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There is a need to develop user-friendly imaging tools estimating robust quantitative biomarkers (QIBs) from multiparametric (mp)MRI for clinical applications in oncology. Quantitative metrics derived from (mp)MRI can monitor and predict early responses to treatment, often prior to anatomical changes. We have developed a vendor-agnostic, flexible, and user-friendly MATLAB-based toolkit, MRI-Quantitative Analysis and Multiparametric Evaluation Routines (“MRI-QAMPER”, current release v3.0), for the estimation of quantitative metrics from dynamic contrast-enhanced (DCE) and multi-b value diffusion-weighted (DW) MR and MR relaxometry. MRI-QAMPER’s functionality includes generating numerical parametric maps from these methods reflecting tumor permeability, cellularity, and tissue morphology. MRI-QAMPER routines were validated using digital reference objects (DROs) for DCE and DW MRI, serving as initial approval stages in the National Cancer Institute Quantitative Imaging Network (NCI/QIN) software benchmark. MRI-QAMPER has participated in DCE and DW MRI Collaborative Challenge Projects (CCPs), which are key technical stages in the NCI/QIN benchmark. In a DCE CCP, QAMPER presented the best repeatability coefficient (RC = 0.56) across test–retest brain metastasis data, out of ten participating DCE software packages. In a DW CCP, QAMPER ranked among the top five (out of fourteen) tools with the highest area under the curve (AUC) for prostate cancer detection. This platform can seamlessly process mpMRI data from brain, head and neck, thyroid, prostate, pancreas, and bladder cancer. MRI-QAMPER prospectively analyzes dose de-escalation trial data for oropharyngeal cancer, which has earned it advanced NCI/QIN approval for expanded usage and applications in wider clinical trials.

BackgroundPatients with human papillomavirus-related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy.MethodsIn 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided.ResultsFifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation-related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03).ConclusionsDeescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

The precipitation sequence in Al–Zn–Mg alloys has been subject to many revisions over the years as more structural details of the early-stage Guinier-Preston (GP) zones and precipitates have been uncovered. To further investigate this, a 7003 aluminium alloy naturally aged for one year was subjected to artificial ageing at 140 °C to investigate the evolution of early-stage precipitates. Scanning transmission electron microscopy was coupled with atom probe tomography and hardness measurements to characterise the precipitate structure and chemistry of the alloy at different stages in the heat treatment. The naturally aged condition contained a dense population of GPI zones, co-existing with a smaller distribution of η′ precipitates. After artificial ageing for 10 min, the hardness decreased from 121 HV to 88 HV. The number densities of clusters were similar in the two conditions, while the average size of the clusters had increased during the first 10 min of artificial ageing. The average Zn/Mg ratio of the clusters decreased from 2.0 to 1.7 and the clusters no longer exhibited the GPI zone atomic structure, indicating that the GPI zones had dissolved. Concurrently, the fraction of precipitates having η′ structure increased from 2% to 18%. During further ageing, the hardness increased again, reaching a peak after 5 h. In this condition, η′ was the dominant phase, co-existing with η1, η2 and T′ phases. Atomically resolved scanning transmission electron microscopy images in addition to precession electron diffraction patterns of the disputed T′ phase are presented and compared to literature.

Cytoplasmic accumulation of RNA binding protein, hnRNPK in cancer cells is associated with poor prognosis. Here the authors show that SCFFbxo4 E3 ubiquitin ligase-mediated polyubiquitylation of hnRNPK restricts c-Myc translation and limits cancer progression.

Pancreatic β-cells are naturally prone to ER stress due to their role in insulin production and secretion. Here, the authors show that chronic ER stress adaptive exhaustion results in an irreversible loss of β-cell function leading to T1D pathogenesis

