal inflammation and renal pathology were determined. Results Up to 20 weeks of age, that is, 12 weeks after I3C withdrawal, mean arterial pressure (MAP) was significantly elevated in young I3C-treated rats (141 ± 7 mmHg) compared with controls (125 ± 6 mmHg). In adult rats, renin stimulation caused only a transient elevation in MAP, which returned to control values after I3C withdrawal. In young rats, the sustained pressor response was associated with increased indices of renal vascular resistance, glomerulosclerosis and tubulointerstitial damage as well as with a moderate inflammatory response. In adult rats, renal pathology and inflammation was significantly less than in young rats and was reversible. Conclusion Transient RAS stimulation causes sustained elevation in BP in young, but not in adult Cyp1a1-Ren2 transgenic rats and is associated with irreversible changes in renal structure and function and a moderate renal inflammatory response.
The intergenic region between the divergently transcribed niiA and niaD genes of Aspergillus nidulans contains multiple NirA binding sites which act bidirectionally

The niaD and niiA genes of Aspergillus nidulans, which code, respectively, for nitrate and nitrite reductases, are divergently transcribed, and their ATGs are separated by 1,200 bp. The genes are under the control of the positively acting NirA transcription factor, which mediates nitrate induction. The DNA binding domain of NirA was expressed as a fusion protein with the glutathione S-transferase of Schistosoma japonicum. Gel shift and footprint experiments have shown that in the intergenic region there are four binding sites for the NirA transcription factor. These sites can be represented by the nonpalindromic consensus 5'CTCCGHGG3'. Making use of a bidirectional expression vector, we have analyzed the role of each of the sites in niaD and niiA expression. The sites were numbered from the niiA side. It appeared that site 1 is necessary for the inducibility of niiA only, while sites 2, 3, and to a lesser extent 4 (which is nearer to and strongly affects niaD) act bidirectionally. The results also suggest that of the 10 binding sites for the AreA protein, which mediates nitrogen metabolite repression, those which are centrally located are physiologically important. The insertion of an unrelated upstream activating sequence into the intergenic region strongly affected the expression of both genes, irrespective of the orientation in which the element was inserted.
Development of the physical therapy outpatient satisfaction survey (PTOPS).

BACKGROUND AND PURPOSE The purposes of this 3-phase study were (1) to identify the underlying components of outpatient satisfaction in physical therapy and (2) to develop a test that would yield reliable and valid measurements of these components. SUBJECTS Three samples, consisting of 177, 257, and 173 outpatients from 21 facilities, were used in phases 1, 2, and 3, respectively. METHODS AND RESULTS In phase 1, principal component analyses (PCAs), reliability checks, and correlations with social desirability scales were used to reduce a pool of 98 items to 32 items. These analyses identified a 5-component model of outpatient satisfaction in physical therapy. The phase 2 PCA, with a revised pool of 48 items, indicated that 4 components rather than 5 components represented the best model and resulted in the 34-item Physical Therapy Outpatient Satisfaction Survey (PTOPS). Factor analyses conducted with phase 2 and phase 3 data supported this conclusion and provided evidence for the internal validity of the PTOPS scores. The 4-component scales were labeled "Enhancers," "Detractors," "Location," and "Cost. " Responses from subsamples of phase 3 subjects provided evidence for validity of scores in that the PTOPS components of "Enhancers," "Detractors," and "Cost" appeared to differentiate overtly satisfied patients from overtly dissatisfied patients. "Location" and "Enhancer" scores discriminated subjects with excellent attendance at scheduled physical therapy sessions from those with poor attendance. CONCLUSION AND DISCUSSION In this study, we identified components of outpatient satisfaction in physical therapy and used them to develop a test that would yield valid and reliable measurements of these components.
Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection.

IMPORTANCE Treatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon. OBJECTIVE To determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment. DESIGN, SETTING, AND PARTICIPANTS Open-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants. INTERVENTIONS Treatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks. MAIN OUTCOMES AND MEASURES The primary study outcome was the proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks (SVR12) after cessation of HCV therapy. RESULTS Among treatment-naive participants, 87 patients (76%) of 114 (95% CI, 67%-84%) with genotype 1, 23 patients (88%) of 26 with genotype 2 (95% CI, 70%-985), and 28 patients (67%) of 42 with genotype 3 (95% CI, 51%-80%) achieved SVR12. Among treatment-experienced participants, 22 patients (92%) of 24 with genotype 2 (95% CI, 73%-99%) and 16 patients (94%) of 17 (95% CI, 71%-100%) achieved SVR12. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed. CONCLUSIONS AND RELEVANCE In this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12. Further studies of this oral regimen in diverse populations of coinfected patients are warranted. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01667731.
Subjective well-being and quality of life following traumatic brain injury in adults: A long-term population-based follow-up

Primary objective: To assess subjective well-being and quality-of-life in nationally representative samples of patients at long intervals following traumatic brain injuries. Methods and procedures: Patients with either cranial fractures or cerebral lesions were identified in a national computer-based register of hospital admissions and random samples were selected among those who had suffered the injury at 5, 10 or 15 years prior to the follow-up. Postal questionnaires were sent to them covering quality of life, e.g. return to employment, family relations and current subjective well-being in terms of symptomatology, e.g. somatic complaints, cognitive dysfunction. A response rate of 76% was obtained, comprising 114 patients with cranial fracture and 126 with cerebral lesions. Main outcomes and results: The group with cerebral lesions had markedly poorer quality of life and subjective well-being than the group with cranial fractures and this did not vary across time. In both groups, the most common symptoms concerned cognition. Among the cerebral lesion group, quality of life outcome was fairly well predicted by severity of injury, but subjective well-being was less well predicted. Conclusions: The negative consequences of traumatic cerebral lesions are marked and do not vary at long periods following injury.
Oxygen consumption during walking and running under fractional weight bearing conditions.

