Dependence Scores Research Articles

Immunotherapy Responsive Recurrent Post-Infectious Ataxia Associated With Recurrent ATP2B2 Gene Variant.

We detail a case of recurrent, postinfectious, cerebellar ataxia associated with a likely pathogenic previously documented gene variant in ATP2B2. The patient was identified after her second hospitalization for postinfectious cerebellar ataxia. Genetic testing was performed after discharge. An 11-year-old girl with 1 prior episode of self-resolving parainfectious acute cerebellar ataxia at age 4 years presented with acute-onset ataxia, dysarthria, and gait instability in the setting of influenza A infection. The patient had CSF pleocytosis but negative influenza PCR and antibody detection in the CSF. Because of clinical deterioration, she received empiric IV methylprednisolone without improvement. She was subsequently administered IVIg and improved dramatically over the subsequent 7 days. The patient was found to have a rare de novo ATP2B2 gene (c.3028G>A, p.(Glu1010Lys)) variant previously reported in the literature. The variant was analyzed to have a Combined Annotation Dependent Depletion score of 33 and Polyphen-2 score of 1.0 and was determined to be likely pathogenic according to American College of Medical Genetics PP3 and PM2 criterion. Recurrent episodes of cerebellar ataxia are an especially rare occurrence, and genetic testing may be warranted in these individuals. It is possible that immunotherapy with IVIg may augment clinical outcomes in those with pathogenic ATP2B2 gene variants.

Expression Profile of Thymidine Kinase Genes in Cervical Squamous Cell Carcinoma Confirmed by Various Detection Methods.

Thymidine kinases (TKs) are key enzymes involved in DNA synthesis and repair, with alterations in their expression associated with various cancers. Thymidine kinase 1 (TK1) and TK2 are cytosolic enzyme proteins that catalyze the addition of a gamma-phosphate group to thymidine. The existing literature on TK1 in cervical squamous cell carcinoma (CESC) fails to address the clinical role of TK1 overexpression and its possible molecular mechanism in CESC. The clinical significance of TK2 in CESC is also unknown. The objective was to explore the differential expression, clinical significance, and molecular mechanisms of TK1 and TK2 in CESC. The researchers collected global high-throughput data, extracted the expression levels of TK1 and TK2, and calculated the integrated standardized mean difference (SMD) and summarized receiver's operating characteristics (sROC) of TK1 or TK2 mRNA to investigate the expression profiles of TK genes fully and objectively in 918 CESC tissues and 360 control tissues. In-house tissue microarrays for immunohistochemical testing were used to verify the protein level of TK1 in 62 CESC tissues and control tissues. The growth effect of TK1 and TK2 in CESC cell lines was assessed using Chronos dependency scores derived from CRISPR knockout screen in the Achilles project. We also analyzed the potential mechanism of TK genes by studying the relationship between TK gene expression and immune infiltration, gene alternations as well as the related signal pathways. The various detection methods employed all confirmed that the TK1 expression is upregulated and TK2 is downregulated in CESC tissues (SMD: 2.44, 95% confidence interval (CI): 1.36 - 3.51, area under curve (AUC): 0.88, 95% CI: 0.85 - 0.90; SMD: -0.69, 95% CI: -1.25 to -0.14, AUC: 0.75, 95% CI: 0.71 - 0.78). Inhibition of TK1 expression by CRISPR knockout had negative influence on the biological functions of 11 CESC cell lines. The expression of TK2 was negatively correlated with the malignant progression of CESC. Expression of TK genes showed significant association with the immune infiltration of macrophages, CD4+ T cells, and neutrophils. Genes related with TK1 or TK2 were involved in pathways related to DNA replication, proteasome, and homologous recombination. Clinically, these findings suggest that the differential expression of TK1 and TK2 could serve as potential biomarkers, as well as therapeutic targets for personalized treatment strategies in CESC patients.

Conceptual Knowledge of Oral Health Among Primary School Teachers in Riyadh, Saudi Arabia-A Cross Sectional Survey.

