Association between dichotomized VASARI feature and overall survival in glioblastoma patients: a single-institution propensity score matching analysis.

OBJECTIVES: This study aimed to investigate the intra- and inter-observer consistency of the Visually Accessible Rembrandt Images (VASARI) feature set before and after dichotomization, and the association between dichotomous VASARI features and the overall survival (OS) in glioblastoma (GBM) patients. METHODS: This retrospective study included 351 patients with pathologically confirmed IDH1 wild-type GBM between January 2016 and June 2022. Firstly, VASARI features were assessed by four radiologists with varying levels of experience before and after dichotomization. Cohen's kappa coefficient (κ) was calculated to measure the intra- and inter-observer consistency. Then, after adjustment for confounders using propensity score matching, Kaplan-Meier curves were used to compare OS differences for each dichotomous VASARI feature. Next, patients were randomly stratified into a training set (n = 211) and a test set (n = 140) in a 3:2 ratio. Based on the training set, Cox proportional hazards regression analysis was adopted to develop combined and clinical models to predict OS, and the performance of the models was evaluated with the test set. RESULTS: Eleven VASARI features with κ value of 0.61-0.8 demonstrated almost perfect agreement after dichotomization, with the range of κ values across all readers being 0.874-1.000. Seven VASARI features were correlated with GBM patient OS. For OS prediction, the combined model outperformed the clinical model in both training set (C-index, 0.762 vs. 0.723) and test set (C-index, 0.812 vs. 0.702). CONCLUSION: The dichotomous VASARI features exhibited excellent inter- and intra-observer consistency. The combined model outperformed the clinical model for OS prediction.

Two-Dimensional M-Chalcogene Family with Tunable Superconducting, Topological, and Magnetic Properties.

An interesting question is whether chalcogen atoms can emulate the role of carbon or boron elements stabilized between two transition metal layers, as observed in MXenes or MBenes. Here, we predict a new family of two-dimensional ternary compounds M4XY2 (where M = Pd, Y, Zr, etc.; X = S, Se, Te; and Y = Cl, Br, I), named M-chalcogene. Through first-principles calculations, we reveal diverse physical properties in these compounds, including superconducting, topological, and magnetic characteristics, where the bilayer transition metals play crucial roles. Moreover, the expected helical edge states and superconducting transition temperatures in Pd4SCl2 can be finely tuned by strains. Additionally, the Ti4SCl2 is predicted to be a topological insulator and shows promise as a gas sensor candidate for certain exotic gases. Our findings expand two-dimensional material families and provide promising platforms for diverse physical phenomena with efficient tunability by external stimuli for various applications.

Comprehensive analysis of single-nucleotide variants and alternative polyadenylation between inbred and outbred pigs.

Inbreeding can lead to the accumulation of homozygous single nucleotide polymorphisms (SNPs) in the genome, which can significantly affect gene expression and phenotype. In this study, we examined the impact of homozygous SNPs resulting from inbreeding on alternative polyadenylation (APA) site selection and the underlying genetic mechanisms using inbred Luchuan pigs. Genome resequencing revealed that inbreeding results in a high accumulation of homozygous SNPs within the pig genome. 3' mRNA-seq on leg muscle, submandibular lymph node, and liver tissues was performed to identify differences in APA events between inbred and outbred Luchuan pigs. We revealed different tissue-specific APA usage caused by inbreeding, which were associated with different biological processes. Furthermore, we explored the role of polyadenylation signal (PAS) SNPs in APA regulation under inbreeding and identified key genes such as PUM1, SCARF1, RIPOR2, C1D, and LRRK2 that are involved in biological processes regulation. This study provides resources and sheds light on the impact of genomic homozygosity on APA regulation, offering insights into genetic characteristics and biological processes associated with inbreeding.

Wedging crystals to fabricate crystalline framework nanosheets via mechanochemistry.

