Family history and genetic risk score combined to guide cancer risk stratification: A prospective cohort study.

Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

Free bone flap reconstruction in retrosigmoid approach for microvascular decompression: a comparative cohort study.

Titanium plates and screws are common material used for rigid bone flap fixation after retrosigmoid craniotomy such as microvascular decompression (MVD). We conducted this study to evaluate outcomes of the free bone flap cranioplasty without fixation in MVD and compared its postoperative complication rate with routine methods. We retrospectively reviewed all patients who underwent MVD at our institution from May 2017 to August 2022. Patients were divided into two groups according to whether the bone flap was fixed or not. Follow-ups periods spanned 6-28 months after the operation. Of 189 patients who underwent MVDs via retrosigmoid approach, 79 cases (42%) had their bone flaps replaced without titanium fixation after craniotomies (< 3 cm x 3 cm). Compared to fixed bone flap group, free bone flap group had shorter operative time (105.56 ± 15.87 min vs. 113.72 ± 17.80 min, P = 0.001), less in-patient costs (¥23059.66 ± 4488.54 vs. ¥27714.82 ± 2705.74, P < 0.001), and less proportion of postoperative headache and incisional pain (43.0% vs. 60.9%, P = 0.015). One case of incisional cerebrospinal fluid leak happened in free bone flap group while one case of incisional infection happened in fixed bone flap group. No statistical difference in bone flap displacement, duration of postoperative hospital stays or complication rate was found between the two groups. Nineteen patients in free bone flap group received long-term CT follow-up and all were proved to have good skull union. This study proves that free bone flap cranioplasty in MVD without titanium plate fixation can shorten the operation time and reduce hospitalization expenditure without increasing complication rates.

Machine Learning-Driven discovery of immunogenic cell Death-Related biomarkers and molecular classification for diabetic ulcers.

In this study, we redefine the diagnostic landscape of diabetic ulcers (DUs), a major diabetes complication. Our research uncovers new biomarkers linked to immunogenic cell death (ICD) in DUs by utilizing RNA-sequencing data of Gene Expression Omnibus (GEO) analysis combined with a comprehensive database interrogation. Employing a random forest algorithm, we have developed a diagnostic model that demonstrates improved accuracy in distinguishing DUs from normal tissue, with satisfactory results from ROC analysis. Beyond mere diagnosis, our model categorizes DUs into novel molecular classifications, which may enhance our comprehension of their underlying pathophysiology. This study bridges the gap between molecular insights and clinical practice. It sets the stage for transformative strategies in DUs management, marking a significant step forward in personalized medicine for diabetic patients.

Evanescent Electron Wave-Spin.

This study demonstrates the existence of an evanescent electron wave outside both finite and infinite quantum wells by solving the Dirac equation and ensuring the continuity of the spinor wavefunction at the boundaries. We show that this evanescent wave shares the spin characteristics of the wave confined within the well, as indicated by analytical expressions for the current density across all regions. Our findings suggest that the electron cannot be confined to a mathematical singularity and that quantum information, or quantum entropy, can leak through any quantum confinement. These results emphasize that the electron wave, fully characterized by Lorentz-invariant charge and current densities, should be considered the true and sole entity of the electron.

Characteristics and partitions of traditional and emerging organophosphate esters in soil and groundwater based on machine learning.

Organophosphate esters (OPEs) pose hazards to both humans and the environment. This study applied target screening to analyze the concentrations and detection frequencies of OPEs in the soil and groundwater of representative contaminated sites in the Pearl River Delta. The clusters and correlation characteristics of OPEs in soil and groundwater were calculated by self-organizing map (SOM). The risk assessment and partitions of OPEs in industrial park soil and groundwater were conducted. The results revealed that 14 out of 23 types of OPEs were detected. The total concentrations (Σ23OPEs) ranged from 1.931 to 743.571 ng/L in the groundwater, and 0.218 to 79.578 ng/g in the soil, the former showed highly soluble OPEs with high detection frequencies and concentrations, whereas the latter exhibited the opposite trend. SOM analysis revealed that the distribution of OPEs in the soil differed significantly from that in the groundwater. In the industrial park, OPEs posed acceptable risks in both the soil and groundwater. The soil could be categorized into Zone I and II, and the groundwater into Zone I, II, and III, with corresponding management recommendations. Applying SOM to analyze the characteristics and partitions of OPEs may provide references for other new pollutants and contaminated sites.

Acute ischemic stroke with or without asymptomatic intracranial hemorrhage after endovascular treatment: a propensity-score matching study.

