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Abstract Background Rectal neuroendocrine neoplasms (NENs) are rare neoplasms with limited understanding of its genomic alterations and molecular typing. Methods The paraffin‐embedded tissue specimens of 38 patients with rectal NENs after surgery were subjected to whole gene sequencing (WGS), and mutation profilings were drawn to identify high‐frequency mutation genes, copy‐number variations (CNVs), tumor mutation burden (TMB), signal pathways, mutation signatures, DNA damage repair (DDR) genes, and molecular types. The differences of mutated genes and signaling pathways in different pathological grades and metastatic/non‐metastatic groups were compared. It helped to search for potential targets. Results C > T and T > C transitions are the most common base substitutions in rectal NENs. DNA mismatch repair deficiency, DNA base modifications, smoking and exposure to ultraviolet light might play a role in the occurrence of rectal NENs. DAXX, KMT2C, BCL2L1, LTK, MERTK, SPEN, PKN1, FAT3, and LRP2 mutations were found in only low‐grade rectal NETs, whereas APC, TP53, NF1, SOX9, and BRCA1 mutations were common in high‐grade rectal NECs/MiNENs. These genes helped in distinguishing poorly‐differentiated or well‐differentiated rectal NENs. Alterations in P53, Wnt and TGFβ signaling pathways were more pronounced in rectal NECs and MiNENs. Alterations in Wnt, MAPK and PI3K/AKT signaling pathways promoted metastases. Rectal NENs were classified into two molecular subtypes by cluster analysis based on the mutant genes and signaling pathways combined with clinicopathological features. Patients with mutations in the LRP2, DAXX, and PKN1 gene showed a trend of well‐differentiated and early‐stage tumors with less metastasis (p = 0.000). Conclusions This study evaluated risk factors for regional lymphatic and/or distant metastases, identified high‐frequency mutated genes, mutation signatures, altered signaling pathways through NGS. Rectal NENs were divided into two molecular types. This helps to evaluate the likelihood of metastasis, formulate follow‐up strategies for patients and provide a target for future research on precision treatment of rectal NENs. PARP inhibitors, MEK inhibitors, mTOR/AKT/PI3K and Wnt signaling pathway inhibitors may be effective drugs for the treatment of metastatic rectal NENs.

Background: Programmed cell death protein-1 inhibitors combined with lenvatinib have become a popular treatment option for patients with unresectable hepatocellular carcinoma. Transarterial chemoembolization combined with programmed cell death protein-1 inhibitors and lenvatinib has also shown preliminary efficacy in the unresectable hepatocellular carcinoma. We conducted this observational, retrospective, cohort study to compare the clinical outcomes and safety of transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib versus programmed cell death protein-1 inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma. Methods: Between November 2019 and November 2021, patients who were diagnosed with unresectable hepatocellular carcinoma and received transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib or programmed cell death protein-1 inhibitors plus lenvatinib treatment were reviewed for eligibility. The primary endpoints included objective response rate, overall survival, and progression-free survival. The secondary endpoint was the frequency of key adverse events. Results: In total, 105 patients were eligible for the present study, and they were divided into the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group (n = 46) and the programmed cell death protein-1 inhibitors plus lenvatinib group (n = 59). The patient cohort after a one-to-one propensity score matching (n = 86) was also analyzed. The transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had a higher objective response rate both in the patient cohort before propensity score matching (54.3% vs 25.4%, P = .002) and after propensity score matching (55.8% vs 30.2%, P = .017). The patients in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had prolonged overall survival (median, 20.5 vs 12.6 months, P = .015) and progression-free survival (median, 10.2 vs 7.4 months, P = .035). For patient cohort- propensity score matching, the overall survival (20.5 vs 12.8 months, P = .013) and progression-free survival (12.1 vs 7.8 months, P = .030) were also significantly better in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group than in the programmed cell death protein-1 inhibitors plus lenvatinib group. There were no significant differences between the 2 groups concerning adverse reactions caused by immunotherapy and lenvatinib. The adverse reactions caused by transarterial chemoembolization were transient and were quickly reversed. Conclusions: Compared to programmed cell death protein-1 inhibitors plus lenvatinib, transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib may provide better treatment response and survival benefits for patients with unresectable hepatocellular carcinoma, and the adverse events were manageable.