Background/Objectives: School teachers need to have a better understanding of oral health aspects as schools serve as an effective environment for learning. Educators hold a significant position in conveying the importance they attribute to oral health in their lives. According to the World Health Organization, school teachers should include oral health promotion activities to evaluate students' oral health, track injuries, illnesses, and absenteeism related to oral health, advocate oral health prevention, and serve as role models. The aim of this study was to evaluate the conceptual understanding of oral health among primary school teachers in Riyadh, Saudi Arabia. Methods: Data for this study were collected from 404 primary school teachers using a structured and pre-validated comprehensive measure of oral health knowledge (CMOHK) questionnaire. Results: The distribution of CMOHK scores indicated that 247 (61.2%) participants demonstrated good conceptual knowledge, 95 (23.5%) participants exhibited fair knowledge, and 62 (15.3%) participants were classified as having poor knowledge. The male group exhibited lower values for the CMOHK score in comparison with the female group; however, these findings were not statistically significant. The findings indicated that the group of government school teachers exhibited higher values for the dependent variable CMOHK score compared to their private school counterparts. Conclusions: The average CMOHK score observed in this study is regarded as fair. It is crucial for school teachers to possess strong oral health knowledge, as they significantly influence the oral health knowledge and behaviors of children.

ESG rating declines and stock price crash risk

ABSTRACT This study examines the association between ESG rating declines and stock price crash risk. Using a sample of China’s A-share listed companies from 2011-2022 and the Hua Zheng index as ESG rating, we find that ESG rating declines increase stock price crash risk. Our main findings are robust to various tests, including replacing the measurement of independent and dependent variables, Heckman two-stage, and propensity score matching analysis. We find evidence that ESG rating declines influence crash risk through increasing agency costs and business risk. Furthermore, this relationship is more pronounced for firms audited by non-Big Four accounting firms, non-state-owned enterprises (SOEs), those with lower analyst coverage, lower information transparency, and those operating in heavy pollution industries. Our research shows how the market responds to non-financial indicators, highlighting the necessity for entities to transparently disclose their ESG performance and improve methods to mitigate stock price crash risk.

Analysis of the relationship between self-neglect and spiritual well-being in older adults

ABSTRACT This study was conducted to examine the relationship between self-neglect and spiritual well-being in older adults. This descriptive, cross-sectional and correlational study was conducted with 232 older adults. Data were collected using the “Elder Self-Neglect Scale (ESNS)” and “Spiritual Well-Being Scale (FACIT Sp-12).” It was found that 54% of the participants were female, 86% were married, 35% were primary school graduates, 66% lived in the district, 27% had hypertension, 54% had income equal to expenses, and 76% were retired. Mean ESNS total score of older adults was 102.83 ± 24.82 and mean FACIT Sp-12 total score was 33.73 ± 9.70. FACIT Sp-12 total score was found to be a significant negative predictor of the dependent variable ESNS total score (p < .05). In this study, it was determined that the spiritual well-being levels of older adults were above average and their self-neglect levels were low. It was determined that as the spiritual well-being levels of older adults increased, their self-neglect levels decreased.

Sex and income level can be determinants for meat attachment behavior among Turkish university students

