Online Version Research Articles

Rational Design of HER2-Targeted Combination Therapies to Reverse Drug Resistance in Fibroblast-Protected HER2+ Breast Cancer Cells.

Fibroblasts, an abundant cell type in the breast tumor microenvironment, interact with cancer cells and orchestrate tumor progression and drug resistance. However, the mechanisms by which fibroblast-derived factors impact drug sensitivity remain poorly understood. Here, we develop rational combination therapies that are informed by proteomic profiling to overcome fibroblast-mediated therapeutic resistance in HER2+ breast cancer cells. Drug sensitivity to the HER2 kinase inhibitor lapatinib was characterized under conditions of monoculture and exposure to breast fibroblast-conditioned medium. Protein expression was measured using reverse phase protein arrays. Candidate targets for combination therapy were identified using differential expression and multivariate regression modeling. Follow-up experiments were performed to evaluate the effects of HER2 kinase combination therapies in fibroblast-protected cancer cell lines and fibroblasts. Compared to monoculture, fibroblast-conditioned medium increased the expression of plasminogen activator inhibitor-1 (PAI1) and cell cycle regulator polo like kinase 1 (PLK1) in lapatinib-treated breast cancer cells. Combination therapy of lapatinib with inhibitors targeting either PAI1 or PLK1, eliminated fibroblast-protected cancer cells, under both conditions of direct coculture with fibroblasts and protection by fibroblast-conditioned medium. Analysis of publicly available, clinical transcriptomic datasets revealed that HER2-targeted therapy fails to suppress PLK1 expression in stroma-rich HER2+ breast tumors and that high PAI1 gene expression associates with high stroma density. Furthermore, we showed that an epigenetics-directed approach using a bromodomain and extraterminal inhibitor to globally target fibroblast-induced proteomic adaptions in cancer cells, also restored lapatinib sensitivity. Our data-driven framework of proteomic profiling in breast cancer cells identified the proteolytic degradation regulator PAI1 and the cell cycle regulator PLK1 as predictors of fibroblast-mediated treatment resistance. Combination therapies targeting HER2 kinase and these fibroblast-induced signaling adaptations eliminates fibroblast-protected HER2+ breast cancer cells. The online version contains supplementary material available at 10.1007/s12195-024-00823-0.

Acetate attenuates lead-induced dysregulation of testicular steroidogenesis and spermatogenesis by targeting oxidative stress, inflammatory cytokines, and apoptosis.

The online version contains supplementary material available at 10.1007/s43188-024-00250-3.

Impact of heat stress on physiological characteristics and expression of heat shock proteins (HSPs) in groundnut (Arachis hypogaea L.).

The online version contains supplementary material available at 10.1007/s12298-024-01520-y.

Comparison of the Efficacy and Safety of Bilastine 20mg versus Fexofenadine 180mg for Treatment of Perennial Allergic Rhinitis: Randomized Controlled Study.

Antihistamines has always remained the mainstay drug treatment for Allergic Rhinitis (AR). Bilastine is a novel, non-sedative antihistamine with a super-selective H1 receptor antagonist property. Both bilastine and fexofenadine are second generation antihistamine drugs commonly used to manage AR and Chronic Urticaria (CU). Autologous Skin Serum Test (ASST) is a practical test for histamine release in CU. These tests have been studied in AR patients with limited data studies. 114 patients diagnosed with perennial AR were recruited and divided into two groups of 57 each. One group was started Bilastine 20mg once a day and other group, fexofenadine 180mg once a day. Total Nasal Symptom Score (TNSS) was calculated at presentation and two weeks of antihistamine therapy. ASST was hypothesized to be the test for AR and performed at the time of presentation and at two weeks follow-up. Intergroup and Intragroup assessment of TNSS, ASST and its variables were done using unpaired and paired t test respectively. Patients showed reduction in symptoms of AR with both antihistamines. A significant improvement of sneezing and rhinorrhoea was seen in Fexofenadine group as compared to Bilastine group. TNSS showed statistically significant improvement in both the groups. ASST had statistically significant reduction in both the groups. Both Bilastine and fexofenadine were found to be effective in reduction of symptoms of allergic rhinitis. Bilastine was found to be more effective in overall as well as sneezing and rhinorrhoea noted two weeks after therapy. The online version contains supplementary material available at 10.1007/s12070-024-04770-0.

