Cuproptosis-related lncRNA signature as a prognostic tool and therapeutic target in diffuse large B cell lymphoma.

Cuproptosis is a newly defined form of programmed cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis and metastasis. However, whether cuproptosis-related lncRNAs are involved in the pathogenesis of diffuse large B cell lymphoma (DLBCL) remains unclear. This study aimed to identify the prognostic signatures of cuproptosis-related lncRNAs in DLBCL and investigate their potential molecular functions. RNA-Seq data and clinical information for DLBCL were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Cuproptosis-related lncRNAs were screened out through Pearson correlation analysis. Utilizing univariate Cox, least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analysis, we identified seven cuproptosis-related lncRNAs and developed a risk prediction model to evaluate its prognostic value across multiple groups. GO and KEGG functional analyses, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. Additionally, drug sensitivity analysis identified drugs with potential efficacy in DLBCL. Finally, the protein-protein interaction (PPI) network were constructed based on the weighted gene co-expression network analysis (WGCNA). We identified a set of seven cuproptosis-related lncRNAs including LINC00294, RNF139-AS1, LINC00654, WWC2-AS2, LINC00661, LINC01165 and LINC01398, based on which we constructed a risk model for DLBCL. The high-risk group was associated with shorter survival time than the low-risk group, and the signature-based risk score demonstrated superior prognostic ability for DLBCL patients compared to traditional clinical features. By analyzing the immune landscapes between two groups, we found that immunosuppressive cell types were significantly increased in high-risk DLBCL group. Moreover, functional enrichment analysis highlighted the association of differentially expressed genes with metabolic, inflammatory and immune-related pathways in DLBCL patients. We also found that the high-risk group showed more sensitivity to vinorelbine and pyrimethamine. A cuproptosis-related lncRNA signature was established to predict the prognosis and provide insights into potential therapeutic strategies for DLBCL patients.

Stimulus-Responsive Four-Stranded DNA Nanoring Assembly to Host Multiple Nanosilver Clusters for Cooperatively Enhanced Fluorescence Biosensing.

Exploring the ability of four-stranded DNA nanorings (fsDNRs) to host multiple nanosilver clusters (NAgCs) for cooperatively amplifiable fluorescence biosensing to a specific initiator (tI*) is fascinating. By designing three DNA single strands and three analogous stem-loop hairpins, we developed a functional fsDNR through sequential cross-opening and overlapped hybridization. Note that a substrate strand (SS) was programmed with six modules: two severed splits (sT and sT') of NAgCs template, two sequestered segments by a middle unpaired spacer, and a partition for tI*-recognizable displacement, while sT and sT' were also tethered in two ends of three hairpins. At first, a triple dsDNA complex with stimulus-responsiveness was formed to guide the specific binding to tI*, while the exposed toehold of the SS activated the forward cascade hybridization of three hairpins, until the ring closure in the tailored self-assembly pathway for forming the fsDNR. The resulting four duplexes forced each pair of sT/sT' to be merged as the parent template in four nicks, guiding the preferential synthesis of four clusters in the shared fsDNR, thereby cooperatively amplifying the green fluorescence signal for sensitive assay of tI*. Meanwhile, the topological conformation of fsDNR can be stabilized by the as-formed cluster adducts to rivet the pair of two splits in the nicks. Benefitting from the self-enhanced effect of multiple emitters, this label-free fluorescent sensing strategy features simplicity, rapidity, and high on-off contrast, without involving complicated nucleic acid amplifiers.

Leveraging Social Media to Predict COVID-19-Induced Disruptions to Mental Well-Being Among University Students: Modeling Study.