Background: The Meat Attachment Questionnaire (MAQ) is a scale to measure the positive bond in meat consumption. Aims: This study aimed to validate and assess reliability of the Turkish version of the MAQ and to explore its relationship with various factors, including sociodemographic characteristics, meat consumption habits, and subscales of the Green Eating Survey (GES). Subjects and Methods: The study was carried out with 214 university students. Participants completed the MAQ, the Food Frequency Questionnaire, and the GES. Statistical analyses including item analysis, Cronbach’s alpha, intraclass correlation coefficient test - retest reliability, one-way ANOVA, Welch ANOVA, t-test, Pearson’s correlation, and post hoc tests (Tukey’s HSD and Games-Howell), were performed using SPSS (version 26). Confirmatory factor analysis (CFA) was conducted with the lavaan (version 0.6 – 13) and semPlot (version 1.1.6) R packages. Results: All factor loadings were statistically significant, and high fit indices were obtained for the model tested in the second-order CFA model. (χ2/df = 151,93/101 = 1.50; RMSEA = 0.05; SRMR = 0.08; NFI = 0.97; NNFI = 0.99; CFI = 0.99; GFI = 0.98; AGFI = 0.97). Significant differences were found in several MAQ subscale scores: hedonism, entitlement, dependence, and global scores were higher among men (p &lt; 0.05). The entitlement score was significantly higher in the “income &lt; expenses “group compared to the “income = expenses “group (p &lt; 0.05). Participants with higher red meat and poultry consumption exhibited significantly higher hedonism, dependence, and global MAQ scores (p &lt; 0.05). Conclusions: The Turkish version of the MAQ can be accepted as a reliable and valid scale for use among university students. While factors such as sex, income level, and meat consumption appear to influence MAQ scores, body mass index and green eating behaviors do not have a direct effect. Keywords: Green eating, meat, reliability, sustainability, validity.

Rehabilitation after intercurrent morbid event of patients suffering from neurocognitive disorders in a pilot unit: management and outcomes

People suffering from a neurodegenerative disease, at a stage still allowing physical activity, encounter more difficulties to access to re-education and rehabilitation care. A trial unit specialized in medical care and rehabilitation (SMR) was created to handle these patients, who suffered a morbid intercurrent event not related to the neurocognitive disorder. The trial unit was created thanks to a dedicated funding from the Brittany Health Regional Agency (ARS) following-up a call for projects in October 2021. A retrospective monocentric descriptive study focusing on the overall evolution of the patient. To describe the social and medical characteristics of admitted patients and access the benefits regarding the patients regain of independence. Results: One hundred forty-nine patients (55men, 94women) were included, average age 85 ±6.5 years. The average length of stay was 24 ±11days and the rehabilitative load was high (scores RR 275,2 ±175,2). A significant improvement in the autonomy of patients was noted, of their physical dependence scores (p <0,001) and cognitive dependence scores (p <0,001), of their overall physical condition at SPPB (p<0,001) as well as a decrease in the use of psychotropic drugs (p <0,001); their nutritional status was unchanged (p =0.2). One in two patients went home. Our work seems to confirm the importance of specialized units in the care of patients suffering from neurodegenerative disease in SMR.

Effect of Electronic Cigarettes on the Change of Fagerstrom Test for Nicotine Dependence Scores during 1-Year Follow-up.

The use of e-cigarettes is increasing globally, particularly among young adults. Although several use them to quit smoking, their effects are controversial. The Fagerstrom Test for Nicotine Dependence (FTND) was used to assess nicotine dependence in the smoking cessation process. This study examined changes in FTND scores among young adults using different types of cigarettes over a 1-year period. Prospective cohort data were collected from cigarette users at higher education institutions in the lower northern region of Thailand to analyze changes in FTND scores over a 1-year period. E-cigarette users and combined users were compared with conventional cigarette users. A marginal structural model (MSM) with an inverse probability of weighting (IPW) was used to adjust for time-dependent and time-independent confounders. Of the 133 participants, 58 were e-cigarette users (43.6%), 33 were combined cigarette users (24.8%), and 42 were conventional cigarette users (31.6%). The results revealed that when both time-dependent and time-independent confounders were adjusted using MSM with IPW, e-cigarette users had a 0.20 decrease in the mean FTND score, and combined users had a 0.47 decrease in the mean FTND score compared to conventional cigarette users. However, the difference was not statistically significant. The use of e-cigarettes or combined cigarettes did not significantly affect nicotine dependence levels in young adults over a 1-year period. Consequently, e-cigarettes should not be recommended to reduce nicotine dependence among young adult cigarette users. Further studies are required to determine whether e-cigarettes affect smoking cessation rates.

Connectivity Changes Following Episodic Future Thinking in Alcohol Use Disorder.