Unveiling the link between arsenic toxicity and diabetes: an in silico exploration into the role of transcription factors.

The online version contains supplementary material available at 10.1007/s43188-024-00255-y.

Seed priming using different agents can alleviate salt stress in kenaf (Hibiscus cannabinus L.) by activating antioxidant system and related genes expression.

The online version contains supplementary material available at 10.1007/s12298-024-01521-x.

Enablers of and Barriers to Self-Regulated and Self-Directed Aptitudes of Learning (SELF-ReDiAL) in Health Professional Education: A Systematic Review and Meta-analysis.

Recently, accrediting organizations have focused on developing lifelong learners who possess self-regulated and self-directed aptitudes of learning (hereinafter SELF-ReDiAL or in short, SR). This meta-analysis aimed to identify factors which promote or deter SR in health professionals. Original studies which, by using self-reports, evaluated enablers of and barriers to SR in health professionals (dentistry, medicine, nursing, and pharmacology), and were indexed in Scopus® and PubMed® databases from 1 January 2000 to 31 August 2022, were retrieved. Major themes suggested to affect SR were determined, and enablers or barriers related to those themes, were considered eligible for inclusion. Studies were excluded if they were not in English, and if the full text could not be retrieved. From 149 identified papers, 43 studies were subsequently included in the meta-analysis. The strongest effect was generated by wellbeing (d = 0.806; 95% confidence of interval [CI]: 0.296, 1.316). In respect of teaching method, problem-based learning (d = 0.590; 95%CI: 0.375, 0.806), team-based learning (d = 0.382; 95%CI: 0.232, 0.531), and flipped classroom (d = 0.095; 95%CI: -0.088, 0.279) showed positive effects on SR, whereas lectures were negatively associated with SR (d = -0.079; 95%CI: - 0.389, 0.230). Further, the analysis showed that SR generally decreases during the first year of enrolment (d = -0.144; 95%CI: - 0.284, -0.004), while no major change in SR is observed in the second year (d = 0.027; 95%CI: -0.044, 0.099). Considering that student wellbeing had the strongest observed effect on SR, policy-setting and governing bodies should incorporate methods which improve wellbeing to develop health professionals with high levels of SR. The online version contains supplementary material available at 10.1007/s40670-024-02068-y.

Allantoin regulated oxidative defense, secondary metabolism and ions homeostasis in maize (Zea mays L.) under heat stress.

The online version contains supplementary material available at 10.1007/s12298-024-01519-5.

The reliability and validity of in-person and remote behavioural screening tools for people with amyotrophic lateral sclerosis

ObjectiveThis study aimed to assess the psychometric properties of and relationships between total scores on different screening tools assessing behavioural change for people with amyotrophic lateral sclerosis (ALS), and whether administering the screens as online questionnaires (rather than on paper, in-person) influences total scores. MethodsThe behavioural component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASb); the behavioural component of the ALS Cognitive Behavioural Screen (ALS-CBSb), the ALS-Frontotemporal Dementia Questionnaire (ALS-FTD-Q), the Beaumont Behavioural Inventory (BBI), and the Motor Neuron Disease Behavioural Instrument (MiND-B) were administered to 35 informants on paper. Online questionnaire versions of the behavioural screens were administered to 49 informants.Forward stepwise linear regressions were conducted to assess whether scores on behavioural screens were predicted by scores on the other behavioural screens and to assess whether total scores were predicted by the mode of administration (paper or online) of the screens. ResultsBehavioural screening tools, except the ECASb, had good internal consistency but mixed item-total correlations. All regression models assessing whether behavioural screen scores predict other behavioural screen scores were significant. The BBI performed best and the ECASb performed worst in terms of their predictive relationships with other screening tools. The administration mode of the questionnaires did not significantly affect total scores. ConclusionsThe psychometric properties of the scales varied. The scales predicted each other's scores, supporting convergent validity. Online and paper versions performed similarly, and demographics did not predict scores.