BACKGROUND: The long-term follow-up of asymptomatic intracranial hemorrhage (aICH) in patients with acute ischemic stroke after endovascular treatment (EVT) remains controversial.ObjectiveTo evaluate the potential effect of aICH in a real-world practice setting using a matched prospective database. METHODS: This observational cohort study enrolled patients between January 2015 and December 2022 in a prospective database. Eligible patients with occlusions in the anterior circulation were given endovascular treatment and achieved successful reperfusion. The primary outcome was functional independence (modified Rankin Scale (mRS) score 0-2). Propensity score (PS)-weighted multivariable logistic regression analyses were adjusted and were repeated in subsequent 1:1 PS-matched cohorts. RESULTS: 732 patients, 516 without any ICH and 216 with aICH, were included. 418 and 348 patients were identified after matching in the aICH substudy and hemorrhagic infarction type aICH substudy, respectively. In the postmatched population, patients with aICH had worse functional outcomes (mRS score 0-2) at 90 days than patients without any ICH (37.8% vs 55.5%: P<0.001). Worse functional outcomes were seen in patients with aICH who were older (OR=5.59 (95% CI 2.91 to 10.74)), had higher baseline National Institutes of Health Stroke Scale score (OR=6.80 (95% CI 3.72 to 12.43)), lower baseline Alberta Stroke Program Early CT Score (OR=2.08 (95% CI 1.23 to 3.51)), and who received general anesthesia (OR=3.37 (95% CI 1.92 to 5.90)). CONCLUSIONS: This matched-control study largely confirmed that asymptomatic ICH after EVT is associated with worse functional outcomes, and the harmful effect is more significant in older patients and those with severe baseline clinical and radiological features.

[Advances in genetic research on Non-syndromic congenital joint synostosis].

Congenital joint synostosis (CJS) is a functional impairment resulting from failure in joint morphogenesis during embryonic development. Clinically, it may be classified as syndromic (sCJS) and non-syndromic (nsCJS) disorders. Common sCJS include chromosomal disorders such as Klinefelter syndrome and single-gene disorders like Apert/Pfeiffer/Crouzon syndromes, Holt-Oram syndrome, Ehlers-Danlos syndrome, and Radial-ulnar synostosis with thrombocytopenia, presenting with multiple system/organ anomalies. By contrast, nsCJS manifest with only joint abnormalities, affecting one or multiple joints. This review has focused on human nsCJS and its genetic etiology. To date, variants in seven genes (NOG, GDF5, FGF9, GDF6, FGF16, SMAD6, and MECOM) have been identified as causative factors for nsCJS. This review has focused on such genes and provided a comprehensive review for the clinical phenotypes, genetic patterns, common variants, and underlying mechanisms associated with nsCJS based on a literature review. In addition, it has also analyzed other candidate genes for nsCJS within the context of relevant signaling pathways involved in joint morphogenesis.

Study of tree shrew biology and models: A booming and prosperous field for biomedical research.

The tree shrew ( Tupaia belangeri) has long been proposed as a suitable alternative to non-human primates (NHPs) in biomedical and laboratory research due to its close evolutionary relationship with primates. In recent years, significant advances have facilitated tree shrew studies, including the determination of the tree shrew genome, genetic manipulation using spermatogonial stem cells, viral vector-mediated gene delivery, and mapping of the tree shrew brain atlas. However, the limited availability of tree shrews globally remains a substantial challenge in the field. Additionally, determining the key questions best answered using tree shrews constitutes another difficulty. Tree shrew models have historically been used to study hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, myopia, and psychosocial stress-induced depression, with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases. Despite these efforts, the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research. This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model. We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies. The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models, meeting the increasing demands of life science and biomedical research.

Biomechanical changes in lower extremity in individuals with knee osteoarthritis in the past decade: A scoping review.

Biomechanic studies can provide a powerful theoretical and scientific basis for studies on knee osteoarthritis (OA), which is of great significance for clinical management as it provides new concepts and methods in clinical and research settings. This study aimed to discuss and summarize biomechanical research on lower extremities in individuals with knee OA in the past ten years. The methodology of this review followed the framework outlined in the Joanna Briggs Institute (JBI) guidelines and strictly followed the checklist for drafting the findings. A literature search was conducted using PubMed, Scopus, Cochrane Library, Embase, Web of Science, Grey literature search in Open Library, and Google Academic databases. Relevant literature was searched from 2011 to 2023. Sixteen studies were included in this scoping review. Biomechanical research on knee OA in the last decade demonstrates that the biomechanics of the hip, knee, and ankle have a profound influence on the pathogenesis and treatment of knee OA. Individuals with knee OA have biomechanical changes in hip, knee, and ankle joints such as a significant defect in the strength of ankle varus muscles, weakness of hip abductor muscle, walking with toes outwards, increased knee adduction moment and angle, and decreased knee extensor moment. As the severity of knee OA increases, the tendency of hip abduction positions also increases. Further research with a longitudinal study design should focus on the determination of the relative importance of different biomechanical and neuromuscular factors in the development and progression of the disease.

