Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents.

A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.

Spatio-temporal variation in prostate cancer testing in Stockholm: A population-based study.

Prostate cancer screening using prostate-specific antigen (PSA) testing is controversial but remains prevalent in many countries. There is little information in Sweden or elsewhere on the spatial variation in PSA testing. This study aims to describe the spatio-temporal variation in PSA testing prior to a prostate cancer diagnosis in the Stockholm region at the municipality and small area levels. A population-based register study comprised men aged 40 years and over living in the Stockholm region during 2007-2016. For Stockholm in 2016, we reported the proportion of men who had a PSA test for the preceding one, two, five and ten years by ten-year age groups. The age-standardised proportion of men having a PSA test was reported for municipalities by calendar years. We used spatial smoothing for calculating the age-standardised proportion of men having a PSA test in a small area for each calendar year. In 2016, 74.0% and 77.8% of men aged 60-69 and 70-79 years respectively had taken a PSA test in the previous ten years. The municipalities of Danderyd and Ekerö showed high proportions of PSA testing. A marked heterogeneity in such proportions within each municipality was observed. The odds ratio for having a PSA test for those born in Sweden was 2.22 (95% CI 2.00-2.52). Opportunistic PSA testing is widespread with three quarters of men in their sixties and seventies having had a test in the preceding decade. We found evidence for marked geographical heterogeneity, where more affluent and metropolitan areas had higher levels of testing. Variations in PSA testing was associated with socio-economic position and demographic factors including education, income and country of birth.

Neoadjuvant anthracycline followed by toripalimab combined with nab-paclitaxel in patients with early triple-negative breast cancer (NeoTENNIS): a single-arm, phase II study.

Background: Toripalimab, a novel PD-1 antibody, is approved for treatment of multiple solid tumors; however, its neoadjuvant use with chemotherapy for triple-negative breast cancer (TNBC) remains unevaluated. Additionally, induction chemotherapy followed by de-escalation of neoadjuvant immunotherapy remains underexplored. Therefore, we conducted a phase II trial investigating a novel neoadjuvant chemoimmunotherapy regimen including de-escalation of immunotherapy for early-stage TNBC. Methods: Chemotherapy and anti-PD-1 therapy were sequentially administered in a neoadjuvant setting to female patients with histologically confirmed stage II-III TNBC between June 9, 2020, and March 24, 2022. Patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks, followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was total pathological complete response (tpCR; ypT0/is ypN0). Key secondary endpoints included breast pCR (bpCR; ypT0/is), event-free survival and biomarker analysis. Safety was also assessed. This study was registered with ClinicalTrials.gov (NCT04418154). Findings: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 completed treatment without progression and subsequently underwent surgery. The percentages of patients with a tpCR and bpCR were 39 of 70 (55.7%, 95% confidence interval [CI]: 43.3-67.6) and 41 of 70 (58.6%, 95% CI 46.2-70.2), respectively. Sixteen (22.9%) patients experienced grade ≥3 adverse events (AEs), frequently neutropenia (12, 17.1%) and leukopenia (11, 15.7%). The most common immune-related AE was hypothyroidism (5, 7.1%, all grade 1-2). Interpretation: Including 12 weeks of toripalimab in neoadjuvant chemotherapy conferred encouraging activity and manageable toxicity in patients with early TNBC, and this regimen warrants further investigation. Funding: National Natural Science Foundation of China, Junshi Biosciences, and Jiangsu Hengrui Pharmaceuticals.

Effectiveness and Cost-effectiveness of Artificial Intelligence-assisted Pathology for Prostate Cancer Diagnosis in Sweden: A Microsimulation Study.

