Miracle-dz/UniFAR-FTUs huggingface dataset:
Hsp90, an unlikely ally in the war on cancer

On the surface heat shock protein 90 (Hsp90) is an unlikely drug target for the treatment of any disease, let alone cancer. Hsp90 is highly conserved and ubiquitously expressed in all cells. There are two major isoforms α and β encoded by distinct genes and together they may constitute 1%–3% of the cellular protein. Deletion of the protein is embryonic lethal and there are no recognized polymorphisms suggesting an association or causal relationship with any human disease. With respect to cancer, the proteins absence from two recent high profile articles, ‘Hallmarks of cancer: the next generation’ [Hanahan & Weinberg (2011) Cell 144, 646–674] and ‘Comprehensive molecular portraits of human breast tumours’ [Koboldt et al. (2012) Nature] underlines the perception that it is an unlikely bona fide target to treat this disease. Yet, to date, there are 17 distinct Hsp90 inhibitors in clinical trials for multiple indications in cancer. The protein has been championed for over 20 years by the National Cancer Institute (Bethesda, MD, USA) as a cancer target since the discovery of the antitumor activity of the natural product geldanamycin. This review aims to look at the conundrum of why Hsp90 can even be considered a druggable target for the treatment of cancer. We propose that in contrast to the majority of chemotherapeutics our growing armamentarium of investigational Hsp90 drugs represents an elegant choice that offers real hope in the long‐term treatment of certain cancers.
Genetic control of mast cell development in bone marrow cultures. Strain-dependent variation in cultures from inbred mice.

A comparison was made of the capacity of bone marrow cells (BM) from genetically distinct strains of mice to develop into mast cells under defined conditions of in vitro culture. In the presence of conditioned media derived from ConA treated spleen cells from normal or Trichinella spiralis-infected mice, mast cell development occurred readily. After 21 days of culture mast cells comprised more than 90% of the total cell population. BM taken from certain strains of mice (SWR and NIH) produced large numbers of mast cells, total cell numbers increasing between 2 and 5 fold; other strains (C57BL/10 [B10] B10 congenics) produced relatively few mast cells, total cell numbers not increasing above the starting concentration or declining during culture. The genetic factors determining the strain-response phenotype (no. of mast cells in culture) were predominantly associated with the background genome. No significant differences in response were noted between the B10 congenic strains B10 [H-2b], B10.G [H-2q] or B10.BR [H-2k], which differ only at the MHC, whereas major differences were seen between B10.G and the other H-2q strains [SWR and NIH]. Response phenotype was not inherited as a simple dominant trait; F1 progeny of high x low responder strains were intermediate between the parental values. The expression of genetic influences upon mast cell response phenotype appears to be at both the level of mast cell precursor cells, as determined from limiting dilution assays of BM from high, low and F1 (high x low) strains, and at the level of mast cell proliferation, as determined by repeated sub-culture of mast cells from these strains.
A longitudinal study of follow-up activities after curative treatment for head and neck cancer

Abstract Purpose. To test the hypothesis that head and neck cancer (HNC) patients are in need of specialized follow-up (FU). This was done by an evaluation of the FU activities in a cohort of patients followed longitudinally for five years with focus on optimal duration and interval of post-therapeutic follow-up. Methods. The study evaluated a cohort consisting of 197 consecutive patients with HNC treated at Aarhus University Hospital from 1 January to 31 December 2009. The inclusion criteria was that patients should be deemed free of disease two months after completed primary curative intended treatment or after primary curative salvage. It left 141 patients available for analysis. Data were collected through a medical chart review and from the Danish Head and Neck Cancer Group (DAHANCA) database. Parameters recorded were: regular or extraordinary visit, alarm symptoms, late morbidity and the consequences of these. Results. The 141 patients underwent 1408 FU visits. Only 15 of the 141 patients had no tumor problems or morbidity issues raised at any FU visit. Suspicion of recurrent disease was observed at 207 of the 1408 FU visits, involving 97 patients and resulted in a total of 370 diagnostic procedures; 170 (82%) visits with suspicion of recurrence occurred within 3½ years after end of treatment. A recurrence was verified in 30 patients. Additionally four new primary head and neck cancer was diagnosed during follow-up. There were 1150 visits (82%) involving 135 patients in which late treatment-related morbidity was recorded. Actions taken related to morbidity happened in 71 patients, but no new problems appeared after three years. Conclusion. The study document the need of specialized FU, as 86% of all HNC survivors have tumor or severe morbidity issues during FU. The data suggest that 3½-year FU after ended therapy may be sufficient for the majority of patients.
Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case‐control study in nonsmoking postmenopausal women from the EPIC cohort

