A retrospective analysis of 1600 infertility patients with azoospermia and severe oligozoospermia.

OBJECTIVE: This study aimed to investigate the genetic etiology of male infertility patients. METHOD: A total of 1600 male patients with infertility, including 1300 cases of azoospermia and 300 cases of severe oligozoospermia, underwent routine semen analysis, chromosomal karyotype analysis and sex hormone level testing. The Azoospermia factor (AZF) on the Y chromosome was detected using the multiple fluorescence quantitative PCR technique. Additionally, copy number variation (CNV) analysis was performed on patients with Sertoli-cell-only syndrome who had a normal karyotype and AZF. RESULT: Chromosomal abnormalities were found in 334 cases (20.88 %) of the 1600 male infertility patients. The most common type of abnormality was sex chromosome abnormalities (18.94 %), with 47, XXY being the most frequent abnormal karyotype. The rates of chromosomal abnormalities were significantly different between the azoospermia group and the severe oligospermia group (23.69 % and 8.67 %, respectively; P<0.05). AZF microdeletions were detected in 155 cases (9.69 %), with various deletion types and AZFc region microdeletion being the most prevalent. The rates of AZF microdeletions were not significantly different between the azoospermia group and the severe oligospermia group (9.15 % and 12 %, respectively; P=0.133). In 92 patients with Sertoli-cell-only syndrome who had a normal karyotype and AZF, the detection rate of CNV was 16.3 %. Compared to the severe oligospermia group, the azoospermia group had higher levels of FSH and LH and lower levels of T and E2, and the differences were statistically significant (P<0.05). CONCLUSIONS: Male infertility is a complex multifactorial disease, with chromosomal abnormalities and Y chromosome microdeletions being important genetic factors leading to the disease. Initial genetic testing of infertile men should include karyotyping and Y chromosome microdeletions. If necessary, CNV testing should be performed to establish a clinical diagnosis and provide individualized treatment for male infertility.

Caring Behavior of Filipinos toward their Elderly Family Members.

The Philippines has an increasingly aging population thereby increasing the demand for healthcare and support from families. Studies showed that the family is the main caregiver of elderly parents/adults as dictated by the Filipino culture of filial piety and respectful behavior towards older people. However, this caring culture is now slowly declining, and Filipino older adults also experience abuse, exploitation, and other forms of neglect from their families. This special article described that the declining caring culture was due to deteriorating family values and societal influences brought about by modernization. This paper also highlights the crucial role of the family and the community in inculcating the preservation of this valued caring Filipino culture, especially among the youth. In cases where senior citizens are being abused and neglected by their families, the state steps in to safeguard the welfare and protection of Filipino senior citizens. Enacted and promulgated laws ensure social justice and protection of human dignity among Filipino older adults as well as the provision of socioeconomic and health needs. In conclusion, the preservation of a caring culture through educating the youth coupled with the implementation of enacted and promulgated laws of the country ensures the quality of aging life among Filipino older adults.

A novel modified penile disassembly procedure for isolated male epispadias repair: preliminary outcomes.

Purpose: This study aimed to evaluate the preliminary outcome of a novel modification of a penile disassembly procedure. Methods: We retrospectively reviewed the data of 15 patients with isolated male epispadias (IME) who underwent a modified penile disassembly procedure. This modification involved leaving the glans connected while dissecting the urethral plate from the corpus cavernosum. This approach reserves the bundles of the anastomosis at the glans, which can prevent ischemic changes. Results: One of the first two patients experienced glans ischemic changes on the first day after the operation, which ultimately resulted in the loss of half of the hemiglans. Urethral plate shortening was observed in two patients and was addressed with a transverse preputial island flap. Two patients developed a penopubic urethral fistula, which was repaired 6 months postoperatively. Of the 15 patients, 10 (66%) were continent or social continent, while 4 were incontinent and needed bladder neck reconstruction. One patient had not yet reached the age for continence evaluation. Additionally, Two patients had a residual dorsal curvature of approximately 10-15° and were advised to undergo continuous follow-up. Conclusions: The modified penile disassembly procedure is a simple, effective, and safe method for IME repair with an acceptable penile appearance and complication rate.

Study of LFG bubble accumulation and discontinuous flow in the highly saturated region of landfill below the leachate level.