Conditions of endoplasmic reticulum (ER) stress reduce protein synthesis by provoking translation regulation, governed by the eIF2a kinase PERK. When PERK is inhibited during ER stress, retention of a selective subset of glycoproteins occurs, a phenomenon we termed selective ER retention (sERr). sERr clients are enriched with tyrosine kinase receptors (RTKs), which form large molecular weight disulfide bonded complexes in the ER. The protein disulfide isomerase ERp44 promotes sERr and increases the size of sERr complexes. Here we show that sERr is reversible upon washout. Pulse chase analyses show that upon recovery, only a small fraction of the sERr complexes disintegrates and contributes to the matured proteins, while most are newly synthesized. Sequential inductions of sERr and washouts demonstrate an accelerated recovery that is dependent on the unfolded protein response transducer IRE1. Since IRE1 regulates the expression level PDIA6, we analyzed its contribution to sERr. We found that PDIA6 and ERp44 constitu-tively interact by disulfides and have opposite effects on resumed recovery of trafficking following removal of sERr conditions. Deletion of ERp44 accelerates, while deletion of PDIA6 slows down recovery with a minimal effect on total protein synthesis. ERp44 is a primary interactor with sERr clients. When missing, PDIA6 partitions more into sERr complexes. Deletion of the tumor suppressor PTEN, which induces RTK signaling, promoted sERr formation kinetics, and accelerated the recovery, suggesting feedback between RTKs signaling and sERr. This study suggests that sERr, should develop physiologically or pathologically, is counteracted by adaptation responses that involve IRE1 and PDIA6. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the self-reported risk of obstructive sleep apnea syndrome (OSAS) in the municipality of Thessaly, Greece, and the level of awareness of both the disease and its diagnosis. Inhabitants of Thessaly (254 total; 84 men and 170 women) were studied by means of questionnaires via a telephone-randomized survey. This comprised: (a) the Berlin questionnaire for evaluation of OSAS risk; (b) the evaluation of daytime sleepiness by the Epworth Sleepiness Scale; and (c) demographic and anthropometric data. The percentage of participants at high risk for OSA was 26.77%, and the percentage of people who were at high risk of excessive daytime sleepiness was 10.63%. High risk for OSAS was found to be 3.94%. No significant differences were found between high- and low-risk OSAS participants associated with age, smoking and severity of smoking. Regarding the knowledge of the community about OSAS, the majority of the sample was aware of the entity (64.17%), while fewer had knowledge about the diagnosis (18.50%) and polysomnography (24.80%). The high risk of OSA prevalence and the low awareness of the diagnosis of OSA highlights the need for the development of health promotion programs aiming at increasing the disease awareness in the general population in order to address OSA more effectively.

Background: Relationships among perinatal depression occurring a number of weeks before and after childbirth and smoking have been identified. Depression may lead to the inability to abstain from smoking during pregnancy. Objectives: This study aims to determine factors affecting smoking during pregnancy revealing potential relationships between depression and smoking patterns during and after pregnancy. Methods: A total of 206 mothers participated in the study. Data were collected through self-reporting as respondents were asked to answer questionnaires during the 12th week of pregnancy, during the 30th week of pregnancy, after childbirth, and during the period after pregnancy. Relationships between smoking behavior, sociodemographic variables, and feelings of perinatal depression were examined using chi-square test and binary logistic regression analysis. A follow-up investigation has been conducted after 2 years revealing the percentage of women returning to their smoking habits. Results: Smokers before (B?=?0.568; p?=?0.026) and during pregnancy (B?=?1.238; p?=?0.009) were more likely to express depression before childbirth. Average daily cigarette consumption before (B?=?1.110; p?=?0.001) and during pregnancy (B?=?1.167; p?=?0.002) was associated with depression during pregnancy. Women who smoked during pregnancy reported significantly more depressive symptoms after pregnancy (B?=?1.757; p?=?0.005) compared with nonsmokers and smokers who abstained during pregnancy. Average daily cigarette consumption during pregnancy (B?=?1.402; p?=?0.002) affects the expression of depression after pregnancy. Women who smoked before pregnancy (B?=?0.568; p?=?0.025) and their average daily cigarette consumption before pregnancy (B?=?1.465; p?=?0.025) were highly associated with the inability to abstain from smoking during pregnancy. However, the knowledge of risks of maternal smoking during pregnancy (B?=??1.110; p?=?0.001) and medical consult on abstaining (B?=??1.238; p?=?0.009) reinforced the maternal attempt to quit smoking. The follow-up investigation revealed an elevated amount of women returning to previous smoking patterns. Discussion: Perinatal depression is associated with smoking patterns during pregnancy. Assessment of depression and smoking is needed throughout perinatal period to support the health of women.

Abstract Background There is a knowledge gap in whether psychopathology aspects can shape and mark the social representations about health and lifestyle. In this work, we investigated the association of psychopathology and shame with the centrality of the words describing eight common social representations of health and lifestyle. Methods A convenience sample of 288 adults participated with an average age of 44.7, and 62.6% were women. The participants were asked to express three consecutive words associated with eight different health and lifestyle experiences by utilizing the free association method. The participants also were completed the Symptom Checklist-90-Revised (SCL-90-R), the Experiences of Shame Scale (ESS), and the Other as Shamer Scale (OAS). Canonical correlation analysis was applied to investigate the relationship between the set of the eight-word centralities and the psycho-demographic variables consisting of the subject's age and gender, the SCL 90 subscales, the OAS, and the ESS. Based on these findings, a structural equation explorative model was formed to test the unidimensionality of the five centralities construct. Results Τhe psychological characteristics of interpersonal sensitivity, depression, external shame, and hostility were found to affect the word selection process on the social representations concerning nightlife, health, diet, lifestyle, and alcohol consumption. Participants with increased levels of depression tend to choose more centrally positioned words when the stimulus word was diet and more decentralized responses when the stimulus word was health. At the same time, higher external shame corresponded to more decentralized words for the categories of health and lifestyle. Conclusions Our results indicate that there is a potential interaction between the psychological state and how a social representation of health and lifestyle is constructed through selected words. Graph theory emerged as an additional tool to use to study these relations.