Coordination analysis and evaluation of population, water resources, economy, and ecosystem coupling in the Tuha region of China.

The non-coordination between the socio-economic systems and ecosystems of a region is a crucial obstacle to sustainable development. To reveal the relationships between complex urban systems and achieve the goal of sustainable and coordinated urban development, we constructed a coupling coordination degree model (CCDM) and coupling angle model (CAM) and analyzed the degree of coupling coordination and evolution process among the population, water resources, economy, and ecology (PWEE) system of the Tuha region for 2005-2020. The results indicated that: (1) During 2005-2020, the comprehensive development index (CDI) of the population, water resources and economy subsystems was 0.21-0.65, with the three subsystems portraying an overall increase; the average values of the RSEI at five-year intervals were 0.29, 0.28, 0.28, and 0.26, indicating a downward trend in the environmental quality. (2) The coupling coordination effect of the PWEE system portrayed a low level; the coupling coordination degree (CCD) values were 0.28-0.58, portraying a fluctuating upward trend. The level of CCD increased from low disorder to marginal coordination. (3) The PWEE system's scissor difference reflects large evolutionary characteristics. The ecological support capacity was not observed until the late stage. We conclude that the PWEE composite system of the region is in a stage of disordered development. These findings significantly bolster the theoretical underpinnings of sustainable development studies, offering essential scientific theories and methodological frameworks for crafting sustainable development policies tailored to urban systems in the Tuha region.

Sirtuin-6 knockout causes exacerbated stalled healing of diabetic ulcers in mice.

BACKGROUND: Diabetic ulcers (DUs) are characterized by chronic inflammation and delayed re-epithelialization, with a high incidence and weighty economic burden. The primary therapeutic strategies for refractory wounds include surgery, non-invasive wound therapy, and drugs, while the optimum regimen remains controversial. Sirtuin-6 (SIRT6) is a histone deacetylase and a key epigenetic factor that exerts anti-inflammatory and pro-proliferatory effects in wound healing. However, the exact function of SIRT6 in DUs remains unclear. METHODS: We generated tamoxifen-inducible SIRT6 knockout mice by crossing SIRT6flox/flox homozygous mice with UBC-creERT2+ transgenic mice. Systemic SIRT6 null mice, under either normal or diabetic conditions, were utilized to assess the effects of SIRT6 in DUs treatment. Gene and protein expressions of SIRT6 and inflammatory cytokines were measured by Western blotting and RT-qPCR. Histopathological examination confirmed the altered re-epithelialization (PCNA), inflammation (NF-κB p50 and F4/80), and angiogenesis (CD31) markers during DUs restoration. RESULTS: Knockout of SIRT6 inhibited the healing ability of DUs, presenting attenuated re-epithelialization (PCNA), exacerbated inflammation responses (NF-κB p50, F4/80, Il-1ß, Tnf-α, Il-6, Il-10, and Il-4), and hyperplasia vascular (CD31) compared with control mice. CONCLUSIONS: SIRT6 could boost impaired wound healing through improving epidermal proliferation, inflammation, and angiogenesis. Our study highlighted the therapeutic potential of the SIRT6 agonist for DUs treatment.

Advances in the etiology and neuroimaging of children with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children, characterized by age-inappropriate inattention, hyperactivity, and impulsivity, which can cause extensive damage to children's academic, occupational, and social skills. This review will present current advancements in the field of attention deficit hyperactivity disorder, including genetics, environmental factors, epigenetics, and neuroimaging features. Simultaneously, we will discuss the highlights of promising directions for further study.

The effect of PAP on UACR and metabolic indexes in patients with MS and OSAHS.