BackgroundSince the introduction of the neurodevelopmental perspective of schizophrenia research on individuals at ultra-high risk for psychosis (UHR) has gained increasing interest, aiming at early detection and intervention. Results from fMRI studies investigating behavioral and brain functional changes in UHR during facial emotion recognition, an essential component of social cognition, showed heterogenous results, probably due clinical diversity across these investigations. This fMRI study investigated emotion recognition in a sub-group of the UHR spectrum, namely non-help-seeking, drug-naïve UHR with high cognitive functioning to reveal the neurofunctional underpinnings of their social functioning in comparison to healthy controls.MethodsTwo large cohorts of students from an elite University (n1 = 4,040, n2 = 4,364) were screened firstly with the Prodromal Questionnaires and by surpassing predefined cut-offs then interviewed with the semi-structured Interview for Psychosis-Risk Syndromes to verify their UHR status. Twenty-one identified non-help-seeking UHR and 23 non-UHR control subjects were scanned with functional magnetic resonance imaging while classifying emotions (i.e., neutral, happy, disgust and fear) in a facial emotion recognition task.ResultsBehaviorally, no group differences were found concerning accuracy, reaction times, sensitivity or specificity, except that non-help-seeking UHR showed higher specificity when recognizing neutral facial expressions. In comparison to healthy non-UHR controls, non-help-seeking UHR showed generally higher activation in the superior temporal and left Heschl's gyrus as well as in the somatosensory, insular and midcingulate cortex than the control subjects during the entire recognition task regardless of the emotion categories. In an exploratory analysis, in the non-help-seeking UHR group, functional activity in the left superior temporal gyrus was significantly correlated with deficits in the ability to experience emotions at uncorrected statistical thresholds.ConclusionsCompared to healthy controls, non-help-seeking UHR show no behavioral deficits during facial emotion recognition, but functional hyperactivities in brain regions associated with this cognitive process. Our study may inspire future early intervention and provide loci for treatment using neural stimulation.

BackgroundSystemic therapies, including immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), have challenged the use of conventional therapies for hepatocellular carcinoma (HCC). It is crucial to determine which patients could benefit most from combination therapy. This study aims to examine the associations of sarcopenia and systemic inflammation response index (SIRI) with the treatment responses and efficacies in patients with HCC treated with ICIs and tyrosine kinase inhibitors TKIs, as well as investigate the correlation between sarcopenia and inflammatory or immune states.MethodsWe reviewed 160 patients with HCC treated with TKIs and ICIs. The patients’ psoas muscle size was measured on axial computed tomography scans and normalized for the patients’ height squared. This value was referred to as the psoas muscle index (PMI). Sarcopenia was determined from PMI and their relationships with patients’ clinicopathological characteristics, inflammation indexes, peripheral blood T-cell subsets and survival were evaluated.ResultsSarcopenia and systemic inflammation response index (SIRI) were independent predictors for overall survival and progression-free survival. Patients with high PMI and low SIRI demonstrated significantly better median overall survival and progression-free survival (36.0 months and 9.6 months, respectively) than those with either low PMI or high SIRI (20.8 months and 6.0 months, respectively) and those with both high SIRI and low PMI (18.6 months and 3.0 months, respectively). Portal vein tumor thrombus (P=0.003), eastern cooperative oncology group performance status score of 1 (P=0.048), high alkaline phosphatase (P=0.037), high neutrophil-to-lymphocyte ratio (NLR) (P=0.012), low lymphocyte-to-monocyte ratio (LMR) (P=0.031), high platelet-to-lymphocyte ratio (PLR) (P=0.022) and high SIRI (P=0.012) were closely associated with an increased incidence of sarcopenia. PMI was negatively correlated with SIRI (r = -0.175, P=0.003), NLR (r = -0.169, P=0.036), and PLR (r = -0.328, P=0.000) and was significantly positively correlated with LMR (r = 0.232, P=0.004). The CD3+ and CD4+ T-cell counts of the high PMI group were significantly higher than those of the low PMI group.ConclusionSarcopenia and high SIRI were associated with reduced survival in patients with HCC treated with ICIs and TKIs. Sarcopenia could affect inflammatory states and the immune microenvironment.