Introduction: Recent addiction and obesity-related research suggests that episodic future thinking (EFT) can serve as a promising intervention to promote healthy decision-making. We used data from a pilot study to investigate the acute neural effects of EFT in alcohol use disorder (AUD). Because of the limitations of those data, we additionally used data from a previously published functional MRI (fMRI) study in which participants had not received any intervention for their AUD. Methods: In an out-of-scanner, guided interview, participants (n = 24; median age = 37.3 years; median AUDIT = 22.5) generated scenarios and cues about their future (EFT intervention, n = 15) or recent past (control episodic thinking [CET] control intervention, n = 9). Then, they performed both resting-state and task-based (delay discounting [DD]) fMRI. We used nodes from the default mode network and salience networks as well as the hippocampus to perform seed-based analyses of the resting-state data. The results then guided psychophysiological interaction analyses in the DD task. In addition, we used data from a larger, previously reported study as a "no intervention" group of AUD participants (n = 50; median age = 43.3; median Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence score = 7) to reproduce and aid in interpreting our key findings. Results: EFT, but not CET, participants showed statistically improved DD rates-a behavioral marker for addiction. Resting-state analyses of the left hippocampus revealed connectivity differences in the frontal poles. The directionality of this difference suggested that EFT may reduce a hypo-connectivity relationship between these regions in AUD. We also found resting-state connectivity differences between the salience network and the right dorsolateral prefrontal cortex (R DLPFC), which then led us to discover R-to-L DLPFC psychophysiological interaction differences during DD. Moreover, the resting-state salience-to-DLPFC functional connectivity showed an inverse relationship to DD rate while hyperconnectivity between left and right DLPFC reflected slower reaction times during DD trials. Discussion: These findings suggest that previously noted benefits of EFT such as the improved DD replicated here might coincide with changes in neural connectivity patterns in AUD. The alterations in connectivity highlight potential mechanisms underlying the effectiveness of EFT in improving decision-making in AUD. Understanding these neural effects may contribute to the further development of targeted interventions for AUD and related disorders.

Multimodal AI/ML for discovering novel biomarkers and predicting disease using multi-omics profiles of patients with cardiovascular diseases

Cardiovascular diseases (CVDs) are complex, multifactorial conditions that require personalized assessment and treatment. Advancements in multi-omics technologies, namely RNA sequencing and whole-genome sequencing, have provided translational researchers with a comprehensive view of the human genome. The efficient synthesis and analysis of this data through integrated approach that characterizes genetic variants alongside expression patterns linked to emerging phenotypes, can reveal novel biomarkers and enable the segmentation of patient populations based on personalized risk factors. In this study, we present a cutting-edge methodology rooted in the integration of traditional bioinformatics, classical statistics, and multimodal machine learning techniques. Our approach has the potential to uncover the intricate mechanisms underlying CVD, enabling patient-specific risk and response profiling. We sourced transcriptomic expression data and single nucleotide polymorphisms (SNPs) from both CVD patients and healthy controls. By integrating these multi-omics datasets with clinical demographic information, we generated patient-specific profiles. Utilizing a robust feature selection approach, we identified a signature of 27 transcriptomic features and SNPs that are effective predictors of CVD. Differential expression analysis, combined with minimum redundancy maximum relevance feature selection, highlighted biomarkers that explain the disease phenotype. This approach prioritizes both biological relevance and efficiency in machine learning. We employed Combination Annotation Dependent Depletion scores and allele frequencies to identify variants with pathogenic characteristics in CVD patients. Classification models trained on this signature demonstrated high-accuracy predictions for CVD. The best performing of these models was an XGBoost classifier optimized via Bayesian hyperparameter tuning, which was able to correctly classify all patients in our test dataset. Using SHapley Additive exPlanations, we created risk assessments for patients, offering further contextualization of these predictions in a clinical setting. Across the cohort, RPL36AP37 and HBA1 were scored as the most important biomarkers for predicting CVDs. A comprehensive literature review revealed that a substantial portion of the diagnostic biomarkers identified have previously been associated with CVD. The framework we propose in this study is unbiased and generalizable to other diseases and disorders.