PURPOSE: To investigate the effects of positive airway pressure (PAP) device on urinary albumin to creatinine ratio (UACR) and metabolic indexes in patients with metabolic syndrome (MS) and obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: This study is a retrospective cohort study. Grouped according to whether to use PAP treatment, there were 25 cases in the PAP group and 44 cases in the no OSAHS treatment group. The PAP group received positive airway pressure device and routine treatment of MS. The no OSAHS treatment group received routine treatment of OSAHS and MS. The treatment period is 3 months. RESULTS: 1. The PAP group demonstrated significant reductions in Body Mass Index (BMI), Waist circumference (WC), Neck circumference (NC), Visceral fat area (VFA), Fasting C peptide (FCP), high-sensitivity C-reactive protein (hs-CRP), and UACR compared to the no OSAHS treatment group, with significant differences (P all <0.05). Among them, the UACR in the PAP group decreased significantly (from 86.05(52.55,131.61)mg/g to 16.76(8.70,25.12)mg/g, P<0.001). 2. Linear regression analysis using the decrease in UACR values as the dependent variable demonstrated a positive linear relationship with the decrease in BMI, VFA, fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR). Furthermore, multiple linear regression analysis indicated that the decrease in VFA (B=0.537 [95% confidence interval, 0.084 to 0.989]; P = 0.021) and HOMA-IR (B=1.000 [95% confidence interval, 0.082 to 1.917]; P = 0.033) values independently correlated with decrease in UACR values. CONCLUSIONS: PAP treatment can reduce UACR in patients with MS and OSAHS, and has the effect of improving metabolic disorders. The decrease of UACR in patients may be related to the decrease of visceral fat and the improvement of insulin resistance.

Sevoflurane postconditioning ameliorates cerebral hypoxia/reoxygenation injury in zebrafish involving the Akt/GSK-3ß pathway activation and the microtubule-associated protein 2 promotion.

Sevoflurane postconditioning has been shown to provide neuroprotection against cerebral hypoxia-ischemia injury, but the mechanisms remain elusive. Microtubule-associated protein 2 (MAP2) is implicated in early neuronal hypoxia-ischemia injury. This study aimed to investigate whether the neuroprotective effects of sevoflurane postconditioning are related to the Akt/GSK-3ß pathway and its downstream target MAP2 in zebrafish hypoxia/reoxygenation (H/R) model. Sevoflurane postconditioning or GSK-3ß inhibitor TDZD-8 were used to treat H/R zebrafish. The cerebral infarction, neuronal apoptosis, and mitochondrial changes were evaluated using TTC staining, TUNEL staining, and transmission electron microscopy, respectively. The distribution of MAP2 in the brain was determined by immunofluorescence imaging. The levels of Akt, p-Akt, GSK-3ß, p-GSK-3ß, and MAP2 proteins were evaluated by Western blotting. The neurobehavioral recovery of zebrafish was assessed based on optokinetic response behavior. Our results indicated that sevoflurane postconditioning and TDZD-8 significantly reduced the cerebral infarction area, suppressed cell apoptosis, and improved mitochondrial integrity in zebrafish subjected to H/R. Furthermore, sevoflurane postconditioning and TDZD-8 elevated the ratios of p-Akt/Akt and p-GSK-3ß/GSK-3ß. However, the neuroprotective effect of sevoflurane postconditioning was effectively abolished upon suppression of MAP2 expression. In conclusion, sevoflurane postconditioning ameliorated cerebral H/R injury and facilitated the restoration of neurobehavioral function through the activation of Akt/GSK-3ß pathway and promotion of MAP2 expression.

Emerging evidence of context-dependent synapse elimination by phagocytes in the CNS.

Precise synapse elimination is essential for the establishment of a fully developed neural circuit during brain development and higher function in adult brain. Beyond immune and nutrition support, recent groundbreaking studies have revealed that phagocytic microglia and astrocytes can actively and selectively eliminate synapses in normal and diseased brains, thereby mediating synapse loss and maintaining circuit homeostasis. Multiple lines of evidence indicate that the mechanisms of synapse elimination by phagocytic glia are not universal but rather depend on specific contexts and detailed neuron-glia interactions. The mechanism of synapse elimination by phagocytic glia is dependent on neuron-intrinsic factors and many innate immune and local apoptosis-related molecules. During development, microglial synapse engulfment in the visual thalamus is primarily influenced by the classic complement pathway, whereas in the barrel cortex, the fractalkine pathway is dominant. In Alzheimer's disease, microglia employ complement-dependent mechanisms for synapse engulfment in tauopathy and early ß-amyloid pathology, but microglia are not involved in synapse loss at late ß-amyloid stages. Phagocytic microglia also engulf synapses in a complement-dependent way in schizophrenia, anxiety, and stress. In addition, phagocytic astrocytes engulf synapses in a MEGF10-dependent way during visual development, memory, and stroke. Furthermore, the mechanism of a phenomenon that phagocytes selectively eliminate excitatory and inhibitory synapses is also emphasized in this review. We hypothesize that elucidating context-dependent synapse elimination by phagocytic microglia and astrocytes may reveal the molecular basis of synapse loss in neural disorders and provide a rationale for developing novel candidate therapies that target synapse loss and circuit homeostasis.