BACKGROUND AND OBJECTIVE: Image-based artificial intelligence (AI) methods have shown high accuracy in prostate cancer (PCa) detection. Their impact on patient outcomes and cost effectiveness in comparison to human pathologists remains unknown. Our aim was to evaluate the effectiveness and cost-effectiveness of AI-assisted pathology for PCa diagnosis in Sweden. METHODS: We modeled quadrennial prostate-specific antigen (PSA) screening for men between the ages of 50 and 74 yr over a lifetime horizon using a health care perspective. Men with PSA ≥3 ng/ml were referred for standard biopsy (SBx), for which cores were either examined via AI followed by a pathologist for AI-labeled positive cores, or a pathologist alone. The AI performance characteristics were estimated using an internal STHLM3 validation data set. Outcome measures included the number of tests, PCa incidence and mortality, overdiagnosis, quality-adjusted life years (QALYs), and the potential reduction in pathologist-evaluated biopsy cores if AI were used. Cost-effectiveness was assessed using the incremental cost-effectiveness ratio. KEY FINDINGS AND LIMITATIONS: In comparison to a pathologist alone, the AI-assisted workflow increased the number of PSA tests, SBx procedures, and PCa deaths by ≤0.03%, and slightly reduced PCa incidence and overdiagnosis. AI would reduce the proportion of biopsy cores evaluated by a pathologist by 80%. At a cost of €10 per case, the AI-assisted workflow would cost less and result in <0.001% lower QALYs in comparison to a pathologist alone. The results were sensitive to the AI cost. CONCLUSIONS AND CLINICAL IMPLICATIONS: According to our model, AI-assisted pathology would significantly decrease the workload of pathologists, would not affect patient quality of life, and would yield cost savings in Sweden when compared to a human pathologist alone. PATIENT SUMMARY: We compared outcomes for prostate cancer patients and relevant costs for two methods of assessing prostate biopsies in Sweden: (1) artificial intelligence (AI) technology and review of positive biopsies by a human pathologist; and (2) a human pathologist alone for all biopsies. We found that addition of AI would reduce the pathology workload and save money, and would not affect patient outcomes when compared to a human pathologist alone. The results suggest that adding AI to prostate pathology in Sweden would save costs.

A case-control study of the risk factors for fistula-in-ano in infants and toddlers.

BACKGROUND: Limited data are available regarding the risk factors for fistula-in-ano (FIA) in infants and toddlers, potentially affecting their daily lives. OBJECTIVES: The purpose of this study was to identify potential risk factors for FIA in infants and toddlers, in order to implement early preventive interventions, avoid disease progression, and develop therapeutic strategies. DESIGN AND SETTINGS: A retrospective case-control study was conducted, comparing 41 infants and toddlers diagnosed with FIA with 41 healthy controls, between August 2020 and December 2021. INDEPENDENT VARIABLES: (a) maternal characteristics during pregnancy and delivery, (b) perinatal characteristics, dietary behaviors, and defecation-related behaviors in infants and toddlers, (c) family dietary behaviors. RESULTS: Mothers of infants and toddlers with FIA had given birth more times in the past, while the infants and toddlers themselves had less mealtime, a higher rate of exclusive breastfeeding, frequent loose stools, and a larger proportion of used wipes, experiencing perianal skin anomalies. The logistic regression analysis revealed that there are four significant risk factors associated with the development of FIA in infants and toddlers, including the number of previous deliveries by the mother (OR 6.327), defecation frequency score (OR 5.351), stool consistency score (OR 5.017), and cleaning with wipes after defecation (OR 8.089). CONCLUSION: Based on our data, it appeared that FIA in infants and toddlers could be attributed to several factors. These included an increased number of previous deliveries by mothers, frequent loose stools, and repeated wipe use. To prevent the occurrence and worsening of the disease, it is important to improve the frequency and consistency of stooling and provide proper care. Further research is required to verify these findings in other clinical settings.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China.

BACKGROUND: Within the normal range, elevated alanine aminotransferase (ALT) levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM: To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively. METHODS: A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected. The incidence rate, cumulative times, and equally and unequally weighted cumulative effects of excess high-normal ALT levels (ehALT) were measured. Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD. RESULTS: A total of 83.13% of participants with MAFLD had normal ALT levels. The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group. Compared with those in the low-normal ALT group, the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651 [95% confidence interval (CI): 1.199-2.273] and 1.535 (95%CI: 1.119-2.106) in the third quartile and 1.616 (95%CI: 1.162-2.246) and 1.580 (95%CI: 1.155-2.162) in the fourth quartile, respectively. CONCLUSION: Most participants with MAFLD had normal ALT levels. Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Organizational climate of kindergartens and teacher professional learning: mediating effect of teachers' collective efficacy and moderating effect of mindfulness in teaching.