Acrylamide, classified in 1994 by IARC as “probably carcinogenic to humans,” was discovered in 2002 in some heat‐treated, carbohydrate‐rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case‐control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non‐smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type‐I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1: 0.84, 95%CI: 0.49–1.48; HRHbGA;Q5vsQ1: 0.94, 95%CI: 0.54–1.63) or type‐I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. ≥25 kg m−2, alcohol drinkers vs. never drinkers, oral contraceptive users vs. non‐users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type‐I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort.
Immobilization of Aspergillus beta-glucosidase on chitosan

beta-Glucosidase of Aspergillus phoenicis QM 329 was immobilized on chitosan, using the bifunctional agent glutaraldehyde. The most active preparation based on the amount of support contained a 1:2.5 enzyme-to-chitosan ratio (wt/wt). However, the specific activity of the bound enzyme decreased from 10 to 1% with increasing enzyme-to-chitosan ratio. Compared with free beta-glucosidase, the immobilized enzyme exhibited: (i) a similar pH optimum but more activity at lower pH values; (ii) improved thermal stability; (iii) a similar response to inhibition by glucose; and (iv) mass transfer limitations as reflected by higher apparent Km and lower energy of activation.
De‐escalation techniques used, and reasons for seclusion and restraint, in a forensic psychiatric hospital

In Finland, the Mental Health Act determines the legal basis for seclusion and restraint. Restrictive measures are implemented to manage challenging situations and should be used as a last resort in psychiatric inpatient care. In the present study, we examined the reasons for seclusion and restraint, as well as whether any de-escalation techniques were used to help patients calm down. Seclusion and restraint files from a 4-year period (1 June 2009-31 May 2013) were retrospectively investigated and analysed by content analysis. Descriptive statistics were calculated. A total of 144 episodes of seclusion and restraint were included to analyse the reasons for seclusion and restraint, and 113 episodes were analysed to examine unsuccessful de-escalation techniques. The most commonly-used techniques were one-to-one interaction with a patient (n = 74, 65.5% of n = 113) and administration of extra medication (n = 37, 32.7% of n = 113). The reasons for seclusion and restraint were threatening harmful behaviour (n = 51, 35.4% of n = 144), direct harmful behaviour (n = 43, 29.9%), indirect harmful behaviour (n = 42, 29.1%), and other behaviours (n = 8, 5.6%). In general, the same de-escalation techniques were used with most patients. Most episodes of seclusion or restraint were due to threats of violence or direct violence. Individual means of self-regulation and patient guidance on these techniques are needed. Additionally, staff should be educated on a diverse range of de-escalation techniques. Future studies should focus on examining de-escalation techniques for the prevention of seclusion.
Molecular signatures of soy‐derived phytochemicals in androgen‐responsive prostate cancer cells: A comparison study using DNA microarray

The present study utilized microarray technology as a tool to elucidate the molecular signatures of soy‐derived phytochemicals in the human androgen‐responsive prostate cancer cell line LNCaP. Global gene expression pattern analysis of LNCaP cells exposed to 0, 1, 5, or 25 µM of the soy‐derived phytochemicals equol and daidzein were conducted and compared. The data were further compared with previously generated data from exposure of LNCaP cells to the same doses of genistein, a soy isoflavone. Multidimensional scaling (MDS) analyses of the expression patterns suggest that these compounds exerted differential effects on gene expression in LNCaP cells. Further examination of specific gene changes revealed that these compounds differentially modulated genes in multiple cellular pathways, including the cell‐cycle pathway genes. However, the three compounds also exerted similar effect on genes belonging to several other important cellular pathways. A universal effect of the three compounds on androgen‐responsive genes, IGF‐1 pathway gene, and MAP kinase‐related pathway gene was observed. These results provide the foundation for establishing molecular signatures for equol, daidzein, and genistein. Moreover, these results also allow for the identification of candidate mechanism(s) by which soy phytochemicals and soy may act in prostate cancer cells. © 2006 Wiley‐Liss, Inc.
Is Gaydar Affected by Attitudes Toward Homosexuality? Confidence, Labeling Bias, and Accuracy