3D-Printed Permanent Resin Crowns on Pre-Molar and Molar Teeth; Two-Year Results of a Prospective Clinical Study.

The aim of this prospective clinical study was to evaluate the 12 and 24-month clinical results of overlay and one-piece endodontic crown restorations applied with additively manufactured 3D printed permanent ceramic-filled resin (PCR) according to the Modified US Public Health Service (USPHS) criteria. A total of 33 indirect restorations (16 overlay, 17 endocrown) (4 premolar, 29 molar) produced using PCR (Formlabs) were applied to 30 patients by a single dentist. The restorations were evaluated according to the modified USPHS criteria at baseline (7 days), 12 and 24 months times by two independent evaluators. The study registration number is NCT05168852. In the comparisons of the dependent criteria scores, the Related Samples Cochran Q test was used, and in post-hoc paired comparisons, the Bonferroni test. The Fisher-Freeman-Halton test was applied in the comparisons of categorical variables according to the restoration type groups (α = 0.05). No statistically significant difference was determined between the evaluation criteria scores at baseline, 12 months, and 24 months for the marginal adaptation (P=0.05), retention (P=1), interproximal contact (P=0.368), color match (P=1), surface texture (P=1), and patient satisfaction (P=1). The only score criteria that showed a statistically significant difference between baseline and 24 months (P=0.001) among all other criteria was marginal discoloration. This criteria's score change was from 100% A score to 69.7% A score. In the 2-year follow-up of indirect single-tooth restorations produced with 3D-printed PCR, all restorations showed acceptable clinical performance. (≥99.5%A&#43;B score at 2 years).

Need Frustration and E-Cigarette Use and Dependence Among College Students: The Mediating Role of Ruminative Thinking

Background: The prevalence and dependence of e-cigarettes have increased among young adult college students in recent years. Though several independent risk factors for e-cigarette use and dependence have been identified, research employing theory-informed models to predict e-cigarette use and dependence is limited. Objectives: Using Self Determination Theory (SDT), e-cigarette use and dependence may be understood as stemming from need frustration that impairs autonomy, competence, and relatedness, which increases vulnerability for negative health outcomes, including e-cigarette use. Further, need frustration may relate to more e-cigarette use and dependence via higher ruminative thinking, which is known to relate to both need frustration and tobacco use. Method: This study tested this path model (i.e., SDT need frustration components [autonomy, relatedness, competency]→rumination facets [problem-focused thoughts, counterfactual thinking, repetitive thinking, anticipatory thoughts]→e-cigarette use frequency and dependence outcomes) among 1001 college students (75.3% female; 60.4% White, non-Hispanic; 52% first-year students) who endorsed past-month e-cigarette use. Results: Within our path model, we found significant indirect effects via problem-focused thoughts on e-cigarette use frequency and e-cigarette dependence. Specifically, higher scores on SDT autonomy, competence, and relatedness frustration were associated with greater problem-focused thoughts, which was associated with higher e-cigarette use frequency and e-cigarette dependence scores. Conclusions/Importance: Results highlight the importance of distinguishing between the unique facets of rumination in understanding relations with e-cigarette use. Further intervention research targeting need frustration and ruminative thinking (particularly problem-focused thoughts) among college student e-cigarette-dependent users is needed.

Interest in the Use of Herbal Supplements to Close the Treatment Gap for Hazardous Alcohol Use Among Men Who Have Sex With Men: Secondary Analysis of a Cross-Sectional Study.