BACKGROUND: Large-scale crisis events such as COVID-19 often have secondary impacts on individuals' mental well-being. University students are particularly vulnerable to such impacts. Traditional survey-based methods to identify those in need of support do not scale over large populations and they do not provide timely insights. We pursue an alternative approach through social media data and machine learning. Our models aim to complement surveys and provide early, precise, and objective predictions of students disrupted by COVID-19. OBJECTIVE: This study aims to demonstrate the feasibility of language on private social media as an indicator of crisis-induced disruption to mental well-being. METHODS: We modeled 4124 Facebook posts provided by 43 undergraduate students, spanning over 2 years. We extracted temporal trends in the psycholinguistic attributes of their posts and comments. These trends were used as features to predict how COVID-19 disrupted their mental well-being. RESULTS: The social media-enabled model had an F1-score of 0.79, which was a 39% improvement over a model trained on the self-reported mental state of the participant. The features we used showed promise in predicting other mental states such as anxiety, depression, social, isolation, and suicidal behavior (F1-scores varied between 0.85 and 0.93). We also found that selecting the windows of time 7 months after the COVID-19-induced lockdown presented better results, therefore, paving the way for data minimization. CONCLUSIONS: We predicted COVID-19-induced disruptions to mental well-being by developing a machine learning model that leveraged language on private social media. The language in these posts described psycholinguistic trends in students' online behavior. These longitudinal trends helped predict mental well-being disruption better than models trained on correlated mental health questionnaires. Our work inspires further research into the potential applications of early, precise, and automatic warnings for individuals concerned about their mental health in times of crisis.

Evaluation of the efficacy of intervention in the management of AD chronic disease based on the theory of "prevention of the recrudescence of disease".

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with a chronic course and a high recurrence. OBJECTIVE: Based on the theory of "prevention and recovery after ulceration", the application value and significance of compound ginseng cicada decoction in the intervention of chronic disease management in patients with AD were retrospectively analyzed. METHODS: Through clinical retrospective observation, 60 patients with spleen deficiency and moisture type AD admitted to the outpatient clinic of our hospital after January 2019 were analyzed. After comprehensive treatment until the patient's Investigator's Global Assessment (IGA) Scale score is lower than 2 points, the study group was divided into a research group and a control group, according to the actual clinical follow-up whether to take compound ginseng cicada soup. The control group carried out chronic disease management education, conventional emollient topical with no drug maintenance intervention, and the research group included clinical patients who were orally administered to compound ginseng cicada decoction for 1 month, observed for 3 months, and compared with the clinical recurrence (recurrence rate, time to first recurrence, severity at recurrence, degree of pruritus), and the quality of life. RESULTS: After 3 months, the relapse rate, recurrence severity, itching degree and quality of life impact scores of the study group were significantly lower than those of the control group, and there were no obvious adverse events. CONCLUSION: The combined application of compound ginseng cicada decoction in the management of chronic diseases in patients with atopic dermatitis has the positive significance of reducing AD recurrence, alleviating the severity of recurrence, and effectively improving the life quality of patients. This method has high safety and is worthy of wide application.

Targeted delivery of HSP90 inhibitors for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer.

Heat shock protein 90 (HSP90) is overexpressed in numerous cancers, promotes the maturation of numerous oncoproteins and facilitates cancer cell growth. Certain HSP90 inhibitors have entered clinical trials. Although less than satisfactory clinical effects or insurmountable toxicity have compelled these trials to be terminated or postponed, these results of preclinical and clinical studies demonstrated that the prospects of targeting therapeutic strategies involving HSP90 inhibitors deserve enough attention. Nanoparticulate-based drug delivery systems have been generally supposed as one of the most promising formulations especially for targeting strategies. However, so far, no active targeting nano-formulations have succeeded in clinical translation, mainly due to complicated preparation, complex formulations leading to difficult industrialization, incomplete biocompatibility or nontoxicity. In this study, HSP90 and CD44-targeted A6 peptide functionalized biomimetic nanoparticles (A6-NP) was designed and various degrees of A6-modification on nanoparticles were fabricated to evaluate targeting ability and anticancer efficiency. With no excipients, the hydrophobic HSP90 inhibitor G2111 and A6-conjugated human serum albumin could self-assemble into nanoparticles with a uniform particle size of approximately 200 nm, easy fabrication, well biocompatibility and avoidance of hepatotoxicity. Besides, G2111 encapsulated in A6-NP was only released less than 5% in 12 h, which may avoid off-target cell toxicity before entering into cancer cells. A6 peptide modification could significantly enhance uptake within a short time. Moreover, A6-NP continues to exert the broad anticancer spectrum of Hsp90 inhibitors and displays remarkable targeting ability and anticancer efficacy both in hematological malignancies and solid tumors (with colon tumors as the model cancer) both in vitro and in vivo. Overall, A6-NP, as a simple, biomimetic and active dual-targeting (CD44 and HSP90) nanomedicine, displays high potential for clinical translation.