ABSTRACT Previous research has largely ignored the relationship between sexual orientation judgement accuracy, confidence, and attitudes toward homosexuality. In an online study, participants (N = 269) judged the sexual orientation of homosexual and heterosexual targets presented via a series of facial photographs. Participants also indicated their confidence in each judgment and completed the Modern Homonegativity Scale (Morrison & Morrison, 2002). We found that (1) homosexual men and heterosexual women were more accurate when judging photographs of women as opposed to photographs of men, and (2) in heterosexual men, negative attitudes toward homosexual men predicted confidence and bias when rating men’s photographs. Findings indicate that homosexual men and heterosexual women are similar in terms of accuracy in judging women’s sexuality. Further, especially in men, homophobia is associated with cognitive biases in labeling other men but does not have a relationship with increased accuracy.
Development and Experimental Evaluation of a Novel Piezoresistive MEMS Strain Sensor

This paper presents the experimental evaluation of a new piezoresistive microelectromechanical systems strain sensor. The sensing chip is highly capable of measuring biaxial state of strain/stress. The sensing elements are p-type piezoresistors on (100) single crystal silicon aligned along [110] and its in-plane transverse. The concept of introducing geometric features to enhance the sensor sensitivity is investigated. The results of experimental evaluation and finite-element analysis (FEA) proved the viability of this concept to improve the sensor sensitivity. The microfabrication process utilizes five doping concentrations to explore the effect of doping level on the sensor performance. The sensor is developed considering applications under varying temperature conditions. Therefore, high doping concentration (more than 1 ×1019 atoms/cm3) is favorable to reduce the sensor thermal drift. As a result, the sensor sensitivity is significantly reduced. Hence, geometric features are introduced in the sensor silicon carrier to compensate for the signal loss through stress concentration effect, which magnified the strain field in the proximity of the sensing elements. In addition, the use of full-bridge configuration reduced the overall temperature coefficient of resistance (TCR). At doping concentration of ~5 ×1019 atoms/cm3, the measured strain sensitivity is 0.035 mV/με for input voltage of 5 volts, which corresponds to an effective gauge factor of ~7 and piezoresistive gauge factor of ~44. The effective gauge factor includes all the signal losses and the effect of bonding adhesive. Design and analysis, prototyping, and experimental evaluation are presented. Finally, guidelines to select the bonding adhesive and packaging scheme are provided.
Evidence of Extrahepatic Sites of Replication of the Hepatitis E Virus in a Swine Model