Background: Cerebral venous thrombosis (CVT) refers to a stroke subtype characterized by the disturbance of cerebral venous outflow caused by venous thrombosis. Previous studies have reported a range of factors that predict the prognosis of CVT. This study is aimed to find out whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) are suitable as potential indicators of the severity and clinical outcome in CVT patients.Methods: The CVT patients admitted to Xuanwu Hospital from January 2014 to December 2019 were enrolled. The severity of CVT was assessed by the National Institute of Health Stroke Scale (NIHSS) and intracranial pressure (ICP) at the time of admission. The modified Rankin score (mRS) was assessed at 6 months of follow-up.Results: One hundred fifty-six CVT patients were enrolled with a mean age of 35.8 ± 12.8 years. A percentage of 55.8% of the CVT patients recruited were female, and 17.3% were either pregnant or in perinatal period. Headache was the most common symptom. SBP and DBP were not correlated with NIHSS at admission. Furthermore, SBP and DBP had no impact on the disturbance of consciousness, epilepsy, intracranial hemorrhage, and mental disorders. However, SBP and DBP were positively correlated with ICP at admission. SBP > 129.5 mmHg and/or DBP > 77.5 mmHg suggested the presence of intracranial hypertension (IH). Based on current results, SBP was not correlated with mRS at 6 months of follow-up. However, DBP was found to be positively correlated with mRS at 6 months of follow-up. DBP in CVT patients with good prognosis was significantly lower than in those with poor prognosis. DBP > 79.5 mmHg was identified as a cutoff value to predict a poor clinical outcome. A higher mRS and a higher rate of poor clinical outcome were found in CVT patients with SBP > 146 mmHg or DBP > 79.5 mmHg compared to those with SBP ≤ 146 mmHg or DBP ≤ 79.5 mmHg.Conclusion: SBP > 129.5 mmHg and DBP > 77.5 mmHg suggested the presence of IH in CVT patients. DBP > 79.5 mmHg predicted a poor clinical outcome.

Ecological ternary cements (ECP) were prepared with powders of phosphogypsum (PG), fly ash (FA) and Portland cement (PC). The evolution mechanism of the hydration product structure was characterized through macro and micro experiments. The thermodynamic characteristics of the solid phase, solid solution phase and aqueous solution in the process of hydration about the phosphogypsum–fly ash–cement ternary cementitious system were studied based on the Gibbs-free-energy C-S-H thermodynamic model and GEM-Selektor software and compared with the experimental results. The results show that, in the hydration reaction, the thermodynamic interaction between the mineral single-phase and hydration products plays an important role in the spatio-temporal distribution of ions in the cementitious system. The values of CaO, SiO2H and H2Ohyd gradually increased with the increase in the Ca/Si ratio, while the values of CaOext and H2OOH showed a positive proportional relationship and the values of SiO2H and SiO2 showed an inverse proportional relationship. GEM-Selektor accurately simulated the total amount of AFt and AFm mineral phases, and quantitatively analyzed the correlation of complex ion groups about C-S-H gels and C3S.

Due to the wider application of wireless sensor networks in real life, 3D coverage closer to the actual application environment has become a research hotspot of current sensor networks. To this end, this paper proposes a three-dimensional coverage deployment method based on RSS (Received Signal Strength) under a probabilistic model. According to the path loss of the wireless signal in the propagation process, the distance between the nodes can be roughly calculated, and the maximum distance between the nodes is defined by setting a threshold of the path loss, thereby further ensuring network connectivity and network quality. The probability coverage model is used and the cube-based network coverage is constructed. Based on this, the optimal coverage deployment problem in 3D-WSN is explored. Combining and improving the traditional particle swarm optimization algorithm can converge faster and avoid falling into local optimum. The simulation results show that the proposed method can converge quickly to improve network coverage and effectively reduce network energy consumption. In addition, we built a real experimental environment to verify the network quality by observing the RSSI (Received Signal Strength Indicator) changes. The experimental results verify the effectiveness of the proposed method.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple autoantibody production and often affects the kidneys, known as lupus nephritis. However, the mechanism underlying lupus nephritis development is unclear. Biofilms that protect bacteria from stress are ubiquitous in almost every environment. Here, we identified that a conserved peptide (HU1) derived from DNABII proteins, one of major bacterial biofilm components, was specifically recognized by sera from about 47% patients with SLE. Moreover, the serum anti-HU1 levels showed a significant positive correlation with lupus nephritis occurrence. Presence of antibodies against HU1 in pristane-induced mice aggravated lupus nephritis, although these antibodies also attenuated bacterial biofilm formation. We further identified that antibodies against HU1 cross-recognized protein disulfide isomerase (P4HB) located on the renal cell surface and inhibited the activities of this enzyme. Our findings reveal a novel mechanism underlying the development of lupus nephritis triggered by bacterial biofilms.