Unlocking the Potential: A Systematic Review of Master Protocol in Pediatrics.

The use of master protocols allows for innovative approaches to clinical trial designs, potentially enabling new approaches to operations and analytics and creating value for patients and drug developers. Pediatric research has been conducted for many decades, but the use of novel designs such as master protocols in pediatric research is not well understood. This study aims to provide a systematic review on the utilization of master protocols in pediatric drug development. A search was performed in September 2022 using two data sources (PubMed and ClinicalTrials.gov) and included studies conducted in the past10 years. General study information was extracted such as study type, study status, therapeutic area, and clinical trial phase. Study characteristics that are specific to pediatric studies (such as age of the participants and pediatric drug dosing) and important study design elements (such as number of test drug arms and whether randomization and/or concurrent control was used) were also collected. Our results suggest that master protocol studies are being used in pediatrics, with platform and basket trials more common than umbrella trials. Most of this experience is in oncology and early phase studies. There is a rise in the use starting in 2020, largely in oncology and COVID-19 trials. However, adoption of master protocols in pediatric clinical research is still on a small scale and could be substantially expanded. Work is required to further understand the barriers in implementing pediatric master protocols, from setting up infrastructure to interpreting study findings.

Diagnosis of Pediatric Appendicovesical Fistula by Contrast-enhanced Ultrasound: A Case Report.

Appendicovesical fistula is a rare complication associated with appendicitis, Crohn's disease, or appendiceal tumors, posing significant diagnostic challenges. We reported a pediatric case of appendicovesical fistula that remained undiagnosed by non-contrast computed tomography, fluoroscopic voiding cystourethrography (VCUG). Although identified during cystoscopy, its connection to the fistula site could not be determined. However, the transvesical contrast-enhanced ultrasound clearly demonstrated the presence of fistula. Subsequently, laparoscopic appendectomy and bladder repair were performed successfully, leading to complete recovery in the patient. To our knowledge, this is the first reported diagnosis of appendicovesical fistula in children using contrast-enhanced ultrasound.

Efficacy and Safety of BTKis in Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of Bruton tyrosine kinase inhibitors (BTKis) for central nervous system lymphoma (CNSL). METHODS: A systematic review was carried out to identify relevant studies from the PubMed, Embase, Cochrane Library, Web of Science, WanFang, CNKI, and CBM databases. The studies included patients with CNSL who received BTKis and reported the overall response (OR), complete remission (CR), and partial response (PR). An overall effect analysis was performed using STATA 15.0. A random-effects model was utilized to calculate the pooled rates, and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: A total of 21 studies involving 368 patients were included in the meta-analysis. For newly diagnosed CNSL, due to the small simple size, we conducted a quantitative description, and the ORR could reach up to 100%. For relapsed/refractory patients, the pooled ORR was 72% (95% CI: 64-80%, I2 = 54.89%, p = 0.00), with a pooled CR and PR of 43% (95% CI: 33-54%, I2 = 65.40%, p = 0.00) and 23% (95% CI: 13-35%, I2 = 78.05%, p = 0.00), respectively. Most adverse events were hematology-related and generally manageable. CONCLUSION: BTKis showed acceptable efficacy and safety in treating patients with CNSL. However, large and well-designed trials are still required to confirm BTKis as a treatment for CNSL.

A Patient Similarity Network (CHDmap) to Predict Outcomes After Congenital Heart Surgery: Development and Validation Study.