Landfills in developing countries are typically characterized by high waste water content and elevated leachate levels. Despite the ongoing biodegradation of waste in the highly saturated regions of these landfills, which leads to gas accumulation and bubble formation, the associated gas pressure that poses a risk to landfill stability is often overlooked. This paper introduces a landfill gas (LFG) bubble generation model and a two-fluid model that considers bubble buoyancy and porous medium resistance. The entire process can be divided into two stages based on the force balance and velocity of bubbles: Bubble Development Stage and the Two-Fluid Flow Stage. The models were validated using a one-dimensional analytical solution of hydraulic distribution that considers bubble generation, as well as an experiment involving air injection into a saturated medium. The mechanisms of LFG accumulation and ascent, leachate level rise, and discontinuous leachate-gas flow were then investigated in conjunction with continuous flow in the unsaturated region. The results indicate that the generation of LFG bubbles below the leachate level can cause a rise in the level height of more than 20%. During the Bubble Development Stage, there is a critical height for bubble ascent, above which the buoyancy exceeds the combined forces of gravity and resistance, resulting in less than 10% of bubbles continuously flowing into the unsaturated zone for recovery. The developed model effectively captures the accumulation and flow of LFG bubbles below the leachate level and could be further utilized to study leachate-gas pumping in the future.

Discovery of Novel Nicotinamide Derivatives by a Two-Step Strategy of Azo-Incorporating and Bioisosteric Replacement.

Azobenzene moieties can serve as active fragments in antimicrobials and exert trans/cis conversions of molecules. Herein, a series of novel nicotinamide derivatives (NTMs) were developed by employing a two-step strategy, including azo-incorporating and bioisosteric replacement. Azo-incorporation can conveniently provide compounds that can be easily optically interconverted between trans/cis isomers, enhancing the structural diversity of azo compounds. It is noteworthy that the replacement of the azo bond with a 1,2,4-oxadiazole motif through further bioisosteric replacement led to the discovery of a novel compound, NTM18, which made a breakthrough in preventing rice sheath blight disease. A control effect value of 94.44% against Rhizoctonia solani could be observed on NTM18, while only 11.11% was determined for boscalid at 200 mg·L-1. Further mechanism validations were conducted, and the molecular docking analysis demonstrated that compound NTM18 might have a tight binding with SDH via an extra π-π interaction between the oxadiazole ring and residue of D_Y586. This work sets up a typical case for the united applications of azo-incorporating and bioisosteric replacement in fungicide design, posing an innovative approach in structural diversity-based development of pesticides.

FXR, MRP-1 and SLC7A5: New Targets for the Treatment of Hepatocellular Carcinoma.

Detect the expression of Farnesoid X Receptor(FXR), Multiple Drug Resistance Associated Protein-1(MRP-1) and Solute Carrier Family 7, Member 5 (SLC7A5) in hepatocellular carcinoma(HCC) of rat model, so as to provide new therapeutic targets for gene therapy of HCC. Sixty male Wistar rats were randomly divided into three groups. The rats in experimental group were given 0.2% diethylnitrosamine (DEN) by gavage with a dose of 10 mg/kg, 3 times a week, and it stopped at 12 weeks. The control group rats were given physiological saline by gavage, while the sham operation group did not receive anything by gavage. At 10 weeks, one rat in the experimental group was euthanized, and the changes of livers were recorded. The procedure was repeated at 12 weeks. After 12 weeks, HCC only occurred in the experimental group. After confirming the formation of the tumor through pathological examination, liver tissues and tumor tissues were taken from the three groups. FXR, MRP-1 and SLC7A5 expression in liver tissues and tumor tissues was detected. After 7 weeks the rats in experimental group ate less, and their weight was significantly reduced. Three months later, HCC was detected in 15 rats in the experimental group. The ratio of FXR/GAPDH mRNA, MRP-1/GAPDH mRNA, SLC7A5/GAPDH mRNA were significantly different among the three groups. Under the light microscope the FXR protein, MRP-1 protein, and SLC7A5 protein react with their respective antibodies, and they showed granular expression. Every pathological section included different numbers of positive cells in each group. FXR expression in HCC of rats was significantly lower than that in normal liver tissues, but MRP-1 and SLC7A5 expression in HCC were significantly higher than that in normal liver tissues, suggesting that drugs targeting FXR, MRP-1 and SLC7A5 may be new strategies for the treatment of HCC.

Anesthesia for cesarean delivery and subsequent depression: A nationwide retrospective cohort study.

