Miracle-dz/UniFAR-FTUs huggingface dataset:
Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer

Purpose: A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled. Experimental Design: We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients. Results: We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286–9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial–mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed. Conclusions: Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095–104. ©2016 AACR. See related commentary by Morris and Kopetz, p. 3989
α‐Conotoxins active at α3‐containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition

Neuronal α3‐containing nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (PNS) and non‐neuronal tissues are implicated in a number of severe disease conditions ranging from cancer to cardiovascular diseases and chronic pain. However, despite the physiological characterization of mouse models and cell lines, the precise pathophysiology of nAChRs outside the CNS remains not well understood, in part because there is a lack of subtype‐selective antagonists. α‐Conotoxins isolated from cone snail venom exhibit characteristic individual selectivity profiles for nAChRs and, therefore, are excellent tools to study the determinants for nAChR‐antagonist interactions. Given that human α3β4 subtype selective α‐conotoxins are scarce and this is a major nAChR subtype in the PNS, the design of new peptides targeting this nAChR subtype is desirable. Recent studies using α‐conotoxins RegIIA and AuIB, in combination with nAChR site‐directed mutagenesis and computational modelling, have shed light onto specific nAChR residues, which determine the selectivity of the α‐conotoxins for the human α3β2 and α3β4 subtypes. Publications describing the selectivity profile and binding sites of other α‐conotoxins confirm that subtype‐selective nAChR antagonists often work through common mechanisms by interacting with the same structural components and sites on the receptor.
The impact of workplace bullying on hotel employees’ well-being

PurposeThe purpose of this study was to investigate the moderating effects of organizational justice and workplace friendship on the relationship between workplace bullying and hotel employees’ well-being.Design/methodology/approachThe research sample included 310 entry-level employees of international tourism hotels in Taiwan. This study adopted hierarchical regression for data analysis.FindingsThe study found that workplace bullying negatively impacted on hotel employees’ well-being. Organizational justice and workplace friendship had significantly positive effects on hotel employees’ well-being. Compared with workplace friendship, organizational justice had a significant moderating effect on the relationship between workplace bullying and hotel employees’ well-being.Originality/valueIn the research fields of hospitality, past studies failed to use organizational justice and workplace friendship to moderate the relationship between workplace bullying and hotel employees’ well-being. This study confirmed that organizational justice could effectively buffer the negative effect of workplace bullying on hotel employees’ well-being.
Cancer Care Burden among Primary Family Caregivers of Iranian Hematologic Cancer Patients.

BACKGROUND Providing care for hematologic cancer patients may lead to many negative complications in different aspects of life in their family caregivers. Based on a wide review of relevant literature, there are limited data about the burden of giving care for hematologic cancer patients on their primary family caregivers in Iran or other Middle Eastern countries. Therefore, the aim of this study was to investigate the cancer care burden on primary family caregivers of hematologic cancer patients, in terms of physical, psychological, social, spiritual, and financial aspects. MATERIALS AND METHODS In this descriptive study, 151 primary family caregivers of hematologic cancer patients referred to two cancer care centers in East Azerbaijan Province in northwest of Iran participated. The Financial Distress/Financial Well-being Scale, Hospital Anxiety and Depression Scale, Vaux Social Support Questionnaire, Spiritual Well-being Scale, and SF-36 were used for data collection. Data analysis was performed with SPSS software. RESULTS The findings of this study indicated that the primary family caregivers experience a high level of financial distress and a significant percentage of them suffered from anxiety and depression. In addition, the physical quality of life in these caregivers was moderate. On the other hand, spiritual health and social support of participants was at an acceptable level. CONCLUSIONS Iranian primary family caregivers of hematologic cancer patients experience many problems in physical, psychological, and financial aspects of their life. Therefore, developing care plans for reducing these problems appears necessary.
The Assessment of Post-Detoxification Anhedonia: Influence of Clinical and Psychosocial Variables

Anhedonia, or the inability to experience pleasure, may be regarded either as a temperamental trait or as a state symptom of negative schizophrenia or melancholic depression. In substance use disorders, anhedonia was linked to hypoactivity of the dopaminergic mesolimbic system during protracted withdrawal. The authors investigated the influence of recent clinical and social-environmental factors on the hedonic capability and related psychopathology in a sample of 70 patients manifesting substance dependence (alcohol, opiates, multiple drugs) without severe comorbidity. Three symptom scales covering anhedonia (Snaith-Hamilton Pleasure Scale, SHAPS; Scale for the Assessment of Negative Symptoms, SANS; Bech-Rafaelsen Melancholia Scale, BRMES) were administered together with the European adaptation of the Addiction Severity Index (EuropASI). The composite scores from the seven areas of the EuropASI were introduced as independent factors in a stepwise regression analysis having symptom scores of anhedonia as dependent variables. Overall, the EuropASI composites do not explain the variability of the scores of anhedonia. Only in few cases, the regression models show a weak predictive capacity for medical status, alcohol use, and drug use composite scores, with R-square values ranging from 10 to 22%. Even if the study's limitations are noted, anhedonia appears as a psychopathological entity independent from other clinical and psychosocial features of treated addicts.
Warfarin resistance in a French strain of rats