Aiming at the problems of low data transmission efficiency and uneven energy consumption caused by unreliable link communication in the routing process of wireless sensor networks, this article designs a routing game algorithm based on link quality. In this article, the index for evaluating link quality is defined first. Then, the link quality, node residual energy, and minimum jump transmission strategy are integrated into the utility function to establish a game model to determine the best next hop transmission node. Finally, the routing optimal transmission path is obtained according to the analysis of the existence of Nash equilibrium in the game. In the simulation experiment, the influence of the change of link quality parameters on the performance of the algorithm is analyzed, and the proposed algorithm is compared with non-linear weight particle swarm optimization (NWPSO) algorithm and Low Energy Adaptive Clustering Hierarchy-Improvement (LEACH-IMPT) algorithm in three aspects: the number of surviving nodes, network lifetime, and network energy consumption. The results show that the network lifetime of this method is 16.8% longer than that of LEACH-IMPT algorithm and 7.5% longer than that of NWPSO algorithm. This shows that the algorithm can effectively balance the network energy consumption and prolong the network life cycle. In addition, according to the routing path obtained in the simulation experiment, the optimality of its link quality is verified in the real experimental environment, and the experimental results prove the feasibility of the method in this article in practice.

Subjects with ultra-high risk (UHR) states for psychosis show brain structural volume changes similar to first-episode psychosis and also elevated incidence of environmental risk factors like childhood trauma. It is unclear, however, whether early neurodevelopmental trajectories are altered in UHR. We screened a total of 12,779 first-year Chinese students to enroll 36 UHR subjects (based on clinical interviews) and 59 non-UHR healthy controls for a case-control study of markers of early neurodevelopment. Subjects underwent 3T MRI scanning and clinical characterization, including the childhood trauma questionnaire (CTQ). We then used the CAT12 toolbox to analyse structural brain scans for cortical surface complexity, a spherical harmonics-based marker of early neurodevelopmental changes. While we did not find statistically significant differences between the groups, a trend level finding for reduced cortical complexity (CC) in UHR vs. non-UHR subjects emerged in the left superior temporal cortex (and adjacent insular and transverse temporal cortices), and this trend level association was significantly moderated by childhood trauma (CTQ score). Our findings indicate that UHR subjects tend to show abnormal cortical surface morphometry, in line with recent research; more importantly, however, this association seems to be considerably modulated by early environmental impacts. Hence, our results provide an indication of environmental or gene × environment interactions on early neurodevelopment leading up to elevated psychosis risk.

3D coverage is not only closer to the actual application environment, but also a research hotspot of sensor networks in recent years. For this reason, a node optimization coverage method under link model in passive monitoring system of three-dimensional wireless sensor network is proposed in this article. According to wireless link-aware area, the link coverage model in three-dimensional wireless sensor network is constructed, and the cube-based network coverage is used to represent the quality of service of the network. This model takes advantage of the principle that the presence of human beings can change the transmission channel of the link. On this basis, the intruder is detected by the data packets transmitted between the wireless links, and then the coverage area is monitored by monitoring the received signal strength of the wireless signal. Based on this new link awareness model, the problem of optimal coverage deployment of the receiving node is solved, that is, how to deploy the receiving node to achieve the optimal coverage of the monitoring area when the location of the sending node is given. In the process of optimal coverage, the traditional genetic algorithm and particle swarm optimization algorithm are introduced and improved. Based on the genetic algorithm, the particle swarm optimization algorithm which integrates the idea of simulated annealing is regarded as an important operator of the genetic algorithm, which can converge to the optimal solution quickly. The simulation results show that the proposed method can improve the network coverage, converge quickly, and reduce the network energy consumption. In addition, we set up a real experimental environment for coverage verification, and the experimental results verify the feasibility of the proposed method.