Hazardous alcohol consumption is highly prevalent for men who have sex with men (MSM). The 4 treatments currently approved by the Food and Drug Administration for alcohol use are reaching an alarmingly low percentage of people who would benefit from a reduction in their alcohol use. There is increasing interest in alternative methods of treatment, such as herbal supplements, to address hazardous drinking. However, research on the acceptability of alternative pharmacotherapies among MSM remains limited. We examined the prevalence and correlates of expressing interest in using herbal supplements for alcohol treatment among MSM with hazardous alcohol consumption. We conducted a secondary data analysis from a cross-sectional study of MSM who use alcohol, conducted from March 2015 to July 2017 in San Francisco, California, to assess the overall prevalence of interest in using herbal supplements to help reduce alcohol consumption. Associations between expressing interest in herbal supplements and demographic, social, and clinical characteristics were examined using bivariate and multivariable logistic regression models. One-third (66/200, 33%) of the participants expressed interest in an herbal supplement for reducing alcohol consumption. In the multivariable analyses, weekly binge drinking (adjusted odds ratio [aOR] 2.85, 95% CI 1.17-6.93), interest in abstaining from alcohol use (aOR 5.04, 95% CI 1.46-17.40), higher severity of alcohol dependence score (aOR 1.22, 95% CI 1.04-1.41), and interest in naltrexone (aOR 3.22, 95% CI 2.12-4.91) were independently associated with higher odds of being interested in using an herbal supplement to reduce alcohol consumption, adjusting for age, race or ethnicity, and education. We found that MSM who have hazardous drinking habits, more severe alcohol dependence, and interest in pharmacotherapy were more likely to express interest in using an herbal supplement for reducing alcohol consumption. To our knowledge, this is the first study that has evaluated correlates of interest in herbal supplements for alcohol use among MSM. As researchers implement novel alcohol treatment studies, they should focus on recruitment efforts among MSM with a motivation to reduce their alcohol use patterns.

Prevalence of Oral Potentially Malignant Lesions, Tobacco use, and Effect of Cessation Strategies among Solid Waste Management workers in Northern India: a pre-post intervention study

BackgroundIndia bears the highest global burden of oral cancer, despite having an operational tobacco cessation framework. Occupational groups like solid waste management personnel face significant health challenges due to prevalent tobacco use, leading to oral potentially malignant lesions and oral cancer. Enhanced tobacco control strategies are essential for these groups.MethodsA pre-post interventional, community-based study enrolled 1200 municipal workers in Varanasi, India, from July 2022 to August 2023. 858 tobacco users underwent screening and were randomly assigned to one of three interventions: Very Brief Advice, Individual Behavioral Counseling, or Group Behavioral Therapy. Follow-up was conducted one year after the baseline interventions Effectiveness was measured by nicotine dependence reduction using the Fagerstrom Test for Nicotine Dependence (FTND) scores and cessation rates defined as at least 6-month abstinence. Appropriate statistical tests assessed the burden of tobacco use, oral potentially malignant lesions, and pre-post differences in FTND scores within and between groups. A p-value of < 0.05 was considered statistically significant.ResultsMunicipal workers exhibited a high prevalence (71.5%) of smokeless tobacco (SLT) use. One-third (32.9%) of the participants screened positive for oral potentially malignant lesions and oral cancer. Leukoplakia was the most common lesion. Screened positivity correlated with significant nicotine dependence. Among 494 follow-up participants, 47.1% reported a significant reduction in nicotine dependence across all intervention groups. Quade’s ANCOVA indicated significant differences in post-test FTND scores, with individual behavioral counselling showing the greatest reduction. However, no cessation was achieved in any group despite the significant decline in dependence.ConclusionSolid waste management personnel in Varanasi show heightened SLT use and associated oral potentially malignant lesions. The persistent tobacco use in these high-risk occupational populations undermines government tobacco control efforts and highlights the need for robust policy and implementation strategies. The study demonstrated a significant reduction in nicotine dependence following interventions, though tobacco cessation was not achieved. More frequent interventions and addressing quitting barriers—such as cultural norms, lack of awareness, easy accessibility, and adverse working conditions—are crucial. Developing a tailored workplace model to tackle tobacco use in occupational settings may facilitate cessation.Clinical trial registration numberTrial registration Clinical Trials Registry India CTRI/2020/07/026479. Date of registration 10/07/2020.

Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequence data

BackgroundDeleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear.MethodsCancer associations for coding variants in ATM...