BACKGROUND: Postpartum depression is a major psychiatric disorder associated with maternal suicide and child developmental disturbances. In this study, we aimed to investigate whether general anesthesia for cesarean delivery is associated with a higher rate of new-onset depression after delivery than neuraxial anesthesia. METHODS: This is a nationwide retrospective cohort study using data retrieved from the National Health Insurance Research Database between 2014 and 2018. Women who had cesarean delivery under general or neuraxial anesthesia were enrolled. After 1:4 propensity score matching, there were 4544 and 18,176 women under the general and neuraxial anesthesia groups, respectively. The primary outcome was new-onset depression diagnosed after delivery in a time-to-event analysis setting. RESULTS: After propensity-score matching, the rate of new-onset depression diagnosed within 1 year was 1.10 % (50/4488) and 0.86 % (157/18176) after cesarean delivery under general and neuraxial anesthesia, respectively. For depression diagnosed within 90 days of delivery, significant difference between the two groups was noted (0.51 % vs. 0.30 %, P = 0.031). In the time-to-event analysis with Cox regression model, women who delivered under general anesthesia were associated with significantly higher risk of postpartum depression within 90 days (Hazard ratio [HR], 1.71; 95 % CI, 1.05-2.79) compared with those under neuraxial anesthesia. LIMITATIONS: The observational design only allows asserting association, rather than establishing causality between exposure and outcomes. CONCLUSIONS: Women who underwent cesarean delivery under general anesthesia had a higher risk of subsequent depression within 90 days than those under neuraxial anesthesia. Early screening for depressive disorders might facilitate timely management.

Investigation of bisphenol S (BPS) in packaged fish, meat, cheese, and price labels on their corresponding packages.

As an alternative to bisphenol A (BPA), bisphenol S (BPS) has been used as an ink developer in thermal paper products including price labels on food packaging which have been suggested as the sources of BPS found at high levels in packaged fish samples. BPS in the printed price labels glued onto the outside of plastic film could migrate indirectly from the printed surface through the paper, adhesive and film into the food. In order to investigate if price labels could also be the sources of BPS detected in the meat samples in our previous studies, meat and other food samples packaged under different conditions were collected, and BPS in these samples together with the price labels on the corresponding packaging were extracted with solvent followed by solid phase extraction and stable isotope dilution LC-MS/MS analysis. BPS was detected at very high levels (161.7-222.4 µg/cm2) in all the five sticker type of price labels, indicating BPS being the dominant if not the sole ink developer. BPS was also detected in all the 26 continuous roll type of price labels but at very low levels (0.017-18 ng/cm2), indicating that the dominant ink developer is likely one of the other alternatives, rather than BPS. Despite BPS being detected in all price labels on packaging of fish, meat, and cheese samples, BPS was not detected or detected in only a few fish, meat, and cheese samples at levels considerably lower than the current EU specific migration limit (SML) of 50 ng/g food for BPS authorised under Regulation (EU) 10/2011.

Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19.

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.

Association Between Osteoporosis and Adiposity Index Reveals Nonlinearity Among Postmenopausal Women and Linearity Among Men Aged over 50 Years.

PURPOSE: Previous research shows conflicting views on the relationship between obesity and osteoporosis, partly due to variations in obesity classification and the nonlinear nature of these relationships. This study investigated the association between adiposity indices and osteoporosis, diagnosed using dual-energy X-ray absorptiometry (DXA), employing nonlinear models and offering optimal thresholds to prevent further bone mineral density decline. METHODS: In 2019, a prospective study enrolled males over 50 years and postmenopausal women. Anthropometric measurements, blood biochemistry, and osteoporosis measured by DXA were collected. Associations between adiposity indices and osteoporosis were analyzed using a generalized additive model and segmented regression model. RESULTS: The study included 872 women and 1321 men. Indices such as abdominal volume index (AVI), visceral adiposity index (VAI), waist circumference (WC), hip circumference, body mass index (BMI), waist-to-hip ratio, and waist-to-height ratio (WHtR) were inversely associated with osteoporosis. In women, the relationship between the risk of osteoporosis and the adiposity indices was U-shaped, with thresholds of WC = 94 cm, AVI = 17.67 cm2, BMI = 25.74 kg/m2, VAI = 4.29, and WHtR = 0.61, considering changes in bone mineral density. Conversely, men exhibited a linear patterns for the inverse association. CONCLUSION: The impact of obesity and adiposity on osteoporosis varies significantly between women and men. In postmenopausal women, the relationship is nonlinear (U-shaped), with both very low and very high adiposity linked to higher osteoporosis risk. In men over 50, the relationship is linear, with higher adiposity associated with lower osteoporosis risk. The study suggests that maintaining specific levels of adiposity could help prevent osteoporosis in postmenopausal women.