The quality of meta-analyses (MAs) on depression remains uninvestigated.To assess the overall reporting and methodological qualities of MAs on depression and to explore potential factors influencing both qualities.MAs investigating epidemiology and interventions for depression published in the most recent year (2014-2015) were selected from PubMed, EMBASE, PsycINFO and Cochrane Library. The characteristics of the included studies were collected and the total and per-item quality scores of the included studies were calculated based on the two checklists. Univariate and multivariate linear regression analyses were used to explore the potential factors influencing the quality of the articles.A total of 217 MAs from 74 peer-reviewed journals were included. The mean score of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was 23.0 of 27 and mean score of Assessment of Multiple Systematic Reviews (AMSTAR) was 8.3 of 11. Items assessing registration and protocol (14.2%, 37/217) in PRISMA and item requiring a full list of included and excluded studies (16.1%, 40/217) in AMSTAR had poorer adherences than other items. The MAs that included only RCTs, pre-registered, had five more authors or authors from Cochrane groups and the MAs found negative results had better reporting and methodological qualities.The reporting and methodological qualities of MAs on depression remained to be improved. Design of included studies, characteristics of authors and pre-registration in PROSPERO database are important factors influencing quality of MAs in the field of depression.

Aquaporin-9 (AQP9) is an aquaglyceroporin that biophysically conducts water, glycerol, and other small solutes. AQP9 is expressed in hepatocytes on the sinusoidal surfaces of hepatocyte plates in the liver, where it is considered responsible for the glycerol uptake in gluconeogenesis. However, limited information is available on the expression and regulating mechanism of AQP9 in different hyperglycemia models. Thus, this study examined the expression patterns of AQP9 and mitogen-activated protein kinase (MAPK) in Types 1 and 2 diabetes mellitus (DM) to clarify the roles and regulating mechanism of AQP9 in gluconeogenesis. Compared with the control group, the AQP9 expression significantly increased in both Types 1 and 2 DM, and the increased expression was associated with the activation of phosphorylated JNK (p-JNK) and the inhibition of phosphorylated p38 (p-p38). By contrast, phosphorylated ERK remained stable in the liver with Type 1 or 2 DM. These effects could be reversed by insulin treatment. That is, insulin downregulated AQP9 by inhibiting p-JNK and activating p-p38. The upregulation of AQP9 could be involved in gluconeogenesis and co-regulated by the JNK and p38 MAPK pathway in both Types 1 and 2 DM. [ABSTRACT FROM AUTHOR]

Metformin is the first-line antidiabetic agent for type 2 diabetes mellitus (T2DM) treatment. Although accumulated evidence has shed light on the consequences of metformin action, the precise mechanisms of its action, especially in the pancreas, are not fully understood. Aquaporin 7 (AQP7) acts as a critical regulator of intraislet glycerol content, which is necessary for insulin production and secretion. The aim of this study was to investigate the effects of different doses of metformin on AQP7 expression and explore the possible mechanism of its protective effects in the pancreatic islets. We used an in vivo model of high-fat diet in streptozocin-induced diabetic rats and an in vitro model of rat pancreatic β-cells (INS-1 cells) damaged by hyperglycemia and hyperlipidemia. Our data showed that AQP7 expression levels were decreased, whereas p38 and JNK mitogen-activated protein kinases (MAPKs) were activated in vivo and in vitro in response to hyperglycemia and hyperlipidemia. T2DM rats treated with metformin demonstrated a reduction in blood glucose levels and increased regeneration of pancreatic β-cells. In addition, metformin upregulated AQP7 expression as well as inhibited activation of p38 and JNK MAPKs both in vivo and in vitro. Overexpression of AQP7 increased glycerol influx into INS-1 cells, whereas inhibition of AQP7 reduced glycerol influx, thereby decreasing subsequent insulin secretion. Our findings demonstrate a new mechanism by which metformin suppresses the p38 and JNK pathways, thereby upregulating pancreatic AQP7 expression and promoting glycerol influx into pancreatic β-cells and subsequent insulin secretion in T2DM. [ABSTRACT FROM AUTHOR]