Introduction: This study was aimed at testing a moderated mediation model of teaching mindfulness and teachers' collective efficacy in the relationships between the organizational climate of kindergartens and teacher professional learning. Methods: A sample of 1,095 kindergarten teachers completed self-report questionnaires assessing their perceptions of the organizational climate of kindergartens, collective efficacy, teaching mindfulness, and professional learning. Results: Controlling for teaching experience and kindergarten level, the results show that kindergarten organizational climate significantly and positively predicted teacher professional learning and the collective efficacy of teachers played a partial mediating role between them.Furthermore, moderation analysis revealed that teaching mindfulness moderated the relationship between kindergarten organizational climate and teacher professional learning. Discussion: These results expand our understanding of how the organizational climate of kindergartens affects teacher professional learning. In practice, professional learning of kindergarten teachers can be facilitated by creating an open organizational climate and improving their ability to perceive the collective. Furthermore, the moderating role of teaching mindfulness suggests that intervening in teachers' teaching mindfulness possibly is an influential way to maximize the impact of kindergarten organizational climate on professional learning.

Improving on mapping long-term surface water with a novel framework based on the Landsat imagery series.

Surface water plays a crucial role in the ecological environment and societal development. Remote sensing detection serves as a significant approach to understand the temporal and spatial change in surface water series (SWS) and to directly construct long-term SWS. Limited by various factors such as cloud, cloud shadow, and problematic satellite sensor monitoring, the existent surface water mapping datasets might be short and incomplete due to losing raw information on certain dates. Improved algorithms are desired to increase the completeness and quality of SWS datasets. The present study proposes an automated framework to detect SWS, based on the Google Earth Engine and Landsat satellite imagery. This framework incorporates implementing a raw image filtering algorithm to increase available images, thereby expanding the completeness. It improves OTSU thresholding by replacing anomaly thresholds with the median value, thus enhancing the accuracy of SWS datasets. Gaps caused by Landsat7 ETM + SLC-off are respired with the random forest algorithm and morphological operations. The results show that this novel framework effectively expands the long-term series of SWS for three surface water bodies with distinct geomorphological patterns. The evaluation of confusion matrices suggests the good performance of extracting surface water, with the overall accuracy ranging from 0.96 to 0.97, and user's accuracy between 0.96 and 0.98, producer's accuracy ranging from 0.83 to 0.89, and Matthews correlation coefficient ranging from 0.87 to 0.9 for several spectral water indices (NDWI, MNDWI, ANNDWI, and AWEI). Compared with the Global Reservoirs Surface Area Dynamics (GRSAD) dataset, our constructed datasets promote greater completeness of SWS datasets by 27.01%-91.89% for the selected water bodies. The proposed framework for detecting SWS shows good potential in enlarging and completing long-term global-scale SWS datasets, capable of supporting assessments of surface-water-related environmental management and disaster prevention.

A Comprehensive Comparison between Primary Liver Cancer and Liver Metastases through scRNA-Seq Data Analysis.

Metastasis is one of the leading causes of cancer-related deaths. A comprehensive comparison of the differences between primary and metastatic cancers within the same organ can aid in understanding the growth mechanisms of cancer cells at metastatic sites, thereby helping to develop more effective targeted treatment strategies. Primary liver cancer is one of the most common types of cancer, and the liver is also one of the main metastatic sites. In this paper, we utilize single-cell RNA-Seq data to compare primary liver cancer and colorectal liver metastases from multiple perspectives, including cell types and proportions, activity of various cell types, cell-cell communication, mRNA expression differences within the same types of cells, key factors associated with cell proliferation, etc. Our analysis results show the following: (i) Compared to primary tissue, metastatic tissue contains more cytotoxic T cells and exhausted T cells, and it retains some specific characteristics of the primary site. (ii) Cells of the same type exhibit functional differences between primary and metastatic cancers, with metastatic cancer cells showing lower metabolism levels and immune cells exhibiting stronger immune activity. (iii) Interactions between monocytes and hepato-associated cells are strong in primary cancer, while depleted T cells frequently communicate with hepatocytes in metastatic cancer. (iv) Proliferation-related genes in primary and metastatic cancers are mainly involved in cell energy supply and basic metabolism activity, respectively.