Molecular Markers in the World Health Organization Classification of Head and Neck Tumors, Fifth Edition.

The past decade has seen exponential advancements in molecular markers and the genetics of tumors, recognizing the limitations of conventional histopathology for grading, classification, and prognostication. Such advances have resulted in changes to classification systems, for example, with the incorporation of objective molecular and genetic information into the 2021 World Health Organization (WHO) classification of central nervous system tumors. The fifth edition of the WHO classification of head and neck tumors (HN5) (beta online version, 2022) also introduced major changes based on molecular markers, including additions, deletions, and reclassifications of entities, with the idea of being more objective and standardized. These changes are highly relevant to therapy decisions, prognosis, and clinical research and for patients with resistant diseases to explore options in clinical trials. The HN5, for the first time, included a radiologist as a member of the writing team to incorporate pertinent imaging findings into the classification. It is important for the radiologist, as an integral part of the multidisciplinary team, to be up to date about these changes for a better understanding of tumor biology, to integrate this into their clinical practice, and to provide more value in their interpretations. The authors provide a basic understanding of pathology and genetics for the radiologist, highlighting the molecular changes in epithelial (including squamous cell) and nonepithelial tumors of the head and neck. The authors also highlight newly recognized and reclassified tumor entities and provide a brief discussion on the genetic tumor syndromes. ©RSNA, 2024 Supplemental material is available for this article. See the invited commentary by Junn and Baugnon in this issue.

A low-cost digital first aid tool to reduce psychological distress in refugees: a multi-country randomized controlled trial of Self-Help Online in the first months after the invasion of Ukraine

Armed conflicts increase distress levels among affected populations, particularly impacting refugees who often face barriers to accessing psychological support. We evaluate an online version of a previously tested in-person and endorsed for online adaptation by the WHO Self-Help Plus (SH+) program among Ukrainian refugees dispersed across 17 countries, internally displaced and not displaced Ukrainians. This is the first randomized controlled trial to test an online psychological intervention simultaneously on refugees, internally displaced, and non-displaced conflict-affected populations. This study is an online two-arm, individually randomized controlled trial among participants above 18 years old in Ukraine or EU countries who were randomly assigned to receive either the Self-Help Online (SHO) intervention and passive informational resource or the passive informational resource alone. We recruited 652 participants starting the program on July 7th, 2022. The analysis focused on 292 participants who completed the final survey one week after the end of the program. Results indicated significant distress reduction among refugees (β −2.16, 95% CI −4.17 to −0.16; p=0.03; d −0.47) but not among internally displaced in Ukraine (β 0.56, 95% CI −1.1 to 2.99; p=0.17; d 0.2) or non-displaced participants in Ukraine (β 0.2, 95% CI −0.95 to 1.35; p=0.73; d 0.08). The effect size in stress reduction for refugees was comparable to other similar interventions but with lower average costs. The average cost per participant was €11, with €46.16 for each benefiting (refugee) participant, suggesting cost-effectiveness for scale-up. These findings suggest that Self-Help Online is an effective psychological intervention for reducing stress among geographically dispersed refugees at a low cost. We also find that the online delivery format of psychological interventions is feasible for internally displaced and non-displaced conflict-affected populations.

TSST-OL: Comparison between online and laboratory application and effects on empathy