Background: Although evidence-based medicine proposes personalized care that considers the best evidence, it still fails to address personal treatment in many real clinical scenarios where the complexity of the situation makes none of the available evidence applicable. "Medicine-based evidence" (MBE), in which big data and machine learning techniques are embraced to derive treatment responses from appropriately matched patients in real-world clinical practice, was proposed. However, many challenges remain in translating this conceptual framework into practice. Objective: This study aimed to technically translate the MBE conceptual framework into practice and evaluate its performance in providing general decision support services for outcomes after congenital heart disease (CHD) surgery. Methods: Data from 4774 CHD surgeries were collected. A total of 66 indicators and all diagnoses were extracted from each echocardiographic report using natural language processing technology. Combined with some basic clinical and surgical information, the distances between each patient were measured by a series of calculation formulas. Inspired by structure-mapping theory, the fusion of distances between different dimensions can be modulated by clinical experts. In addition to supporting direct analogical reasoning, a machine learning model can be constructed based on similar patients to provide personalized prediction. A user-operable patient similarity network (PSN) of CHD called CHDmap was proposed and developed to provide general decision support services based on the MBE approach. Results: Using 256 CHD cases, CHDmap was evaluated on 2 different types of postoperative prognostic prediction tasks: a binary classification task to predict postoperative complications and a multiple classification task to predict mechanical ventilation duration. A simple poll of the k-most similar patients provided by the PSN can achieve better prediction results than the average performance of 3 clinicians. Constructing logistic regression models for prediction using similar patients obtained from the PSN can further improve the performance of the 2 tasks (best area under the receiver operating characteristic curve=0.810 and 0.926, respectively). With the support of CHDmap, clinicians substantially improved their predictive capabilities. Conclusions: Without individual optimization, CHDmap demonstrates competitive performance compared to clinical experts. In addition, CHDmap has the advantage of enabling clinicians to use their superior cognitive abilities in conjunction with it to make decisions that are sometimes even superior to those made using artificial intelligence models. The MBE approach can be embraced in clinical practice, and its full potential can be realized.

Considerations for master protocols using external controls.

There has been an increasing use of master protocols in oncology clinical trials because of its efficiency to accelerate cancer drug development and flexibility to accommodate multiple substudies. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple investigational products and/or subpopulations are studied under a single protocol. Master protocols can use external data and evidence (e.g. external controls) for treatment effect estimation, which can further improve efficiency of master protocol trials. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands, assessment of fit-for-use real-world data, and considerations for different types of master protocols. Similarities and differences between regular randomized controlled trials and master protocols when using external controls are discussed. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing sensitivity analyses. Two illustrative examples for master protocols using external controls are discussed for their merits and possible improvement in causal effect estimation.

Short-stranded DNA segment-modulated LAMP/H+ as signal transducer to guide CHA-cooperated amplifiable electrochemical biosensing.

BACKGROUND: Modulating loop-mediated isothermal amplification (mLAMP) by short-stranded DNA segment trigger (T) to generate byproducts H+ ions (mLAMP/H+) as signal transducer is intriguing for developing catalytic hairpin assembly (CHA)-cooperated amplifiable electrochemical biosensors. This would be a big challenge for traditional LAMP that is basically suitable for amplifying long-stranded oligonucleotides up to 200-300 nt. To address this inherent limitation of traditional LAMP, many researchers have put in efforts to explore improvements in this that would allow LAMP to be used for a wider range of target species amplification. RESULTS: Here in this work, we are inspired to explore two-step loop-mediated amplification, firstly forming T-activated double-loop dumbbell structure (DLDS) intermediate by a recognition hairpin and a hairpin precursor, and next DLDS-guided mLAMP process with the aid of two primers to yield mLAMP/H+ during successive DNA incorporation via nucleophilic attacking interaction. To manipulate the mLAMP/H+-directed transduction of input T, a pH-responsive triplex strand is designed with the ability of self-folding in Hoogsteen structure at slightly acidic conditions, resulting in the dehybridization of a fuel strand (FS) to participate in CHA between two hairpins on the modified electrode surface, in which FS is repetitively displaced and recycled to fuel the progressive CHA events. In the as-assembled dsDNA complexes, numerous electroactive ferrocene labels are immobilized in the electrode sensing interface, thereby generating significantly amplified electrochemical current signal that can sense the presented and varied T. SIGNIFICANCE: It is clear that we have creatively constructed a unique electrochemical biosensor for disease detection. Benefited from the rational combination of mLAMP and CHA, our electrochemical strategy is highly sensitive, specific and simplified, and would provide a new paradigm to construct various mLAMP/H+-based biosensors for other short-stranded DNA or microRNAs markers.