Mechanochemistry studies the effect of mechanical force on chemical bonds, bringing opportunities for synthesizing alloys, ceramics, organics, polymers, and biomaterials. A vital issue of applying macro-scale mechanical force to manipulate crystal structures is finding ways to precisely adjust the force directions to break micro-scale target chemical bonds. Inspired by a common technique of driving a wedge into the wood to make wood chopping much easier, a wedging strategy of splitting three-dimensional structured crystalline frameworks and then converting them to nanosheets was proposed, where specific molecules were wedged into crystalline frameworks to drive the directional transmission of mechanical force to break chemical bonds. As a result, various crystalline framework nanosheets including metal-organic framework nanosheets, covalent organic framework nanosheets, and coordination polymer nanosheets were fabricated. This wedging crystal strategy exhibits advantages of operability, flexibility and designability, and furthermore, it is expected to expand mechanochemistry applications in material preparation.

More than red tape: exploring complexity in medical device regulatory affairs.

Introduction: This study investigates the complexity of regulatory affairs in the medical device industry, a critical factor influencing market access and patient care. Methods: Through qualitative research, we sought expert insights to understand the factors contributing to this complexity. The study involved semi-structured interviews with 28 professionals from medical device companies, specializing in various aspects of regulatory affairs. These interviews were analyzed using a mix of qualitative coding and natural language processing (NLP) techniques. Results: The findings reveal key sources of complexity within the regulatory landscape, divided into five domains: (1) regulatory language complexity, (2) intricacies within the regulatory process, (3) global-level complexities, (4) database-related considerations, and (5) product-level issues. Discussion: The participants highlighted the need for strategies to streamline regulatory compliance, enhance interactions between regulatory bodies and industry players, and develop adaptable frameworks for rapid technological advancements. Emphasizing interdisciplinary collaboration and increased transparency, the study concludes that these elements are vital for establishing coherent and effective regulatory procedures in the medical device sector.

Association between Timing of labor Induction and Neonatal and Maternal outcomes: An Observational Study from China.

BACKGROUND: Growing evidence suggests that elective induction of labor at 39 weeks may lead to more favorable perinatal outcomes compared with the expectant management, however, how to weigh the pros and cons of elective labor induction at 39 weeks, the expectation of spontaneous delivery at 40 or 41 weeks, or delayed labor induction at 40 or 41 weeks on neonatal and maternal outcomes remains a practical challenge in clinical decision-making. OBJECTIVE: We compared neonatal and maternal outcomes between elective induction of labor at 39 weeks and expectant management in a real word setting. We also divided the expectantly managed group and compared outcomes between the spontaneous delivery group at 40 or 41 weeks, and the induced group at 40 or 41 weeks versus the elective induced group at 39 weeks. STUDY DESIGN: This retrospective cohort study included 21282 participants between January 1, 2019, and June 30, 2022. Participants were initially categorized into three groups at 39 weeks: elective induction of labor, spontaneous delivery, and expectant management, for the primary analysis comparing elective induction with expectant management. Subsequently, the expectant management group at 39 weeks was similarly divided into three groups at 40 weeks, and participants who underwent expectant management at 40 weeks were then divided into two groups at 41 weeks: elective induction and spontaneous delivery. In total, six groups were compared in the secondary analysis, with elective induction at 39 weeks serving as the reference group. RESULTS: At 39 weeks' gestational age, participants who received elective induction of labor had a significantly lower risk of primary composite outcomes compared to participants who received expectant management (adjusted odds ratio [aOR]: 0.72, 95% confidence interval [CI]: 0.55-0.95), and there was no significant difference in risk of cesarean delivery between the two groups. After further dividing the expectantly managed group, compared to participants with elective induction of labor at 39 weeks, those with spontaneous delivery at 40 weeks had significant lower risks of cesarean delivery (0.61, 0.52-0.71) and chorioamnionitis (0.78, 0.61-1.00), but a higher risk of fetal distress (1.39, 1.22-1.57); those with spontaneous delivery at 41 weeks had a significant higher risk of fetal distress (1.44, 1.16-1.79), postpartum hemorrhage (1.83, 1.26-2.66), and prolonged/arrested labor (1.61, 1.02-2.54). Moreover, compared to participants with elective induction of labor at 39 weeks, participants induced at later weeks had significantly higher risks of neonatal and maternal outcomes, especially at 40 weeks. CONCLUSIONS: Our findings indicate that elective induction of labor at 39 weeks was significantly associated with lower risks of short-term neonatal and maternal outcomes compared to expectant management. Moreover, our study highlights the nuanced trade-offs in risks and benefits between elective induction at 39 weeks versus waiting for spontaneous labor or delayed induction at 40/41 weeks, thus providing valuable insights for clinical decision-making in practice.