A warfarin‐resistant strain and a warfarin‐susceptible strain of wild rats (Rattus norvegicus) maintained in enclosures of the National Veterinary School of Lyon (France) were studied to determine the mechanism of the resistance to anticoagulant rodenticides. A low vitamin K epoxide reductase (VKOR) activity has been reported for many resistant rat strains. As recently suggested, mutations in the vitamin K epoxide reductase subunit 1 (VKORC1) gene are the genetic basis of anticoagulant resistance in wild populations of rats from various locations in Europe. Here we report, for our strain, one of the seven described mutations (Tyr139Phe) for VKORC1 in rats. In addition, a low expression of mRNA encoding VKORC1 gene is observed in resistant rats, which could explain their low VKOR activity. We calculated kinetic parameters of VKOR in the warfarin‐resistant and warfarin‐susceptible rats. The Vmax and the Km of the VKOR obtained in resistant rats were lowered by 57 and 77%, respectively, compared to those obtained in susceptible rats. As a consequence, the enzymatic efficiency (Vm/Km) of the VKOR was similar between resistant and susceptible rats. This result could be a good explanation to the observation that no clinical signs of vitamin K deficiency was observed in the warfarin‐resistant strain, while a low VKOR activity was found. VKOR activity in warfarin‐resistant rats was poorly inhibited by warfarin (Ki for warfarin is 29 μM and 0.72 μM for resistant and susceptible rats, respectively). © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:379‐385, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20104
Time-dependent inflammatory factor production and NFκB activation in a rodent model of intermittent hypoxia.

OBJECTIVE To study the systemic production of inflammatory factors and activation of transcription factor nuclear factor kappa B (NF-κB) in response to different levels of intermittent hypoxia and time. METHODS A total of 160 male Wistar rats were divided randomly into five groups. The first three groups were exposed to 5%, 7.5% and 10% intermittent hypoxia (referred to as IH-1, IH-2, and IH-3 respectively), the fourth group were subjected to 10% sustained hypoxia (abbreviated as SH), and the control group were exposed to normal oxygen (designated SC). At the second, fourth, sixth, and eighth week, eight rats in each group were sacrificed to collect serum. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum concentration of tumour necrosis factor alpha (TNF-α), interleukin-8 (IL-8), interleukin-6 (IL-6) and interleukin-10 (IL-10). Western blot was used to detect the protein levels of the phosphorylated NF-κB P65 in the nucleus of arterial endothelial cells. RESULTS In all three IH groups serum levels of TNF-α, IL-8 and IL-6 showed consecutive increment from onset to the 6th week under intermittent hypoxia; the levels of TNF-α and IL-8 dropped slightly on the 8th week, whereas those of IL-6 continued to increase. The levels of IL-10 decreased and reached nadir at the 6th week of intermittent hypoxia treatment. The inflammatory response was the most pronounced in the 6th week, at which time the TNF-α, IL-8 and IL-6 levels in IH groups were significantly higher than in the SC and SH group (F = 30.04, 11.77, 18.589; p <0.05). IL-10 levels were significantly lower than the SC and SH group (F = 10.403, p <0.05). Levels of TNF-α and IL-8 in the IH-1 group were significantly higher than those in the IH-3 group (F = 1.20, 34.68; p = 0.049, 0.046). Protein levels of phosphorylated NF-κB P65 in endothelial cells collected from thoracic aorta in all three IH groups were significantly higher than those in SC and SH groups (F = 63.136, p = 0.01). A close correlation was identified between NF-κB p65 phosphorylation and the levels of TNF-α, IL-8, IL-6 and IL-10 (p = 0.01). CONCLUSIONS The inflammatory response, manifested by serum levels of inflammatory factors and nuclear accumulation of activated NF-κB P65, was more serious in the IH group than in the SH and control group, and was dependent on hypoxia levels. This reaction increased initially and then decreased, which indicates the presence of compensatory mechanisms and an adaptive response to such stressors in the body. Notably, the correlation of NFκB activation to production of inflammatory factors under intermittent hypoxia implies an important role of this transcription factor in inflammation-induced cardiovascular damage occurring during obstructive sleep apnoea (OSA), which has a typical breathing pattern of intermittent hypoxia.
Novel Compact Ultra-Wideband Bandpass Filter Employing Short-circuited Stubs with Coupled Stepped-Impedance Resonator