Boosting few-shot rare skin disease classification via self-supervision and distribution calibration.

Due to the difficulty in obtaining clinical samples and the high cost of labeling, rare skin diseases are characterized by data scarcity, making training deep neural networks for classification challenging. In recent years, few-shot learning has emerged as a promising solution, enabling models to recognize unseen disease classes by limited labeled samples. However, most existing methods ignored the fine-grained nature of rare skin diseases, resulting in poor performance when generalizing to highly similar classes. Moreover, the distributions learned from limited labeled data are biased, severely impairing the model's generalizability. This paper proposes a self-supervision distribution calibration network (SS-DCN) to address the above issues. Specifically, SS-DCN adopts a multi-task learning framework during pre-training. By introducing self-supervised tasks to aid in supervised learning, the model can learn more discriminative and transferable visual representations. Furthermore, SS-DCN applied an enhanced distribution calibration (EDC) strategy, which utilizes the statistics of base classes with sufficient samples to calibrate the bias distribution of novel classes with few-shot samples. By generating more samples from the calibrated distribution, EDC can provide sufficient supervision for subsequent classifier training. The proposed method is evaluated on three public skin disease datasets(i.e., ISIC2018, Derm7pt, and SD198), achieving significant performance improvements over state-of-the-art methods.

Design, Synthesis, Bioactivity, and Tentative Exploration of Action Mode for Benzyl Ester-Containing Derivatives.

The active splicing strategy has witnessed improvement in bioactivity and antifungal spectra in pesticide discovery. Herein, a series of simple-structured molecules (Y1-Y53) containing chloro-substituted benzyl esters were designed using the above strategy. The structure-activity relationship (SAR) analysis demonstrated that the fatty acid fragment-structured esters were more effective than those containing an aromatic acid moiety or naphthenic acid part. Compounds Y36 and Y41, which featured a thiazole-4-acid moiety and trifluoromethyl aliphatic acid part, respectively, exhibited excellent in vivo curative activity (89.4%, 100 mg/L Y36) and in vitro fungicidal activity (EC50 = 0.708 mg/L, Y41) against Botrytis cinerea. Determination of antifungal spectra and analysis of scanning electron microscopy (SEM), membrane permeability, cell peroxidation, ergosterol content, oxalic acid pathways, and enzymatic assays were performed separately here. Compound Y41 is cost effective due to its simple structure and shows promise as a disease control candidate. In addition, Y41 might act on a novel target through a new pathway that disrupts the cell membrane integrity by inducing cell peroxidation.

WTAP/IGF2BP3-mediated GBE1 expression accelerates the proliferation and enhances stemness in pancreatic cancer cells via upregulating c-Myc.

BACKGROUND: Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated. METHODS: The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC. RESULTS: GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition. CONCLUSIONS: Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC.

Preparation and Properties of Composite Double-Network Gel for Inhibiting Coal Spontaneous Combustion.

In order to improve the inhibition effect of gel on coal spontaneous combustion, a chitosan (CS)/polyacrylamide (PAM)/metal ion (Al3+) composite double-network gel was developed in this study. The optimum formula of the composite double-network gel was determined using orthogonal experimentation. The microstructure, water retention, compressibility, and anti-destruction properties of the composite double-network gel were analyzed. The inhibition effect of the composite double-network gel on coal spontaneous combustion was studied via infrared spectroscopy and a synchronous thermal analyzer from the micro and macro perspectives. The results show that the composite double-network gel has a denser interpenetrating double-network structure and a larger void ratio than the ordinary gel. The water retention rate was 55% after standing at 150 °C for 12 h. The deformation memory ratio of the composite double-network gel was 78%, which was 26.8% higher than that of the ordinary gel, and the compressive strength also increased by 59.96%. In addition, the critical temperature point and the maximum thermal weight-loss rate temperature point decreased by 7.01 °C and 39.62 °C, respectively, and the composite double-network gel effectively reduced active functional groups in the treated coal sample, such as hydroxyl and aliphatic hydrocarbons. In this study, a CS/PAM/Al3+ composite double-network gel was produced, which exhibited good gel performance and inhibition effects, with physical effects such as the covering, wetting, and cementation of coal.

Relationship between preoperative psychological stress and short-term prognosis in elderly patients with femoral neck fracture.