Assessment of sediment transport in Luxiapuqu watershed using RUSLE-TLSD and InSAR techniques: Yarlung Tsangpo River, China.

The Yarlung Tsangpo River Basin is characterized by its intricate topography and a significant presence of erosive materials. These often coincide with heavy localized precipitation, resulting in pronounced hydraulic erosion and geological hazards in mountainous regions. To tackle this challenge, we integrated the RUSLE-TLSD (Revised Universal Soil Loss Equation-Transportation-limited sediment delivery) model with InSAR (Interferometric Synthetic Aperture Radar) data, aiming to explore the sediment transport process and pinpoint hazard-prone sites within mountainous small watershed. The RUSLE-TLSD model aids in evaluating multi-year sediment transport dynamics in mountainous zones. And, the InSAR data precisely delineates changes in sediment scouring and siltation at sites vulnerable to hazards. Our research estimates that the potential average soil erosion within the watershed stands at 52.33 t/(hm2 a), with a net soil erosion of 0.69 t/(hm2 a), the sediment transport pathways manifest within the watershed's gullies and channels. Around 4.32% of the watershed area undergoes sedimentation, predominantly at the base of slopes and within channels. Notably, areas (d) and (e) emerge as the most susceptible to disasters within the watershed. Further analysis of the InSAR data highlighted four regions in the typical area (e) from 2017 that are either sedimentation- or erosion-prone, referred to as "hotspots." Among them, R1 exhibits a strong interplay between water and sediment, rendering it highly sensitive to environmental factors. In contrast, R4, characterized by a sharp bend in siltation, remains relatively impervious to external elements. The NDVI (normalized difference vegetation index) stands out as the pivotal determinant influencing sediment transport within the watershed, exerting a pronounced impact on the outlet section, especially in spring. By employing this approach, we gained a deeper understanding of sediment transport mechanisms and potential hazards in small watershed in uninformative mountainous areas. This study furnishes a robust scientific framework beneficial for erosion mitigation and disaster surveillance in mountainous watersheds.

Secretory breast carcinoma: clinicopathological features and prognosis of 52 patients.

PURPOSE: Secretory breast carcinoma is a rare histological subtype of invasive breast cancer and considered with an indolent clinical behavior. This study was conducted to analyze the clinicopathological features of patients with secretory breast carcinoma (SBC), explore the outcome, and compare the prognostic difference with invasive ductal breast carcinoma (IDC). METHODS AND MATERIALS: Patients with SBC diagnosed between 2006 and 2017 from Fudan University Shanghai Cancer Center were included in the study, excluding patients with previous malignant tumor history and incomplete clinical data or follow-up records. Peculiar clinicopathological and immunohistochemical features of the cases were fully described. Clinical data of 4979 cases of IDC were also evaluated during this period. After propensity score matching, prognostic analysis of SBCs and IDCs was calculated by Kaplan-Meier method and landmark analysis method. RESULTS: The data of 52 patients diagnosed with SBC were identified from the pathological files. Among them, 47 patients were women, and 5 were men. The median age of the 52 SBCs was 46 years (mean, 48.1 years; range, 10-80 years). The tumor sizes ranged from 0.3 to 6.8 cm, with a mean of 3.5 cm. Eight patients (15.4%) had positive axillary lymph node involvement. The molecular classification was mostly triple-negative breast cancer (65.4%). Fluorescence in situ hybridization confirmed the presence of ETV6::NTRK3 rearrangement in 16 of 18 cases (88.9%). Furthermore, Kaplan-Meier survival analysis and landmark analysis demonstrated that there were no statistically significant differences in DFS and OS between SBC and IDC patients. CONCLUSION: Although SBCs are generally associated with a favorable prognosis, our work exhibited that the clinicopathological features of SBC were partly different from former understandings, indicating that therapeutic procedure should be prudent. Further studies are necessary to fully identify the clinical behavior and predictive markers to improve diagnosis and management in this unique subtype of breast cancer.

Bascom II combined with VSD treatment involving the preservation of tissue bridges for recurrent complex pilonidal sinuses with a literature review.