A novel compact ultra-wideband (UWB) bandpass filter is proposed to meet federal communications commission (FCC)'s spectrum mask. Shunt short-circuited stubs and the parallel coupled stepped-impedance resonators (SIRs) are used to achieve a fraction passband from 3.1 GHz to 10.6 GHz. The equivalent circuit of the newly proposed filter is established, while the corresponding chebyshev-type transfer function is derived for filter synthesis. Compared with formerly proposed UWB filter without short-circuited stubs, the new one significantly improves the selectivity and out-of-band characteristics to completely satisfy the FCC spectrum mask. In addition, the use of the short-stubs effectively enlarged the coupling gaps (from 0.05 mm to 0.15 mm) to successfully alleviate the requirement on fabrication precision. For verification, the proposed filter is synthesized, simulated and fabricated in microstrip line. The good agreement between the measured and predicted results validates the effectiveness of newly proposed synthesis theory. Meanwhile, the designed filter exhibits very compact size, good characteristics of low insertion loss, sharp skirts, flat group delay and good stopband (especially in lower one) as well.
The Asher-McDade Aesthetic Index in Comparison With Two Scoring Systems in Nonsyndromic Complete Unilateral Cleft Lip and Palate Patients

Objective:To compare the Asher-McDade aesthetic index with 2 systems used to score the appearance of the nasolabial area in patients with a complete cleft lip and palate. Design:Retrospective analysis of the results of complete unilateral cleft lip and palate patients. Setting:Academic Center for Dentistry of Amsterdam and the VU University Medical Center. Patients:Six-year-olds with complete unilateral cleft lip and palate. Main outcome measures:Cleft lip and palate patients assessed using the scoring system proposed by Prahl et al, a 5-point ordinal scale, and the scoring system proposed by Asher-McDade et al by 6 judges, 3 orthodontists, and 3 plastic surgeons. A calculation of intra- and interobserver reliability was made. A comparison was made of all the assessment methods using Kendalls’ tau. Results:Photographs of 55 children (38 boys and 17 girls) with complete unilateral cleft lip and palate were assessed. For the scoring system of Prahl et al, interobserver reliability varied from 0.43 to 0.53, for the 5-point scale between 0.45 and 0.57, and for the scoring system by Asher-McDade et al these varied between 0.52 and 0.66. Multiple significant correlations were found between the used scoring systems. Conclusion:It can be concluded that the Asher-McDade aesthetic index is still superior to the other scoring systems used in this study. However, all 3 scoring systems can reliably be used when 3 or more observers are used.
Characterizing HIV Manifestations and Treatment Outcomes of Perinatally Infected Adolescents in Asia

Background: More perinatally HIV-infected children in Asia are reaching adolescence. Methods: We analyzed data from July 1991 to March 2011 reported by 18 clinics in 6 countries of children age >12 years. Results: Of 1254 adolescents, 33 (2.6%) died, and 52 (4.1%) were lost to follow-up within 2.4-year (3566 person-years) median follow-up period. Of 1061 adolescents under active follow-up, 485 (46%) were male, median (interquartile range) age was 14.7 (13.3–16.4) years, 73% had lost a parent(s), 93% attended school and 62% were aware of their HIV status. At the most recent evaluation, 93% were receiving highly active antiretroviral therapy, 71% (N = 737/1035) had CD4 ≥500 cells/mm3 and 87% (N = 718/830) had viral load (VL) <400 copies/mL. Current CD4 ≥200 cells/mm3, no previous World Health Organization stage 3 or 4 and being on a first-line regimen were independently associated with recent VL <400 copies/mL. Current age <15 years, VL <400 copies/mL, CD4 15–24% (vs. <10%) at antiretroviral therapy initiation, no previous World Health Organization stage 3 or 4 and antiretroviral therapy duration of ≥1 year were associated with recent CD4 ≥500 cells/mm3. Primary causes of death after age 12 were opportunistic infections (N = 15/33) and other AIDS- or treatment-related conditions (N = 9/33). Those at age 12 with CD4 <200 versus ≥500 cells/mm3 and those with VL ≥10,000 versus <10,000 copies/mL were 17.4 and 4.76 times more likely to die in adolescence, respectively. Conclusion: Adolescents in this cohort have been successfully maintained in HIV care. Initiating treatment at earlier stages of disease was associated with immune recovery and virologic suppression during adolescence.
Development of an Instrument to Measure the Perceptions of Adopting an Information Technology Innovation