ABSTRACT Hepatitis E virus (HEV) is the major cause of enterically transmitted non-A, non-B hepatitis in many developing countries and is also endemic in many industrialized countries. Due to the lack of an effective cell culture system and a practical animal model, the mechanisms of HEV pathogenesis and replication are poorly understood. Our recent identification of swine HEV from pigs affords us an opportunity to systematically study HEV replication and pathogenesis in a swine model. In an early study, we experimentally infected specific-pathogen-free pigs with two strains of HEV: swine HEV and the US-2 strain of human HEV. Eighteen pigs (group 1) were inoculated intravenously with swine HEV, 19 pigs (group 2) were inoculated with the US-2 strain of human HEV, and 17 pigs (group 3) were used as uninoculated controls. The clinical and pathological findings have been previously reported. In this expanded study, we aim to identify the potential extrahepatic sites of HEV replication using the swine model. Two pigs from each group were necropsied at 3, 7, 14, 20, 27, and 55 days postinoculation (DPI). Thirteen different types of tissues and organs were collected from each necropsied animal. Reverse transcriptase PCR (RT-PCR) was used to detect the presence of positive-strand HEV RNA in each tissue collected during necropsy at different DPI. A negative-strand-specific RT-PCR was standardized and used to detect the replicative, negative strand of HEV RNA from tissues that tested positive for the positive-strand RNA. As expected, positive-strand HEV RNA was detected in almost every type of tissue at some time point during the viremic period between 3 and 27 DPI. Positive-strand HEV RNA was still detectable in some tissues in the absence of serum HEV RNA from both swine HEV- and human HEV-inoculated pigs. However, replicative, negative-strand HEV RNA was detected primarily in the small intestines, lymph nodes, colons, and livers. Our results indicate that HEV replicates in tissues other than the liver. The data from this study may have important implications for HEV pathogenesis, xenotransplantation, and the development of an in vitro cell culture system for HEV.
Resonance behaviour of whole-body averaged specific energy absorption rate (SAR) in the female voxel model, NAOMI

Finite-difference time-domain (FDTD) calculations have been performed of the whole-body averaged specific energy absorption rate (SAR) in a female voxel model, NAOMI, under isolated and grounded conditions from 10 MHz to 3 GHz. The 2 mm resolution voxel model, NAOMI, was scaled to a height of 1.63 m and a mass of 60 kg, the dimensions of the ICRP reference adult female. Comparison was made with SAR values from a reference male voxel model, NORMAN. A broad SAR resonance in the NAOMI values was found around 900 MHz and a resulting enhancement, up to 25%, over the values for the male voxel model, NORMAN. This latter result confirmed previously reported higher values in a female model. The effect of differences in anatomy was investigated by comparing values for 10-, 5- and 1-year-old phantoms rescaled to the ICRP reference values of height and mass which are the same for both sexes. The broad resonance in the NAOMI child values around 1 GHz is still a strong feature. A comparison has been made with ICNIRP guidelines. The ICNIRP occupational reference level provides a conservative estimate of the whole-body averaged SAR restriction. The linear scaling of the adult phantom using different factors in longitudinal and transverse directions, in order to match the ICRP stature and weight, does not exactly reproduce the anatomy of children. However, for public exposure the calculations with scaled child models indicate that the ICNIRP reference level may not provide a conservative estimate of the whole-body averaged SAR restriction, above 1.2 GHz for scaled 5- and 1-year-old female models, although any underestimate is by less than 20%.
Meta-Analysis of 29 Experiments Evaluating the Effects of Rapamycin on Life Span in the Laboratory Mouse

Rapamycin has favorable effects on aging in mice and may eventually be applied to encourage "healthy aging" in humans. This study analyzed raw data from 29 survival studies of rapamycin- and control-treated mice, with the goals of estimating summary statistics and identifying factors associated with effect size heterogeneity. Meta-analysis demonstrated significant heterogeneity across studies, with hazard ratio (HR) estimates ranging from 0.22 (95% confidence interval [CI]: 0.06-0.82) to 0.92 (95% CI: 0.65-1.28). Sex was the major factor accounting for effect size variation, and mortality was decreased more in females (HR = 0.41; 95% CI: 0.35-0.48) as compared with males (HR = 0.63; 95% CI: 0.55-0.71). Rapamycin effects were also genotype dependent, however, with stronger survivorship increases in hybrid mice (14.4%; 95% CI: 12.5-16.3%) relative to pure inbred strains (8.8%; 95% CI: 6.2-11.6%). Number needed to treat was applied as an effect size metric, which consistently identified early senescence as the age of peak treatment benefit. These results provide synthesis of existing data to support the potential translation of findings from mouse to primate species. Because rapamycin's effect on survival depends on sex and genotype, further work is justified to understand how these factors shape treatment response.
Energy Intake, Basal Metabolic Rate, and Within-Individual Trade-Offs in Men and Women Training for a Half Marathon: A Reanalysis