Assessing the efficacy and quality of Life improvements of botulinum toxin type a with topical minoxidil versus topical minoxidil in male androgenetic alopecia: a randomized controlled trial.

Androgenetic alopecia (AGA) is a common type of hair loss in men and efficacy and safety of current medical treatment remain limited. Therefore, the present study aimed to investigate the efficacy and safety of botulinum toxin type A (BTA) combined with Minoxidil in patients with AGA. 60 male patients were included in this study and control group received topical 5% Minoxidil and the treatment group received BTA combined with topical 5% Minoxidil. BTA injections (60-70 U) were administered at 30-35 scalp sites. Head photographs were taken at baseline, 2nd, 4th, and 6th months. Clinical descriptions recorded scalp conditions, and patient satisfaction along with Dermatology Life Quality Index scores were documented. The treatment group (TG) showed significant hair growth differences compared to the control group (CG) at the 4th month (P < 0.001) and 6th month (P = 0.0046) post-treatment. TG had improved Investigator Global Assessment (IGA) scores in the 4th month (P = 0.0001) and 6th month (P = 0.0259) compared to CG. Patient satisfaction in TG for hair growth and scalp improvement was higher than CG (all P < 0.05). TG exhibited substantial quality of life improvement at the 4-month (P = 0.0009) and 6-month (P = 0.0099). No adverse reactions were observed post-botulinum toxin injection. BTA combined with Minoxidil effectively promotes hair growth, enhances the quality of life, and alleviates scalp symptoms in male AGA patients at 4th and 6th months, with no adverse effects compared to Minoxidil alone.Trial registration number: Ethics Committee of Shanghai Tongji Hospital (ID: K-2018-026).

The emerging role of osteoclasts in the treatment of bone metastases: rationale and recent clinical evidence.

The occurrence of bone metastasis is a grave medical concern that substantially impacts the quality of life in patients with cancer. The precise mechanisms underlying bone metastasis remain unclear despite extensive research efforts, and efficacious therapeutic interventions are currently lacking. The ability of osteoclasts to degrade the bone matrix makes them a crucial factor in the development of bone metastasis. Osteoclasts are implicated in several aspects of bone metastasis, encompassing the formation of premetastatic microenvironment, suppression of the immune system, and reactivation of quiescent tumor cells. Contemporary clinical interventions targeting osteoclasts have proven effective in mitigating bone-related symptoms in patients with cancer. This review comprehensively analyzes the mechanistic involvement of osteoclasts in bone metastasis, delineates potential therapeutic targets associated with osteoclasts, and explores clinical evidence regarding interventions targeting osteoclasts.

Association between Red Blood Cell Distribution Width and In-Hospital Mortality among Congestive Heart Failure Patients with Diabetes among Patients in the Intensive Care Unit: A Retrospective Cohort Study.