INTRODUCTION: For patients with large and deep-seated recurrent complex pilonidal sinuses, the use of traditional open excision or flap reconstruction surgery may lead to high surgical difficulty, significant local damage, numerous complications, slow healing, and a high risk of recurrence. This article reports a case of recurrent complex pilonidal sinus and discusses the advantages of Bascom II combined with VSD treatment involving the preservation of tissue bridges. CASE PRESENTATION: The patient, a 31-year-old male, presented with recurrent swelling, pain, and purulent discharge from the sacrococcygeal region for over a year. Upon physical examination, extensive lumps and sinus tracts were observed in the lumbosacral tail area, with the lesion extending from L4 to the tip of the coccyx. Under general anesthesia, a segmental resection was performed, and the lumbosacral mass lesion was excised, preserving normal tissue bridges. The mature sinus tract at the upper part of the coccyx was removed, and Bascom II reconstruction surgery was performed. In the late stage at the site of lumbar sacral lesion excision, VSD was applied to promote wound healing. DISCUSSION: The combination of Bascom II with lesion tunnel-like removal can reduce the damage, elevate gluteal cleft, and lower the recurrence rate. Subsequently, with the addition of VSD, it can accelerate the elimination of necrotic tissue, reduce infection risk, and expedite wound healing. CONCLUSION: This case explores the advantages and characteristics of combining various techniques in the treatment of recurrent complex pilonidal sinuses, emphasizes the utility of VSD as an adjunctive therapy for large lesions.

A prospective comparison of a modified miniaturised hand-held epifluorescence microscope and touch imprint cytology for evaluation of axillary sentinel lymph nodes intraoperatively in breast cancer patients.

BACKGROUND: The management of axillary lymph nodes in early-stage breast cancer patients has changed considerably, with the primary focus shifting from the examination of sentinel lymph nodes (SLNs) to toward the detection of all macro-metastases. However, current methods, such as touch imprint cytology (TIC) and frozen sections, are inadequate for clinical needs. To address this issue, we proposed a novel miniaturised epifluorescence widefield microscope (MEW-M) to assess SLN status intraoperatively for improved diagnostic efficiency. METHODS: A prospective, side-by-side comparison of intraoperative SLN evaluation between MEW-M and TIC was performed. RESULTS: A total of 73 patients with 319 SLNs consecutive enrolled in this study. MEW-M showed significantly superior image quality compared to TIC (median score 3.1 vs 2.1, p < 0.0001) and had a shorter time to issue results (10.3 vs 19.4 min, p < 0.0001). Likelihood ratio analysis illustrated that the positive likelihood ratio value of MEW-M compared with TIC was infinitely great vs 52.37 (95% CI, 21.96-124.90) in model 1 (classifying results into negative/positive), infinitely great vs 52.37 (95% CI, 21.96-124.90) in model 2 (classifying results into macro-metastasis/others, and TIC results followed the same classification as model 1), respectively. Similarly, the negative likelihood ratio values of MEW-M compared with TIC were 0.055 (95% CI, 0.018-0.160) and 0.074 (95% CI, 0.029-0.190) in model 1; and 0.019 (95% CI, 0.003-0.130) vs 0.020 (95% CI, 0.003-0.140) in model 2, respectively. CONCLUSIONS: MEW-M is a promising technique that can be utilised to provide a rapid and accurate intraoperative assessment of SLN in a clinical setting to help improve decision-making in axillary surgery.

Neuromechanism, recovery effect and case study of swimming training intervention in children with cerebral palsy: A case report.