GADD34, a stress-induced regulatory subunit of the phosphatase PP1, is known to function in hyperosmotic stress through its well-known role in the integrated stress response (ISR) pathway. Adaptation to hyperosmotic stress is important for the health of corneal epithelial cells exposed to changes in extracellular osmolarity, with maladaptation leading to dry eye syndrome. This adaptation includes induction of SNAT2, an endoplasmic reticulum (ER)-Golgi-processed protein, which helps to reverse the stress-induced loss of cell volume and promote homeostasis through amino acid uptake. Here, we show that GADD34 promotes the processing of proteins synthesized on the ER during hyperosmotic stress independent of its action in the ISR. We show that GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation and is important for cis- to trans-Golgi trafficking of SNAT2, thereby promoting SNAT2 plasma membrane localization and function. These results suggest that GADD34 is a protective molecule for ocular diseases such as dry eye syndrome.

The Integrated Stress Response (ISR) is a cytoprotective pathway upregulated in many cancers. Here the authors show that the activation of PERK/p-eIF2α arm of ISR enhances ERK phosphorylation through translation repression of DUSP6, thus resulting in KRAS-driven lung tumorigenesis.

Marla K Beauchamp,1– 3 Cindy Ellerton,1,3 Renata Kirkwood,1 Dina Brooks,1,3 Julie Richardson,1 Roger S Goldstein,3,4 Stewart Pugsley,2,5 Diana Hatzoglou2 1School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada; 2Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, Hamilton, ON, Canada; 3Respiratory Rehabilitation, West Park Healthcare Centre, Toronto, ON, Canada; 4Department of Medicine, University of Toronto, Toronto, ON, Canada; 5Department of Medicine, McMaster University, Hamilton, ON, CanadaCorrespondence: Marla K BeauchampMcMaster University, School of Rehabilitation Science, 1400 Main Street West, Room 428, Hamilton, ON, L8S 1C7, CanadaEmail beaucm1@mcmaster.caPurpose: Older adults with chronic obstructive pulmonary disease (COPD) have a high risk and rate of falls. Home-based fall prevention exercise programs reduce falls in older adults and may be an alternative approach for people with COPD without access to hospital-based rehabilitation. Therefore, we aimed to determine the feasibility of a home-based fall prevention exercise program in older adults with COPD and to examine the effect of the program on fall-related outcomes at baseline, 3 and 6 months.Patients and Methods: Adults ≥ 60 years with COPD at risk for falls participated in a single group study. The intervention was a 6-month home-based fall prevention program which included 40 minutes of independent exercise three times per week, four physiotherapist home visits, bimonthly phone calls, and an optional booster session post-exacerbation. An independent assessor collected outcome measures at home at baseline, 3- and 6-months. Primary feasibility criteria were recruitment and retention rates (≥ 70%) and exercise adherence (≥ 60%). Functional outcomes included the Berg Balance Scale (BBS), the Balance Evaluation Systems Test (BESTest), the Activities-Specific Balance Confidence (ABC) scale, the repeated chair-stand test, self-reported function, and fall history.Results: Thirty-six patients (female 63.8%, mean age 74.4 ± 6.1 years; mean FEV1 45.0 ± 13.8% predicted) were enrolled. The recruitment rate was 46.8%, participant retention rate was 69.4%, and exercise adherence rate was 73.6%. Repeated measures ANOVA showed improvements at 3- and 6-months compared to baseline in the BBS (p= 0.001) and the BESTest total scores and sub-scores (p= 0.001).Conclusion: The home-based fall prevention exercise program met one of the three pre-specified feasibility criteria (exercise adherence), and improved balance-related measures of fall risk in older adults with COPD. Our findings highlight important opportunities for refinement of the study design prior to undertaking a full-scale trial.Keywords: COPD, balance training, exercise, falls prevention

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) is a carboxypeptidase B-like proenzyme encoded by the CPB2 gene. After thrombin activation, TAFI downregulates fibrinolysis, thus linking the latter with coagulation. TAFI has been shown to play a role in venous and arterial thrombotic diseases, yet, data regarding the molecular mechanisms underlying its function have been conflicting. In this study, we focused on the prediction and functional enrichment analysis (FEA) of the TAFI interaction network and the microRNAs (miRNAs) targeting the members of this network in an attempt to identify novel components and pathways of TAFI-related thrombosis. To this end, we used nine bioinformatics software tools. We found that the TAFI interactome consists of 28 unique genes mainly involved in hemostasis. Twenty-four miRNAs were predicted to target these genes. Co-annotation analysis of the predicted interactors with respect to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and transcription factors (TFs) pointed to the complement and coagulation cascades as well as neutrophil extracellular trap formation. Cancer, stroke, and intracranial aneurysm were among the top 20 significant diseases related to the identified miRNAs. We reason that the predicted biomolecules should be further studied in the context of TAFI-related thrombosis.