TNO155 is a selective SHP2 inhibitor to target PTPN11-dependent oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is known to be driven by multiple intricated receptor tyrosine kinases (RTKs) including EGFR, PI3K/AKT and MAPK signaling pathways. However, whilst targeting EGFR with cetuximab has been approved for the treatment of OSCC, other single-agent inhibitors of the RTKs have shown modest effects in improving survival. From the genome-wide CRISPR/Cas9 screen on 21 OSCC cell lines, we have identified PTPN11 among the top essential genes in OSCC. PTPN11 encodes for SHP2, a phosphatase that acts as a master signal transducer, downstream of various RTKs. Although PTPN11 overexpression has been reported in OSCC, little is known about its role as an essential gene for OSCC survival and its potential as a therapeutic target. Herein, we confirmed that PTPN11 is an essential gene in OSCC where its deletion significantly impacted cell survival. We evaluated three SHP2 inhibitors on 21 OSCC cell lines and found TNO155 to be significantly associated with CRISPR dependency score. We showed that TNO155 caused dose-dependent suppression on p-ERK and p-MEK, and suppresses the JAK/STAT pathway via downregulating p-JAK1, p-STAT1, p-STAT3. Furthermore, we confirmed that the combination of the mTOR inhibitor, everolimus with TNO155 is synergistic in OSCC. In summary, PTPN11 is a promising therapeutic target in OSCC that can be selectively targeted by SHP2 inhibitor such as TNO155. Our findings on the use of mTOR inhibitor, everolimus to overcome resistance to TNO155 are essential to inform on next phases of clinical trials which is warranted for the treatment of OSCC.

Vulnerability to depression and resolution in mothers of children with cerebral palsy

BackgroundThis study investigated associations between Self-Criticism and Dependency as factors of vulnerability to depression and maternal resolution. Resolution entails parental cognitive and emotional acceptance of the child's developmental disability. MethodsOur sample included 100 mothers whose children had a diagnosis of cerebral palsy. The Reaction to Diagnosis Interview, the Depressive Experiences Questionnaire and the Depression Scale were administered. ResultsThe results showed that unresolved mothers scored higher on the dimensions of Self-Criticism and Dependency compared to their resolved counterparts. The hierarchical cluster analysis yielded three maternal profiles based on the scores obtained on the dimensions of vulnerability to depression, regardless of maternal resolution status. The first profile was labeled Low Vulnerability and was characterized by low scores on Self-Criticism and Dependency. The second profile was labeled Dependent and it included mothers with higher scores on Dependency and lower scores on Self-Criticism. The third profile comprised mothers with higher scores on both Self-Criticism and Dependency. The smallest proportion of unresolved mothers belonged to the third, most vulnerable profile labeled Double Vulnerability. DiscussionWe discussed the implications of the obtained results in light of a need for psychotherapeutic interventions that would focus on individual differences when providing support to parental resolution.

Harnessing the power of AI in precision medicine: NGS-based therapeutic insights for colorectal cancer cohort.

Developing innovative precision and personalized cancer therapeutics is essential to enhance cancer survivability, particularly for prevalent cancer types such as colorectal cancer. This study aims to demonstrate various approaches for discovering new targets for precision therapies using artificial intelligence (AI) on a Polish cohort of colorectal cancer patients. We analyzed 71 patients with histopathologically confirmed advanced resectional colorectal adenocarcinoma. Whole exome sequencing was performed on tumor and peripheral blood samples, while RNA sequencing (RNAseq) was conducted on tumor samples. We employed three approaches to identify potential targets for personalized and precision therapies. First, using our in-house neoantigen calling pipeline, ARDentify, combined with an AI-based model trained on immunopeptidomics mass spectrometry data (ARDisplay), we identified neoepitopes in the cohort. Second, based on recurrent mutations found in our patient cohort, we selected corresponding cancer cell lines and utilized knock-out gene dependency scores to identify synthetic lethality genes. Third, an AI-based model trained on cancer cell line data was employed to identify cell lines with genomic profiles similar to selected patients. Copy number variants and recurrent single nucleotide variants in these cell lines, along with gene dependency data, were used to find personalized synthetic lethality pairs. We identified approximately 8,700 unique neoepitopes, but none were shared by more than two patients, indicating limited potential for shared neoantigenic targets across our cohort. Additionally, we identified three synthetic lethality pairs: the well-known APC-CTNNB1 and BRAF-DUSP4 pairs, along with the recently described APC-TCF7L2 pair, which could be significant for patients with APC and BRAF variants. Furthermore, by leveraging the identification of similar cancer cell lines, we uncovered a potential gene pair, VPS4A and VPS4B, with therapeutic implications. Our study highlights three distinct approaches for identifying potential therapeutic targets in cancer patients. Each approach yielded valuable insights into our cohort, underscoring the relevance and utility of these methodologies in the development of precision and personalized cancer therapies. Importantly, we developed a novel AI model that aligns tumors with representative cell lines using RNAseq and methylation data. This model enables us to identify cell lines closely resembling patient tumors, facilitating accurate selection of models needed for in vitro validation.