Epidemiology of malignant tumors in patients with pemphigus: an analysis of trends from 1955 to 2021.

BACKGROUND: The incidence of malignant tumors has increased in patients with non-paraneoplastic pemphigus, although there has been no systematic analysis of global epidemiology. OBJECTIVE: To explore the epidemiology of various types of non-paraneoplastic pemphigus associated with malignant tumors. METHODS: Five databases from establishment through October 20, 2023, were searched. STATA SE 17 was used for the data analysis. Subgroup, meta-regression, and sensitivity analyses were used to evaluate the heterogeneity of pooled studies. RESULTS: A total of 6679 participants were included in our meta-analysis from 16 studies. The aggregated prevalence of tumors in patients diagnosed with pemphigus was 8%. The prevalence was 7% in patients with pemphigus vulgaris, 10% in those with pemphigus foliaceus, and 12% in individuals diagnosed with other types of pemphigus. The prevalence was 8% in Asia, 11% in Europe, and 8% in North America. From a country-specific perspective, patients with pemphigus from Israel, Greece, and Germany exhibited a higher prevalence of tumors at 11%. Furthermore, when categorized by the duration of the study period, the highest prevalence was observed in studies spanning 10 to 20 years, at 11%. CONCLUSION: These findings demonstrate the incidence and prevalence of malignant tumors in patients with non-paraneoplastic pemphigus, which may achieve early detection and intervention, and then reduce mortality rates.

Sustained increase in suspended sediments near global river deltas over the past two decades.

River sediments play a critical role in sustaining deltaic wetlands. Therefore, concerns are raised about wetlands' fate due to the decline of river sediment supply to many deltas. However, the dynamics and drivers of suspended sediment near deltaic coasts are not comprehensively assessed, and its response to river sediment supply changes remains unclear. Here we examine patterns of coastal suspended sediment concentration (SSC) and river sediment plume area (RPA) for 349 deltas worldwide using satellite images from 2000 to 2020. We find a global increase in SSC and RPA, averaging +0.46% and +0.48% yr-1, respectively, with over 59.0% of deltas exhibiting an increase in both SSC and RPA. SSC and RPA increases are prevalent across all continents, except for Asia. The relationship between river sediment supply and coastal SSCs varies between deltas, with as much as 45.2% of the deltas showing opposing trends between river sediments and coastal SSCs. This is likely because of the impacts of tides, waves, salinity, and delta morphology. Our observed increase in SSCs near river delta paints a rare promising picture for wetland resilience against sea-level rise, yet whether this increase will persist remains uncertain.

Activation of astrocytes by ANXA2-derived extracellular vesicles from lung cancer cells affects aggressiveness, immunotherapy response and microenvironment of lung cancer.

Background: ANXA2 has been extensively documented in relation to cancer. Nevertheless, the involvement of ANXA2 in lung carcinoma remains uncertain. Methods: Data from The Cancer Genome Atlas (TCGA) database was downloaded using open-access methods. The examination of publicly available data was conducted utilizing the R software. The mRNA level of specific molecules was detected using Real-time Quantitative PCR (qPCR). The protein level of specific molecules was detected using the Western blot assay. The cell proliferation ability of cancer cells was assessed using the CCK8 assay. The invasion and migration capability of cancer cells was assessed using the Transwell assay. Validation of exosomes extraction was conducted using electron microscopy and particle size analysis. Results: In this study, based on series experiments, we found that ANXA2 can promote the activation of neuroastrocytes cells CP-H122 through the exosome pathway. Also, we found that ANXA2 can be transmitted from A549 cells to CP-H122 through the exosomes pathway and further promote the activation of CP-H122. Activated CP-H122 cells further enhance the proliferation, invasion and metastasis of A549 cells. Meanwhile, we performed transcriptome sequencing to explore the downstream genes of ANXA2 to screen potential targets for follow-up studies. Analysis based on public data showed that ANXA2 was related to the worse survival performance and clinical features of lung cancer. Gene set enrichment analysis based on the Hallmark gene set indicated that the patient with high ANXA2 expression might have a higher activity of the apical surface, reactive oxygen species pathway, angiogenesis, TGF-ß signaling, MYC target, but lower activity of pancreas-ß cells. More important, our results showed that ANXA2 can affects immunotherapy response and reshape immune microenvironment of lung cancer. Conclusions: This study demonstrates that ANXA2 activates CP-H122 cells, affects A549 cell behavior, and impacts lung cancer prognosis and immunotherapy response.