Background: Elevated red blood cell distribution width (RDW) levels are strongly associated with an increased risk of mortality in patients with congestive heart failure (CHF). Additionally, heart failure has been closely linked to diabetes. Nevertheless, the relationship between RDW and in-hospital mortality in the intensive care unit (ICU) among patients with both congestive heart failure (CHF) and diabetes mellitus (DM) remains uncertain. Methods: This retrospective study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, a comprehensive critical care repository. RDW was assessed as both continuous and categorical variables. The primary outcome of the study was in-hospital mortality at the time of hospital discharge. We examined the association between RDW on ICU admission and in-hospital mortality using multivariable logistic regression models, restricted cubic spline analysis, and subgroup analysis. Results: The cohort consisted of 7,063 patients with both DM and CHF (3,135 females and 3,928 males). After adjusting for potential confounders, we found an association between a 9% increase in mortality rate and a 1 g/L increase in RDW level (OR = 1.09; 95% CI, 1.05∼1.13), which was associated with 11 and 58% increases in mortality rates in Q2 (OR = 1.11, 95% CI: 0.87∼1.43) and Q3 (OR = 1.58, 95% CI: 1.22∼2.04), respectively, compared with that in Q1. Moreover, we observed a significant linear association between RDW and in-hospital mortality, along with strong stratified analyses to support the findings. Conclusions: Our findings establish a positive association between RDW and in-hospital mortality in patients with DM and CHF.

Comparison of the Impacts of Different Middle Ear Mucosal Conditions on Type I Tympanoplasty Outcomes.

BACKGROUND: This study aimed to explore the impacts of different middle-ear mucosal conditions on the outcomes of type I tympanoplasty. METHODS: A retrospective analysis of 164 patients with chronic otitis media was carried out. The patients were divided into 4 groups according to their mucosal condition. Preoperative hearing levels and air-bone gap (ABG) before and after surgery were compared via the Kruskal‒Wallis H test. The chi-squared test and Fisher's exact test were used to assess the postoperative complications and impact factors of functional success. RESULTS: Preoperatively, neither the air conduction nor bone conduction values differed significantly among groups with different mucosal conditions. All of the ABG closed dramatically after type I tympanoplasty (P < .05) regardless of the mucosal conditions. The functional success rates were lower when the intratympanic mucosa was moderately or severely edematous compared with mildly edematous or normal (P < .05). The disease course, perforation site, and perforation size, as well as the status of the opposite ear, were not related to the auditory functional outcome. The differences in postoperative reotorrhea and reperforation among the 4 groups were not statistically significant. CONCLUSION: Preoperative hearing levels were not affected by middle-ear mucosal conditions. The functional success rate was influenced by mucosal conditions, but hearing levels were significantly enhanced after surgical intervention regardless of the mucosal status. Postoperative complications were not related to the mucosal conditions. Thus, type I tympanoplasty is adoptable for mucosal abnormalities when pharmacotherapy cannot result in a healthy tympanum.

A base editor for the long-term restoration of auditory function in mice with recessive profound deafness.

A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88% of the inner hair cells and stably rescued the auditory function of the mice to near-wild-type levels for over 1.5 years while improving synaptic exocytosis in the inner hair cells. We also show that an adenine base editor that targets the prevalent human OTOF mutation restored hearing in humanized mice to levels comparable to those of the wild-type counterparts. Base editors may be effective for the treatment of hereditary deafness.

Unveiling the activity origin of electrochemical oxygen evolution on heteroatom-decorated carbon matrix.

Chemical modification via functional dopants in carbon materials holds great promise for elevating catalytic activity and stability. To gain comprehensive insights into the pivotal mechanisms and establish structure-performance relationships, especially concerning the roles of dopants, remains a pressing need. Herein, we employ computational simulations to unravel the catalytic function of heteroatoms in the acidic oxygen evolution reaction (OER), focusing on a physical model of high-electronegative F and N co-doped carbon matrix. Theoretical and experimental findings elucidate that the enhanced activity originates from the F and pyridinic-N (Py-N) species that achieve carbon activation. This activated carbon significantly lowers the conversion energy barrier from O* to OOH*, shifts the potential-limiting step from OOH* formation to O* generation, and ultimately optimizes the energy barrier of the potential-limiting step. This wok elucidates that the critical role of heteroatoms in catalyzing the reaction and unlocks the potential of carbon materials for acidic OER.

Development and validation of the Social Touch Experiences and Attitudes Questionnaire-Chinese version (STEAQ-C): How interpersonal touch relates to subclinical traits and symptoms.