[Review and prospect of traditional Chinese medicine in treatment of trauma based on bibliometrics].

This study aims to summarize the research hotspots and trends in traditional Chinese medicine(TCM) treatment of trauma and provide suggestions for collaborative research on the treatment of trauma with integrated Chinese and western medicine. The re-levant research articles on TCM treatment of trauma were searched against CNKI, Wanfang, VIP, Web of Science, and PubMed from inception to December 31, 2022 and analyzed using bibliometric. After screening, 315 articles in Chinese and 34 articles in English were included. The articles were mainly published by TCM journals. The core author groups were absent. The author affiliations were dominated by medical institutions and supplemented by universities, research institutions, and government agencies. The research mainly focused on the clinical practice and trials of TCM in trauma treatment. Although the TCM treatment of trauma emerged early, it is still in the initial stage of development. The future research can focus on innovating the service model of trauma treatment, improving clinical research capability, improving medical quality management, and strengthening the TCM talent teams in comprehensive hospitals. Western medicine is precise and effective in the treatment of trauma, while TCM with unique treatment methods and effects can play a complementary role. Therefore, the trauma treatment with integrated Chinese and western medicine demonstrates a promising prospect.

A developmental critical period for ocular dominance plasticity of binocular neurons in mouse superior colliculus.

Detecting visual features in the environment is crucial for animals' survival. The superior colliculus (SC) is implicated in motion detection and processing, whereas how the SC integrates visual inputs from the two eyes remains unclear. Using in vivo electrophysiology, we show that mouse SC contains many binocular neurons that display robust ocular dominance (OD) plasticity in a critical period during early development, which is similar to, but not dependent on, the primary visual cortex. NR2A- and NR2B-containing N-methyl-D-aspartate (NMDA) receptors play an essential role in the regulation of SC plasticity. Blocking NMDA receptors can largely prevent the impairment of predatory hunting caused by monocular deprivation, indicating that maintaining the binocularity of SC neurons is required for efficient hunting behavior. Together, our studies reveal the existence and function of OD plasticity in SC, which broadens our understanding of the development of subcortical visual circuitry relating to motion detection and predatory hunting.

[Knockdown of interferon-γ inducible protein 30 (IFI30) inhibits the proliferation, invasion and migration of human glioma U251 cells by activating STAT1 and promotes their apoptosis].

Objective To establish U251 cells with inhibited expression of interferon-γ inducible protein 30 (IFI30), and to investigate the effect of IFI30 on cell biological function as well as its underlying mechanism. Methods Three knockdown sequences which target IFI30 were designed online and 3 small interfering RNAs (siRNA) were synthesized. After transfection, the inhibition efficiency was detected by real-time quantitative PCR. The siRNA sequence with the highest inhibition efficiency was selected to create short hairpin RNA (shRNA) plasmids. The recombinant plasmids and packaging plasmids were co-transfected into HEK293T cells to prepare lentivirus. The glioma U251 cells were transfected with lentivirus, and the positive cells were screened by puromycin. CCK-8 assay, 5-ethyl-2'-deoxyuridine (EdU) and colony formation assays were used to analyze cell proliferation; the flow cytometry was used to analyze cell cycle and apoptosis; the TranswellTM assay was used to detect cell invasion; the wound-healing assay was employed to detect cell migration, and western blot analysis to detect the protein expresison of cyclin D1, B-cell lymphoma factor 2 (Bcl2), epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), signal transducer and activator of transcription 1 (STAT1). Results The sequence which effectively target IFI30 was screened and U251 cell line capable of inhibiting the IFI30 expression was successfully established. When IFI30 expression was knocked down, the proliferation of U251 cells was inhibited, along with increased ratio of cells in the phase G0/G1, the decreased phase S, the increased rate of cell apoptosis. The cell invasion and migration capabilities was also reduced. The decreased expression of cyclin D1, Bcl2 and N-cadherin were observed in U251 cells, and the expression of E-cadherin and the phosphorylation of STAT1 were found increased. Conclusion Knockdown of IFI30 inhibits the proliferation, invasion and migration of human glioma cell U251 and promotes its apoptosis by activating STAT1.