This paper reports on the development of an instrument designed to measure the various perceptions that an individual may have of adopting an information technology IT innovation. This instrument is intended to be a tool for the study of the initial adoption and eventual diffusion of IT innovations within organizations. While the adoption of information technologies by individuals and organizations has been an area of substantial research interest since the early days of computerization, research efforts to date have led to mixed and inconclusive outcomes. The lack of a theoretical foundation for such research and inadequate definition and measurement of constructs have been identified as major causes for such outcomes. In a recent study examining the diffusion of new end-user IT, we decided to focus on measuring the potential adopters' perceptions of the technology. Measuring such perceptions has been termed a "classic issue" in the innovation diffusion literature, and a key to integrating the various findings of diffusion research. The perceptions of adopting were initially based on the five characteristics of innovations derived by Rogers 1983 from the diffusion of innovations literature, plus two developed specifically within this study. Of the existing scales for measuring these characteristics, very few had the requisite levels of validity and reliability. For this study, both newly created and existing items were placed in a common pool and subjected to four rounds of sorting by judges to establish which items should be in the various scales. The objective was to verify the convergent and discriminant validity of the scales by examining how the items were sorted into various construct categories. Analysis of inter-judge agreement about item placement identified both bad items as well as weaknesses in some of the constructs' original definitions. These were subsequently redefined. Scales for the resulting constructs were subjected to three separate field tests. Following the final test, the scales all demonstrated acceptable levels of reliability. Their validity was further checked using factor analysis, as well as conducting discriminant analysis comparing responses between adopters and nonadopters of the innovation. The result is a parsimonious, 38-item instrument comprising eight scales which provides a useful tool for the study of the initial adoption and diffusion of innovations. A short, 25 item, version of the instrument is also suggested.
The Laws of Distribution of the Values of Turbulent Thermo-physical Characteristics in the Volume of the Flows of Heat Carriers Taking into Account the Surface Forces

Received: 3 June 2018 Accepted: 23 December 2018 The distribution of resistances values of individual thermal zones of coolants flows is analyzed for the example of milk and water in a shell-and-tube heat exchanger, which was calculated and selected by us in the work [11]. It is shown that thermal resistance of turbulent zones of coolants flows is about 37 % of the total thermal resistance of the heat exchange system in this heat exchanger. The specific thermals resistivity the laminar boundary layer (LBL) zones are much larger, but their total thermal resistance is about 1.5 % because of the very small average thickness of these zones. In this case, the method of analyzing the basic dimensions of physical quantities was used. At the same time, we deduced a new dimensionless number Blturb. , which shows the ratio of turbulent viscosities or thermal conductivities to the transitional viscosities or thermal conductivities of the individual coolants zones. Formulas for the calculation of turbulent viscosities and thermal conductivities in coolants of are derived and the law of their distribution in the volume of coolant flows in the pipes and the annular space of the shell-andtube heat exchanger is established. It is shown that this law is an analog of the bell-shaped law of the distribution of Reichardt H. and Ludwig H. , and the main difference is that the equation of this law derived by us contains the coefficients of surface tension and hydrophilicity of the wetting surfaces and also the values, reflecting the rates of thermal motion of the heat carriers molecules at a given temperature. A complete analysis of longitudinal sections of coolants flows is made using the example of milk and water in a shell-and-tube heat exchanger for their values of turbulent viscosities and thermal conductivities as well as the turbulent numbers Blturb. It is shown that the most energy-efficient liquid refrigerants can be selected using a turbulent number Blturb.
LOW‐LEVEL EXPRESSION AND LIMITED ROLE FOR THE INDUCIBLE ISOFORM OF NITRIC OXIDE SYNTHASE IN THE VASCULAR HYPOREACTIVITY AND MORTALITY ASSOCIATED WITH CECAL LIGATION AND PUNCTURE IN THE RAT

ABSTRACT Expression of the inducible isoform of nitric oxide synthase (iNOS) contributes to the hypotension and vascular hyporeactivity in various models of shock induced by bacterial lipopolysaccharide (LPS). However, the role of iNOS in response to shock caused by live bacteria is more controversial. In the present study, we investigated the role of iNOS in a rat model of cecal ligation and puncture (CLP). CLP resulted in increased plasma nitrite/nitrate levels (up to 59 μ.M at 24 h) and increased pulmonary iNOS activity (up to 71 fmoles/mg/min at 12 h) and caused a significant vascular hyporeactivity at 18 h. The degree of NO production and iNOS induction was approximately 30% of that observed several hours after administration of LPS in the same species, and the degree of vascular hyporeactivity was less than that observed after LPS injection. Selective inhibition of iNOS with mercaptoethylguanidine (MEG) reduced plasma nitrite/nitrate levels, but did not prevent the development of vascular hyporeactivity, and did not improve survival in this model of CLP. Thus, CLP-induced sepsis causes low-level induction of iNOS, but factors other than iNOS are the crucial determinants of the vascular failure and mortality in this model.