INTRODUCTION Knowledge of changes in oxygen consumption during reduced body weight loading at different speed levels is important, in particular in astronauts who may lose aerobic fitness as well as in clinical patients (e.g., in obese individuals at walking speeds or in injured athletes at running speeds). Therefore, the aim of this study was to analyze oxygen consumption during unloaded walking and running. METHODS Oxygen consumption (Vo2), heart rate (HR), and Borg rating of perceived exertion (Borg RPE) were quantified in 10 healthy young female and male volunteers at 3 body weight (BW) conditions (100%, 66%, and 33% BW) and 4 treadmill speeds (slow walking at 0.4 m x s(-1), comfortable walking at 1.3 m x s(-1), slow running at 2.2 m x s(-1), and moderately fast running at 3.1 m x s(-1)). Unloading was achieved in a waist-high chamber with increased pressure called Lower Body Positive Pressure (LBPP). RESULTS All parameters (Vo2, HR, and Borg RPE) decreased during unloaded walking and running. Interestingly, our findings confirm a specific linear relationship between each parameter and treadmill speed for each BW condition with smaller slope angles at higher levels of unloading (e.g., for Vo2, the slope angle decreased from 11.9 at 100% BW to 4.4 at 33% BW). DISCUSSION Oxygen consumption, heart rate, and Borg rating of perceived exertion are reduced during unloaded exercise with a relatively greater decline at higher treadmill speeds. That is, the higher the treadmill's speed in unloaded conditions, the relatively "easier" it is to exercise.
Functional and structural characterization of a thermostable acetyl esterase from Thermotoga maritima

TM0077 from Thermotoga maritima is a member of the carbohydrate esterase family 7 and is active on a variety of acetylated compounds, including cephalosporin C. TM0077 esterase activity is confined to short‐chain acyl esters (C2–C3), and is optimal around 100°C and pH 7.5. The positional specificity of TM0077 was investigated using 4‐nitrophenyl‐β‐D‐xylopyranoside monoacetates as substrates in a β‐xylosidase‐coupled assay. TM0077 hydrolyzes acetate at positions 2, 3, and 4 with equal efficiency. No activity was detected on xylan or acetylated xylan, which implies that TM0077 is an acetyl esterase and not an acetyl xylan esterase as currently annotated. Selenomethionine‐substituted and native structures of TM0077 were determined at 2.1 and 2.5 Å resolution, respectively, revealing a classic α/β‐hydrolase fold. TM0077 assembles into a doughnut‐shaped hexamer with small tunnels on either side leading to an inner cavity, which contains the six catalytic centers. Structures of TM0077 with covalently bound phenylmethylsulfonyl fluoride and paraoxon were determined to 2.4 and 2.1 Å, respectively, and confirmed that both inhibitors bind covalently to the catalytic serine (Ser188). Upon binding of inhibitor, the catalytic serine adopts an altered conformation, as observed in other esterase and lipases, and supports a previously proposed catalytic mechanism in which Ser hydroxyl rotation prevents reversal of the reaction and allows access of a water molecule for completion of the reaction. Proteins 2012. © 2012 Wiley Periodicals, Inc.
Bacteria-Triggered Systemic Immunity in Barley Is Associated with WRKY and ETHYLENE RESPONSIVE FACTORs But Not with Salicylic Acid1[C][W]

Infection of barley with bacteria induces systemic resistance against a secondary Xanthomonas translucens infection and does not appear to be associated with salicylic acid. Leaf-to-leaf systemic immune signaling known as systemic acquired resistance is poorly understood in monocotyledonous plants. Here, we characterize systemic immunity in barley (Hordeum vulgare) triggered after primary leaf infection with either Pseudomonas syringae pathovar japonica (Psj) or Xanthomonas translucens pathovar cerealis (Xtc). Both pathogens induced resistance in systemic, uninfected leaves against a subsequent challenge infection with Xtc. In contrast to systemic acquired resistance in Arabidopsis (Arabidopsis thaliana), systemic immunity in barley was not associated with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 or the local or systemic accumulation of salicylic acid. Instead, we documented a moderate local but not systemic induction of abscisic acid after infection of leaves with Psj. In contrast to salicylic acid or its functional analog benzothiadiazole, local applications of the jasmonic acid methyl ester or abscisic acid triggered systemic immunity to Xtc. RNA sequencing analysis of local and systemic transcript accumulation revealed unique gene expression changes in response to both Psj and Xtc and a clear separation of local from systemic responses. The systemic response appeared relatively modest, and quantitative reverse transcription-polymerase chain reaction associated systemic immunity with the local and systemic induction of two WRKY and two ETHYLENE RESPONSIVE FACTOR (ERF)-like transcription factors. Systemic immunity against Xtc was further associated with transcriptional changes after a secondary/systemic Xtc challenge infection; these changes were dependent on the primary treatment. Taken together, bacteria-induced systemic immunity in barley may be mediated in part by WRKY and ERF-like transcription factors, possibly facilitating transcriptional reprogramming to potentiate immunity.