Mapping brain activity and neurotransmitters pre-cigarette smoking evolution: A study of male subjects

BackgroundThe impact of tobacco smoking on global health persists and it is essential to understand the progression of addiction and the involvement of neurotransmitters. MethodsThis study assessed 47 participants with tobacco use disorder (TUD) categorized based on changes in Fagerström Test for Nicotine Dependence (FTND) scores over 6 years: progressive TUD (pTUD), regressive TUD (rTUD), and stable TUD (sTUD). Additionally, 35 healthy controls were included. Resting-state functional magnetic resonance imaging was used to evaluate brain regional homogeneity (ReHo) and correlations with neurotransmitter distributions using JuSpace. ResultsSignificant differences in ReHo were observed among pTUD, rTUD, sTUD, and controls. After strict Bonferroni correction, rTUD exhibited increased ReHo in the dorsolateral superior frontal gyrus compared to sTUD (p < 0.001) and controls (p < 0.001). Both pTUD (p < 0.001) and rTUD (p < 0.001) showed decreased ReHo in the superior temporal gyrus compared to sTUD. sTUD had increased ReHo in the supramarginal gyrus compared to all other groups (p < 0.001, p < 0.001, p = 0.002, separately). The strongest association, which survived rigorous Bonferroni correction, was between the ReHo changes in rTUD compared to sTUD and neurotransmitter distribution. This includes 5-hydroxytryptamine receptor 2A (p = 0.001), gamma-aminobutyric acid type A receptor (p < 0.001), norepinephrine transporter (p < 0.001), and N-Methyl-D-Aspartate (p = 0.002). ConclusionsThis study provides insights into how smoking behaviors correlate with alterations in brain activity and neurotransmitter function. By elucidating these neural links to tobacco use disorder progression, our findings contribute to a deeper understanding of smoking's neurological impact and potentially inform more targeted therapeutic strategies.

Validation and Psychometric Assessment of the Persian Version of the Adult Responses to Children’s Symptoms Questionnaire in Children With Chronic Diseases

Background Measuring the way adults respond to the needs of children with chronic diseases is of therapeutic and research importance due to its effect on the course of the disease and children’s symptoms. Objective This study aims to validate and assess the psychometric properties of the Persian version of the adult responses to children’s symptoms (ARCS) questionnaire in children with chronic diseases. Methods This is a descriptive and psychometrics study. Participants were 290 parents of children aged 4-16 years with chronic diseases who visited 17 Shahrivar Hospital in Rasht, Iran from winter 2021 to spring 2022. They were selected using a consecutive sampling method and answered the Persian versions of ARCS and the child-parent relationship scale (CPRS). Results The correlation coefficients between the total score and the items for the dimension of encouraging/monitoring were in the range of 0.35-0.72, for the protective dimension in the range of 0.44-0.73, and for the minimizing dimension in the range of 0.53-0.66. In addition, the results of regression analysis showed that the scores of ARCS dimensions were able to significantly explain the variance in scores of the CPRS dimensions of conflict (20%), closeness (34%), and dependency (36%) and overall CPRS score Conclusion The Persian ARCS questionnaire is a valid and reliable tool for use in the Iranian samples.