ZCHSound: Open-Source ZJU Paediatric Heart Sound Database With Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) is a common birth defect in children. Intelligent auscultation algorithms have been proven to reduce the subjectivity of diagnoses and alleviate the workload of doctors. However, the development of this algorithm has been limited by the lack of reliable, standardized, and publicly available pediatric heart sound databases. Therefore, the objective of this research is to develop a large-scale, high-standard, high-quality, and accurately labeled pediatric congenital heart disease (CHD) heart sound database, and perform classification tasks to evaluate its performance, filling this important research gap. METHOD: From 2020 to 2022, we collaborated with experienced cardiac surgeons from Zhejiang University Children's Hospital to collect heart sound signals from 1259 participants using electronic stethoscopes. To ensure accurate disease diagnosis, the cardiac ultrasound images for each participant were acquired by an experienced ultrasonographer, and the final diagnosis was confirmed through the consensus of two cardiac experts or cardiac surgeons. To establish the benchmark of ZCHSound, we extracted 84 time-frequency features from the heart sounds and evaluated the performance of the classification task using machine learning models. Additionally, we evaluated the importance scores of the 84 features in distinguishing between normal and pathological heart sounds in children using SHapley Additive exPlanations (SHAP) values. RESULTS: The ZCHSound database contains heart sound data from 1259 participants, with all data divided into two datasets: one is a high-quality, filtered clean heart sound dataset, and the other is a low-quality, noisy heart sound dataset. In the evaluation of the high-quality dataset, our random forest ensemble model achieved an F1 score of 90.3% in the classification task of normal and pathological heart sounds. Moreover, the SHAP analysis results demonstrate that frequency-domain features have a more significant impact on the model output compared to time-domain features. Features related to the cardiac diastolic period have a greater influence on the model's classification results compared to those related to the systolic period. CONCLUSION: This study has successfully established a large-scale, high-quality, rigorously standardized pediatric CHD sound database with precise disease diagnosis. This database not only provides important learning resources for clinical doctors in auscultation knowledge but also offers valuable data support for algorithm engineers in developing intelligent auscultation algorithms. Our data can be accessed and downloaded by the public at http://zchsound.ncrcch.org.cn/.

Molecular mechanism of sex pheromone perception in male Mythimna loreyi revealed by in vitro system.

BACKGROUND: Mythimna loreyi is an important agricultural pest with a sensitive sex pheromone communication system. To clarify the pheromone binding proteins (PBPs) and pheromone receptors (PRs) involved in sex pheromone perception is important for both understanding the molecular olfactory mechanism and developing a new pest control strategy in M. loreyi. RESULTS: First, the electroantennogram (EAG) assay showed that male M. loreyi displayed the highest response to the major sex pheromone component Z9-14:Ac, and higher responses to two minor components, Z7-12:Ac and Z11-16:Ac. Second, the fluorescence competition binding assay showed that PBP1 bound all three pheromones and other tested compounds with high or moderate affinity, while PBP2 and PBP3 each bound only one pheromone component and few other compounds. Third, functional study using the Xenopus oocyte system demonstrated that, of the six candidate PRs, PR2 was weakly sensitive to the major pheromone Z9-14:Ac, but was strongly sensitive to pheromone analog Z9-14:OH; PR3 was strongly and specifically sensitive to a minor component Z7-12:Ac; PR4 and OR33 were both weakly sensitive to another minor component, Z11-16:Ac. Finally, phylogenetic relationship and ligand profiles of PRs were compared among six species from two closely related genera Mythimna and Spodoptera, suggesting functional shifts of M. loreyi PRs toward Spodoptera PRs. CONCLUSION: Functional differentiations were revealed among three PBPs and six PRs in sex pheromone perception, laying an important basis for understanding the molecular mechanism of sex pheromone perception and for developing new control strategies in M. loreyi. © 2023 Society of Chemical Industry.