BACKGROUND: Cerebral palsy, hereinafter referred to as "cerebral palsy", refers to a non progressive injury that occurs during the development of brain tissue in fetuses or infants. The patients often have walking dysfunction, abnormal balance ability and abnormal body stability, which are mainly caused by Cranial nerves injury. PATIENT CONCERNS: One child diagnosed with ataxia cerebral palsy by the hospital was recruited, aged 6 years and 9 months. The symptoms were: lower limb adduction and internal rotation, left neck tilt to the left due to insufficient muscle tension, and eyes squint to the right. The movement is clumsy and the coordination ability of limbs is poor; Its body balance function is poor, the sitting and standing position cannot keep the body upright and balanced for a long time, and the coordination of the random movement of hands and eyes is poor; Weak spatial cognition and orientation ability; Have persistent central motor dysfunction. When walking, the body leans forward and sideways, and the gait is staggered, which is easy to fall; In terms of expression, it shows vague language and unclear speech; Relatively retarded in intelligence. DIAGNOSIS AND INTERVENTION: The study used swimming training intervention to report a twelve months training intervention program for a child with ataxic cerebral palsy, and evaluated it with Berg balance scale and modified Ashworth scale. OUTCOMES: Swimming training has a significant effect on the rehabilitation of children with ataxic cerebral palsy; The forces from different directions in the water can improve the balance of children with cerebral palsy; Muscle endurance training with medium load intensity can help restore unilateral muscle tension deficiency to a certain extent, and make bilateral muscle tension gradually becomes.consistent, thus enhancing the balance ability, gait and body stability of children with cerebral palsy.

Isolation of an Insulin-Like Receptor Involved in the Testicular Development of the Mud Crab Scylla paramamosain.

Insulin-like androgenic gland hormone (IAG) is a key regulator of male sexual differentiation in crustaceans that plays important roles in secondary sexual characteristics and testicular development. As a hormone, IAG interacts with its membrane receptor to initiate downstream signal pathways to exert its biological functions. In this study, we isolated a full-length cDNA of an insulin-like receptor (Sp-IR) from the mud crab Scylla paramamosain. Sequence analysis revealed that this receptor consists of a Fu domain, two L domains, three FN-III domains, a transmembrane domain, and a tyrosine kinase domain, classifying it as a member of the tyrosine kinase insulin-like receptors family. Our results also suggested that Sp-IR was highly expressed in the testis and AG in males. Its expression in the testis peaked in stage I but significantly decreased in stages II and III (p < 0.01). Next, both short- and long-term RNA interference (RNAi) experiments were performed on males in stage I to explore Sp-IR function in mud crabs. The results showed that Sp-vasa and Sp-Dsx expression levels in the testis were significantly down-regulated after the specific knockdown of Sp-IR by RNAi. Additionally, the long-term knockdown of Sp-IR led to a considerable decrease in the volume of seminiferous tubules, accompanied by large vacuoles and a reduced production of secondary spermatocytes and spermatids. In conclusion, our results indicated that Sp-IR is involved in testicular development and plays a crucial role in transitioning from primary to secondary spermatocytes. This study provided a molecular basis for the subsequent analysis of the mechanism on male sexual differentiation in Brachyuran crabs.

Forniceal deep brain stimulation in a mouse model of Rett syndrome increases neurogenesis and hippocampal memory beyond the treatment period.

BACKGROUND: Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT. OBJECTIVES: To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice. METHODS: Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry. RESULTS: After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus. CONCLUSION: Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits.

Quantitatively Unveiling the Structure-Activity Relationship of Polyamide Nanofiltration Membranes with Complex Structures.

Nanofiltration polyamide (NF PA) membranes are widely used in seawater desalination and wastewater treatment due to their excellent permeability. The structure-activity relationship of PA membranes has attracted extensive attention in decades. In this work, NF PA membranes with planar structure, nodular structure, and peak-valley structure were constructed, and the pure water permeance was calculated by nonequilibrium molecular dynamics simulation to quantitatively investigate the structure-activity relationship between the microstructure and water permeance. Results showed that the peak-valley structure had the highest effective utilization rate of the membrane surface, which had the highest number of water molecules that passed through membranes per unit cross-sectional area (7.09). Furthermore, with the increase of the specific surface area ratio, the water permeance of the NF PA with peak-valley increased at a rate about 2.5 times than that of the planar NF PA. Therefore, some molecular scale insights were supplied about the structure-activity relationship of NF PA membranes, which is helpful for the fabrication of high-performance NF PA membranes.

Latissimus dorsi flap - the main force in breast reconstruction for breast tumor in Chinese population.