Social touch has a vital role in human development and psychological well-being. However, there is a lack of measures assessing individual differences in social touch experiences and attitudes, especially under Eastern cultures. This study developed the Social Touch Experiences and Attitudes Questionnaire - Chinese version (STEAQ-C) and examined its psychometric properties with healthy young Chinese adults. In Study 1, an item pool was generated and principal component analysis (PCA) was used to identify the factor structure of the STEAQ. Study 2 recruited an independent sample and examined its reliability and validity. Network analysis further explored the interrelations between social touch and a variety of subclinical traits and symptoms. PCA identified four factors of the STEAQ-C, relating to childhood touch experiences, current touch with intimate partners, with family and friends, and with unfamiliar people. Study 2 confirmed the four-factor structure and upheld its internal consistency and stability. Positive attitudes towards and greater experiences of social touch were negatively correlated with sensory over-responsiveness and sensory hyposensitivity, as well as childhood trauma particularly emotional neglect, supporting the convergent validity. Evidence of criterion-related validity was accrued via its concurrent and predictive associations with secure attachment style, higher levels of social competence, and lower levels of social anxiety. Network analysis highlighted altered perception of social touch may be a shared feature for psychiatric conditions with social dysfunctions (e.g., autism, social anxiety and negative schizotypy). The newly-developed STEAQ-C may be a timely tool in assessing social touch experiences and attitudes under Eastern cultures.

Glucose activated synergistic cascade therapy of diabetic wound by platinum and glucose oxidase decorated camelina lipid droplets.

Hyperglycemia provides a favorable breeding ground for bacteria, resulting in repeated and persistent inflammation of wounds and prolonged healing processes. In this study, platinum (Pt) nanoparticles (NPs) and glucose oxidase (GOx) were decorated on the surface of camelina lipid droplets (OB) linked with hFGF2, forming PGOB through in situ reduction of Pt ions and electrostatic adsorption, respectively. PGOB exhibits cascade enzyme catalytic activity, which can be activated by glucose in diabetic wound tissues. Specifically, GOx on PGOB catalyzes glucose into hydrogen peroxide, which can further decompose into hydroxyl radicals that have higher toxicity for bacterial inactivation. Additionally, glucose decomposition creates a low pH microenvironment, facilitating the cascade catalytic activity that ensures better bacterial suppression within the wound tissues. Furthermore, hFGF2 promotes the proliferation and migration of fibroblasts. Both in vitro and in vivo experiments confirm that PGOB effectively accelerates wound healing processes through bacteria inactivation and tissue regeneration. This study has developed an alternative strategy for glucose-triggered synergistic cascade therapy for diabetic wounds.

Discovery of Novel Mcl-1 Inhibitors with a 3-Substituted-1H-indole-1-yl Moiety Binding to the P1-P3 Pockets to Induce Apoptosis in Acute Myeloid Leukemia Cells.

Mcl-1 is a main antiapoptotic protein in acute myeloid leukemia (AML) and is used as a target to develop inhibitors. Currently, potent Mcl-1 inhibitors primarily interact with the P2-P4 pockets of Mcl-1, but pharmacological modulation by targeting the P1 pocket is less explored. We designed a series of 1H-indole-2-carboxylic acid compounds as novel Mcl-1 inhibitors occupying the P1-P3 pockets and evaluated their Mcl-1 inhibition and apoptosis induction in AML cells. Two-dimensional 15N-HSQC spectroscopy indicated that 47 (Ki = 24 nM) bound to the BH3 binding groove, occupied the P1 pocket in Mcl-1, and formed interactions with Lys234 and Val249. 47 exhibited good microsomal stability and pharmacokinetic profiles, with low potential risk of cardiotoxicity. 47 inhibited tumor growth in HL-60 and THP-1 xenograft models with growth inhibition rate of 63.7% and 57.4%, respectively. Collectively, 47 represents a novel Mcl-1 inhibitor targeting the P1-P3 pockets with excellent antileukemia effects.