Online test protocols are increasingly popular in psychological and neuroscientific research. Despite its relevance to the social functioning, the influence of acute stress on cognitive and affective state empathy is not clearly understood. Recently, a remote online version (TSST-OL) of the Trier Social Stress Test (TSST) was established for use in research with both children and adults. In general, the TSST-OL offers the opportunity for context-independent application (e.g., at the participants’ home or in field contexts). However, in order to exploit this opportunity, it seems crucial to validate the TSST-OL across different settings and contextual variables. We compared stress reactivity in response to the TSST-OL at home and in the laboratory. In a 2 ×2 factorial design, N=120 participants (n=60 women) underwent the TSST-OL and an online adaption of the friendly TSST (fTSST-OL) either at home (n=60) or at the laboratory (n=60). Stress induction was evaluated in terms of physiological (cortisol and salivary alpha-amylase, sAA) and subjective stress and affect measures. Participants also completed an empathy performance task after stress and control exposure. Results confirmed that the TSST-OL successfully induced stress both when conducted at participants’ homes and in the laboratory. Still, cortisol levels were higher during laboratory participation compared to application at home, likely due to anticipatory stress. Consequently, the TSST-OL in a home-based application seems to buffer anticipatory stress thus making it an attractive tool to study experimentally induced stress reactivity. Concerning empathy, positive emotions were generally better identified (cognitive empathy) and empathized (affective empathy) than negative emotions. For the latter, this difference was absent after stress, indicated by decreased affective empathy for positive emotions. Overall, this study indicates that the TSST-OL induces stress and validates the tool using a rigorous study design with sufficient participants and relevant stress parameters. Thus, future studies may apply the TSST-OL in different contexts and diverse samples. The findings on empathy under stress align with mixed results in existing research, highlighting the necessity for further investigations into empathy, considering various measurements, stimulus valence, and sex of the participant.

Development and validation of a deep learning-based survival prediction model for pediatric glioma patients: A retrospective study using the SEER database and Chinese data

ObjectiveDevelop a time-dependent deep learning model to accurately predict the prognosis of pediatric glioma patients, which can assist clinicians in making precise treatment decisions and reducing patient risk. Study designThe study involved pediatric glioma patients from the Surveillance, Epidemiology, and End Results (SEER) Registry (2000–2018) and Tangdu Hospital in China (2010–2018) within specific time frames. For training, we selected two neural network-based algorithms (DeepSurv, neural multi-task logistic regression [N-MTLR]) and one ensemble learning-based algorithm (random survival forest [RSF]). Additionally, a multivariable Cox proportional hazard (CoxPH) model was developed for comparison purposes. The SEER dataset was randomly divided into 80 % for training and 20 % for testing, while the Tangdu Hospital dataset served as an external validation cohort. Super-parameters were fine-tuned through 1000 repeated random searches and 5-fold cross-validation on the training cohort. Model performance was assessed using the concordance index (C-index), Brier score, and Integrated Brier Score (IBS). Furthermore, the accuracy of predicting survival at 1, 3, and 5 years was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and the area under the ROC curves (AUC). The generalization ability of the model was assessed using the C-index of the Tangdu Hospital data, ROC curves for 1, 3, and 5 years, and AUC values. Lastly, decision curve analysis (DCA) curves for 1, 3, and 5-year time frames are provided to assess the net benefits across different models. ResultsA total of 9532 patients with pediatric glioma were included in this study, comprising 9274 patients from the SEER database and 258 patients from Tangdu Hospital in China. The average age at diagnosis was 9.4 ± 6.2 years, and the average survival time was 96 ± 66 months. Through comprehensive performance comparison, the DeepSurv model demonstrated the highest effectiveness, with a C-index of 0.881 on the training cohort. Furthermore, it exhibited excellent accuracy in predicting the 1-year, 3-year, and 5-year survival rates (AUC: 0.903–0.939). Notably, the DeepSurv model also achieved remarkable performance and accuracy on the Chinese dataset (C-index: 0.782, AUC: 0.761–0.852). Comprehensive analysis of DeepSurv, N-MTLR, and RSF revealed that tumor stage, radiotherapy, histological type, tumor size, chemotherapy, age, and surgical method are all significant factors influencing the prognosis of pediatric glioma. Finally, an online version of the pediatric glioma survival predictor based on the DeepSurv model has been established and can be accessed through https://pediatricglioma-tangdu.streamlit.app. ConclusionsThe DeepSurv model exhibits exceptional efficacy in predicting the survival of pediatric glioma patients, demonstrating strong performance in discrimination, calibration, stability, and generalization. By utilizing the online version of the pediatric glioma survival predictor, which is based on the DeepSurv model, clinicians can accurately predict patient survival and offer personalized treatment options.