Background: The latissimus dorsi flap (LDF) is the most commonly used autologous flap for breast reconstruction (BR) in China. We conducted this study to explore the current status of BR using LDF with/without implants. Methods: This study was a single-center retrospective study that included breast tumor patients who underwent LDF breast reconstruction at Fudan University Shanghai Cancer Center (FUSCC) between 2000 and 2021. Results: We analyzed 4918 patients who underwent postmastectomy BR, including 1730 patients (35.2%) with autologous flaps. LDF was used for BR in 1093 (22.2%) patients, and an abdominal flap was used in 637 (13.0%) patients. The proportion of LDFs used in autologous BR patients decreased each year and dropped to approximately 65.0% after 2013 due to the increased use of abdominal flaps. Among these patients, 609 underwent extended LDF (ELDF) BR, 455 underwent LDF BR with implants, and 30 received a LDF as a salvage flap due to previous flap or implant failure. Patients who underwent ELDF reconstruction were older and had a higher BMI than those who received a LDF with implants. There was no significant difference in the mean postoperative hospital stay, neoadjuvant chemotherapy rates, or adjuvant radiotherapy rates between the two groups. Major complications requiring surgical intervention occurred in 25 patients (2.29%). There was no significant difference in the incidence of major complications between the two groups (P=0.542). Conclusions: LDF breast reconstruction is a well-developed and safe procedure. The duration of postoperative hospitalization nor the incidence of major complications was affected by implant use.

Clinical and histological features of patients with chronic hepatitis B virus infection in the grey zone.

Chronic HBV infection patients who do not conform to any of the usual immune states are regarded as 'grey zone' patients. We aimed to investigate the proportion of chronic HBV infection patients in the grey zone, and evaluate the clinical characteristics and liver pathological changes in grey zone patients. Clinical data of 1391 treatment-naive chronic HBV infection patients with liver biopsy were collected. Natural history of HBV infection was determined based on European Association for the Study of the Liver (EASL) 2017, American Association for the Study of Liver Diseases (AASLD) 2018 and Chinese 2019 guidelines for the prevention and treatment of chronic HBV infection. Significant liver histological changes and associated risk factors of normal ALT grey zone patients were analysed. According to EASL, AASLD and Chinese criteria, there were 50.0%, 28% and 37.4% chronic HBV infection patients in the grey zone. Among the 353 grey zone patients with normal ALT, 72.4% had significant liver histological changes. ALT (optimal cut-off value 25 IU/L) and HBV DNA (optimal cut-off value 18,000 IU/mL) were independent risk factors of significant liver histological abnormalities. In conclusion, a substantial proportion of grey zone patients with normal ALT have significant liver histological changes that can be predicted by levels of serum ALT and HBV DNA. These results provide guidance of antiviral treatment in grey zone patients.

TiO2 nanoparticles affect spermatogenesis and adhesion junctions via the ROS-mediated mTOR signalling pathway in Eriocheir sinensis testes.

Recent findings found that TiO2 nanoparticles (TiO2-NPs) have male reproductive toxicity. However, few reports have studied the toxicity of TiO2-NPs in crustaceans. In this study, we first chose the freshwater crustacean Eriocheir sinensis (E. sinensis) to explore the male toxicity of TiO2-NP exposure and the underlying mechanisms. Three nm and 25 nm TiO2-NPs at a dose of 30 mg/kg bw induced apoptosis and damaged the integrity of the haemolymph-testis-barrier (HTB, a structure similar to the blood-testis-barrier) and the structure of the seminiferous tubule. The 3-nm TiO2-NPs caused more severe spermatogenesis dysfunction than the 25-nm TiO2-NPs. We initially confirmed that TiO2-NP exposure affected the expression patterns of adherens junctions (α-catenin and ß-catenin) and induced tubulin disorganization in the testis of E. sinensis. TiO2-NP exposure caused reactive oxygen species (ROS) generation and an imbalance of mTORC1-mTORC2 (mTORC1/rps6/Akt levels were increased, while mTORC2 activity was not changed). After using the ROS scavenger NAC to inhibit ROS generation, both the mTORC1-mTORC2 imbalance and alterations in AJs were rescued. More importantly, the mTORC1 inhibitor rapamycin abolished mTORC1/rps6/Akt hyperactivation and partially restored the alterations in AJs and tubulin. Collectively, the mTORC1-mTORC2 imbalance induced by TiO2-NPs was involved in the mechanism of AJ and HTB disruption, resulting in spermatogenesis in E. sinensis.