Tumor-Agnostic Approvals: Insights and Practical Considerations.

Since the first approval of a tumor-agnostic indication in 2017, a total of seven tumor-agnostic indications involving six drugs have received approval from the FDA. In this paper, the master protocol subteam of the Statistical Methods in Oncology Scientific Working Group, Biopharmaceutical Session, American Statistical Association, provides a comprehensive summary of these seven tumor-agnostic approvals, describing their mechanisms of action; biomarker prevalence; study design; companion diagnostics; regulatory aspects, including comparisons of global regulatory requirements; and health technology assessment approval. Also discussed are practical considerations relating to the regulatory approval of tumor-agnostic indications, specifically (i) recommendations for the design stage to mitigate the risk that exceptions may occur if a treatment is initially hypothesized to be effective for all tumor types and (ii) because drug development continues after approval of a tumor-agnostic indication, recommendations for further development of tumor-specific indications in first-line patients in the setting of a randomized confirmatory basket trial, acknowledging the challenges in this area. These recommendations and practical considerations may provide insights for the future development of drugs for tumor-agnostic indications.

An Overview of Current Statistical Methods for Implementing Quality Tolerance Limits.

BACKGROUND: In 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use updated its efficacy guideline for good clinical practice and introduced predefined quality tolerance limits (QTLs) as a quality control in clinical trials. QTLs are complementary to Quality by Design (QbD) principles (ICH-E8) and are one of the components of the risk-based clinical trial quality management system. METHODS: Currently the framework for QTLs process is well established, extensively describing the operational aspects of Defining, Monitoring and Reporting, but a single source of commonly used methods to establish QTLs and secondary limits is lacking. This paper will primarily focus on closing this gap and include applications of statistical process control and Bayesian methods on commonly used study level quality parameters such as premature treatment discontinuation, study discontinuation and significant protocol deviations as examples. CONCLUSIONS: Application of quality tolerance limits to parameters that correspond to critical to quality factors help identify systematic errors. Some situations pose special challenges to implementing QTLs and not all methods are optimal in every scenario. Early warning signals, in addition to QTL, are necessary to trigger actions to further minimize the possibility of an end-of-study excursion.

Cerebellar contributions to fear-based emotional processing: relevance to understanding the neural circuits involved in autism.

Cerebellar networks have traditionally been linked to sensorimotor control. However, a large body of evidence suggests that cerebellar functions extend to non-motor realms, such as fear-based emotional processing and that these functions are supported by interactions with a wide range of brain structures. Research related to the cerebellar contributions to emotional processing has focussed primarily on the use of well-constrained conditioning paradigms in both human and non-human subjects. From these studies, cerebellar circuits appear to be critically involved in both conditioned and unconditioned responses to threatening stimuli in addition to encoding and storage of fear memory. It has been hypothesised that the computational mechanism underlying this contribution may involve internal models, where errors between actual and expected outcomes are computed within the circuitry of the cerebellum. From a clinical perspective, cerebellar abnormalities have been consistently linked to neurodevelopmental disorders, including autism. Importantly, atypical adaptive behaviour and heightened anxiety are also common amongst autistic individuals. In this review, we provide an overview of the current anatomical, physiological and theoretical understanding of cerebellar contributions to fear-based emotional processing to foster further insights into the neural circuitry underlying emotional dysregulation observed in people with autism.