Biological roles of THRAP3, STMN1 and GNA13 in human blood cancer cells.

The online version contains supplementary material available at 10.1007/s13205-024-04093-5.

Unveiling the anticancer potential of Anamirta cocculus (L.) Wight& Arn.: Evidences from cytotoxicity studies, apoptosis analysis, and molecular docking.

The online version contains supplementary material available at 10.1007/s13205-024-04096-2.

VfLRR-RLK1 benefiting resistance to Fusarium oxysporum reveals infection and defense mechanisms in tung tree.

The online version contains supplementary material available at 10.1007/s12298-024-01512-y.

Xiangchun 37, a spring soybean variety with multiplexed traits of medium maturity period, high yield, and high seed oil content.

The online version contains supplementary material available at 10.1007/s11032-024-01505-5.

Comparison of a guided assessment and an app-based assessment of physical activity using the Global Physical Activity Questionnaire (GPAQ)

Introduction & Purpose The Global Physical Activity Questionnaire (GPAQ; Armstrong & Bull, 2006) is commonly used to assess frequency, duration and intensity of physical activity (PA) in three domains: work, travel and recreation. It is frequently used as a self-administered questionnaire; however, the execution was originally designed for an interviewer. With the continuous development of app-based technology, the evaluation of PA online-assessment is relevant (Mosa et al., 2012). The objective of the study was to compare an online self-administered version of the GPAQ with the original version administered by an interviewer. Methods The physical activity behaviour of 533 participants (70% female, average age 44, ± 13.9) from the LIFE-Tirol Study (Lasting Health through Intermittent Fasting, Emotional Firmness and Exercise) was assessed by an interviewer using the GPAQ. The interviewer used generic show cards for explaining different levels of exercise intensities as recommended in the analysis guidelines (Armstrong & Bull, 2006). After two months, participants were asked to fill in the GPAQ via online app without show cards. Participant were advised not to change their usual physical activity levels during the two months. The movement domains and intensities of the two versions were compared with Jamovi v2.3 using a series of Wilcoxon W-tests and a series of 2 × 2 mixed ANOVAs to analyse gender- and age-specific aspects. Results Total metabolic equivalent task (MET) minutes were significantly different between interview and self-assessed online version (1,971 ± 2,590 vs. 4,143 ± 4,370 MET minutes; p < .001, d = 0.670). Significantly more MET minutes were reported in the online version compared to the interview version across all three PA-domains and both vigorous and moderate intensities (F(1, 552) = 167, p < .001, ƞ² = .232). This difference was not influenced by gender. 18–34-year-old participants reported significantly less MET minutes during recreational PA than participants older than 55 years in both versions (F(1, 551) = 113, p < .001, ƞ²= .170). No further gender/age × assessment interaction effects were found. Male participants tend to report higher intensity minutes more likely than females in both assessment versions (F(1, 551) = 4.43, p = 0.360, ƞ²= .008). Discussion The amount of PA as well as its intensities seem to differ between the self-assessed online version compared to the interview assessment of the GPAQ, although the interview was conducted as the first measurement and PA as well as intensities were explained in detail to participants using generic show cards. It was previously reported that show cards have no significant impact on the results of the self-administered version of the GPAQ (Rudolf et al., 2020). Therefore, the authors suggest that the main differences between both assessments were caused by the presence of the interviewer independent of age or gender. Conclusion Regardless of the use of show cards and detailed explanations of PA, the main difference between guided and self-administered PA-assessments may result from the presence or absence of an interviewer. Therefore, it is important to interpret self-administered app-based GPAQ evaluations with caution. Future studies should validate app-based GPAQ data by using objective PA measurements, such as accelerometers.

Molecular characterization, haplotype analysis and development of markers specific to dzs18 gene regulating methionine accumulation in kernels of subtropical maize.

The online version contains supplementary material available at 10.1007/s13205-024-04088-2.

Physio-morphological and molecular characterization of ethyl methanesulfonate-derived mutant population of Gossypium herbaceum L. cv. (Wagad) for drought tolerance.

The online version contains supplementary material available at 10.1007/s13205-024-04089-1.