Cyclin dependent kinase 9 inhibition reduced programmed death-ligand 1 expression and improved treatment efficacy in hepatocellular carcinoma.

The anti-programmed death-ligand 1 (PD-L1) antibody is a standard therapy for advanced hepatocellular carcinoma (HCC). Tumor expression of PD-L1 can be induced upon stimulus. Because cyclin-dependent kinase 9 (CDK9) inhibition reduces the expression of inducible proteins, we explored the influence of CDK9 inhibition on PD-L1 expression in HCC cells. We found that PD-L1 expression was low in HCC cells; however, IFN-γ treatment increased this expression. CDK9 inhibitors AZD4573 and atuveciclib reduced the IFN-γ induced PD-L1 expression in a dose-dependent manner. CDK9 knockdown yielded similar results, but CDK9 overexpression reversed the influence of the CDK9 inhibitors. In the orthotopic mouse model, mice treated with a CDK9 inhibitor and an anti-PD-L1 antibody had significantly smaller tumors and exhibited longer survival than mice treated with either agent. In conclusion, CDK9 inhibition could reduce the expression of PD-L1 in HCC cells. Using both CDK9 inhibitors and anti-PD-L1 antibodies is more effective than using either agent alone.

Protocol for siRNA-mediated U1 snRNA knockdown using fluorinated α-helical polypeptide in vitro and in vivo.

Here, we present a protocol for small interfering RNA (siRNA)-mediated U1 small nuclear RNA (snRNA) knockdown using fluorinated α-helical polypeptide in macrophages and mouse lungs, providing a dependable approach to silence U1 snRNA in vitro and in vivo. We describe steps for preparing P7F7/siRNA polyplexes and silencing U1 snRNA with P7F7/siRNA polyplexes in macrophages and mouse lungs. Knockdown efficiency is validated through reverse-transcription quantitative real-time PCR analysis. This protocol is applicable for studying the physiological or pathophysiological function of U1 snRNA. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells.

Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer. Currently, therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape, which leads to enhanced aggressive behaviors compared with CSCs that have never been treated. However, the underlying mechanisms regulating the therapeutic escape remain unknown. To this end, we established a model to isolate the therapeutic escaped CSCs (TSCSCs) from breast CSCs and performed the transcription profile to reveal the mechanism. Mechanistically, we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway, resulting in TSCSCs exhibiting enhanced motility and metastasis. Notably, blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo, which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition (EMT)-related proteins vimentin and N-cadherin. The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

XAF1 promotes osteoclast apoptosis by antagonizing the XIAP-caspase axis.

Background: Over-activated osteoclast (OC) is a major cause of diseases related to bone loss and bone metabolism. Both bone resorption inhibition and apoptosis induction of osteoclast are crucial in treating these diseases. X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) is an important interferon-stimulated and apoptotic gene. However, how XAF1 regulates bone formation and remodeling is unknown. Methods: We generate global and chimeric Xaf1 knockout mouse models and utilize these models to explore the function and mechanism of XAF1 in regulating bone formation and remodeling in vivo and in vitro. Results: We show that XAF1 depletion enhances osteoclast generation in vitro. XAF1 knockout increases osteoclast number and bone resorption, thereby exacerbating bone loss in both OVX and osteolysis models. Activation of XAF1 with BV6 (a potent XIAP inhibitor) suppresses osteoclast formation. Mechanistically, XAF1 deletion decreases osteoclast apoptosis by facilitating the interaction between XIAP and caspase-3/7. Conclusions: Our data illustrates an essential role of XAF1 in controlling osteoclastogenesis in both osteoporosis and osteolysis mouse models and highlights its underlying mechanism, indicating a potential role in clinical treatment.The translational potential of this article: The translation potential of this article is that we first indicated that osteoclast apoptosis induced by XAF1 contribute to the progression of osteoporosis and osteolysis, which provides a novel strategy in the prevention of osteoporosis and osteolysis.