Understanding the mechanisms governing energy budgets during periods of high energy expenditure is important from both an evolutionary physiology and behavioral ecology perspective. In particular, we still know too little about the linkages between key components such as daily energy expenditure (DEE), daily energy intake (DEI), and basal metabolic rate (BMR). Westerterp et al. repeatedly measured DEI (self-reported), BMR (respirometry), and body composition (fat mass) in 23 adult subjects as they transitioned from an inactive lifestyle and trained during 44 wk in preparation of running a half marathon. Here, I reanalyzed this data set using bivariate mixed models to partition the phenotypic correlation between DEI and BMR at the among- and within-individual levels. Reported DEI and BMR were positively correlated at the among-individual level (i.e., individuals with high average reported DEI also have a high average BMR). However, reported DEI and BMR were not correlated within individuals. There was a negative within-individual relationship between BMR and surplus energy (i.e., the energy intake above BMR = DEI − BMR), suggesting the presence of compensation mechanisms between BMR and other energy-demanding activities occurring within individuals. Thus, the principles governing energy budget were different at the among- and within-individual levels. To the extent that this situation is applicable to wild animals experiencing different levels of DEE throughout their annual cycle, the results presented here could explain why the relationships between BMR and other components of the energy budget (e.g., activity, growth, reproduction) are often context dependent.
Generation of AKR mink cell focus-forming viruses: a conserved single-copy xenotrope-like provirus provides recombinant long terminal repeat sequences

AKV and AKR mink cell focus-forming virus-specific probes from the envelope and long terminal repeat (LTR) regions were prepared for study of the structure of recombinant proviruses in tumor tissues of AKR mice. The results showed that (i) all somatically acquired proviruses possessed, besides a recombinant gp70 gene, an altered U3 LTR; (ii) in a substantial portion of the somatically acquired AKR mink cell focus-forming proviruses, the LTR comprised sequences derived from the same xenotropic-like provirus; (iii) this U3 LTR donating parental provirus (Xeno-dL) was present only once per genome equivalent in several mouse strains; (iv) in the strains containing the Xeno-dL provirus, the provirus was present in the same chromosomal site; (v) restriction analysis of the Xeno-dL revealed that the mink cell focus-forming gp70 sequences were derived from a parental provirus, different from Xeno-dL. Therefore, at least two non-ecotropic parents participate in the generation of leukemogenic AKR mink cell focus-forming viruses: a xenotropic-like virus, Xeno-dL, donating U3 LTR sequences, and another xenotropic-like virus or viruses providing gp70 sequences.
Increased risk of death due to heart disease after radiotherapy for esophageal cancer.

OBJECTIVE To evaluate the risk of heart disease related death (HDRD) following radiation therapy (RT) for esophageal cancer (EC). METHODS Using the Surveillance, Epidemiology, and End Results (SEER) database, two cohorts of patients with EC were created: (I) patients who received RT with their initial therapy; and (II) those who did not. Heart disease specific survival (HDSS) was analyzed using Kaplan-Meier methods. Cox proportional-hazards regression methods were used for univariate and multivariate analyses. RESULTS We identified 40,778 patients with EC. A total of 26,377 patients received RT and 14,401 did not. HDSS analysis revealed increased risk of HDRD in those receiving RT (P<0.05), with an absolute risk of HDRD of 2.8%, 5.3% and 9.4% at 5-, 10- and 20-year, respectively. Log rank test of HDSS revealed the risk of HDRD became significant at 8 months (P<0.05). The following were associated with HDRD: RT, age, race, stage at presentation, time period of diagnosis, and known comorbid condition keeping one from esophagectomy. On multivariate analysis, RT remained predictive of HDRD [hazard ratio (HR) 1.46, P<0.05]. When considering only candidates for definitive therapy, RT remained predictive of HDRD on univariate (HR 1.53, P<0.0001) and multivariate (HR 1.62, P<0.0001) analyses. CONCLUSIONS The use of RT leads to increased risk of HDRD that is detectable as early as eight months from diagnosis. More research is needed to define optimal dose volume parameters to prevent cardiac death. Consideration should be given to this risk in relation to prognosis and the expected benefits of RT.