BACKGROUND: Older adults are at high risk of femoral neck fractures (FNFs). Elderly patients face and adapt to significant psychological burdens, resulting in different degrees of psychological stress response. Total hip replacement is the preferred treatment for FNF in elderly patients; however, some patients have poor postoperative prognoses, and the underlying mechanism is unknown. We speculated that the postoperative prognosis of elderly patients with FNF may be related to preoperative psychological stress. AIM: To explore the relationship between preoperative psychological stress and the short-term prognosis of elderly patients with FNF. METHODS: In this retrospective analysis, the baseline data, preoperative 90-item Symptom Checklist score, and Harris score within 6 months of surgery of 120 elderly patients with FNF who underwent total hip arthroplasty were collected. We analyzed the indicators of poor short-term postoperative prognosis and the ability of the indicators to predict poor prognosis and compared the correlation between the indicators and the Harris score. RESULTS: Anxiety, depression, garden classification of FNF, cause of fracture, FNF reduction quality, and length of hospital stay were independent influencing factors for poor short-term postoperative prognoses in elderly patients with FNF (P < 0.05). The areas under the curve for anxiety, depression, and length of hospital stay were 0.742, 0.854, and 0.749, respectively. The sensitivities of anxiety, depression, garden classification of FNF, and prediction of the cause of fracture were 0.857, 0.786, 0.821, and 0.821, respectively. The specificities of depression, FNF quality reduction, and length of hospital stay were the highest at 0.880, 0.783, and 0.761, respectively. Anxiety, depression, and somatization scores correlated moderately with Harris scores (r = -0.523, -0.625, and -0.554; all P < 0.001). CONCLUSION: Preoperative anxiety, depression, and somatization are correlated with poor short-term prognosis in elderly patients with FNF and warrant consideration.

The combination of SHP099 inhibits the malignant biological behavior of L-OHP/5-FU-resistant colorectal cancer cells by regulating energy metabolism reprogramming.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are insensitive to tumor cells. Combination medication is an important means to solve the insensitivity of medication alone. The purpose of this project was to explore the effect and molecular mechanism of SHP099 combination on the malignant biological behavior of L-OHP/5-FU resistant strains of CRC. METHODS: HT29 and SW480 cells were cultured in media supplemented with L-OHP or 5-FU to establish drug-resistant strains. HT29 and SW480 drug-resistant cells were subcutaneously injected into the ventral nerves of nude mice at a dose of 5 × 106 to establish CRC drug-resistant animal models. CCK-8, Western blot, flow cytometry, Transwell and kit detection were used to detect the regulatory mechanism of energy metabolism reprogramming in drug-resistant CRC cells. RESULTS: Compared with nonresistant strains, L-OHP/5-FU-resistant strains exhibited greater metabolic reprogramming. Functionally, SHP099 can restrain the metabolic reprogramming of L-OHP/5-FU-resistant strains and subsequently restrain the proliferation, colony formation, migration and spheroid formation of L-OHP/5-FU-resistant strains. Downstream mechanistic studies have shown that SHP099 interferes with the metabolic reprogramming of L-OHP/5-FU drug-resistant strains by suppressing the PI3K/AKT pathway, thereby restraining the malignant biological behavior of L-OHP/5-FU drug-resistant strains and alleviating CRC. CONCLUSION: The combination of SHP099 can restrain the malignant biological behavior of L-OHP/5-FU-resistant CRC cells and alleviate the progression of CRC by interfering with the reprogramming of energy metabolism. This study explored the effect of SHP099 combination on dual-resistant CRC cells for the first time, and provided a new therapeutic idea for solving the problem of SHP099 insensitivity to CRC cells.

Risks associated with cognitive function and management strategies in the clinical use of ADT: a systematic review from clinical and preclinical studies.

Prostate cancer is one of the most common malignancies and a leading cause of death in men. Owing to its excellent anti-tumor effects, androgen deprivation therapy (ADT) is widely used in the treatment of prostate cancer. However, its use is controversial because of its potential for inducing cognitive decline. In this review, we summarized the findings of preclinical and clinical studies investigating the effects of ADT on cognitive function in prostate cancer. We discussed the methods used to assess cognitive function in these studies, elucidated the mechanisms through which ADT affects cognitive function, and highlighted recent advancements in cognitive assessment methods. The findings of this review serve as a valuable reference for examining the relationship between ADT and cognitive function in future studies. Besides, the findings may help clinicians understand the advantages and disadvantages of ADT and optimize the treatment plan so as to minimize the adverse effects of ADT.

Analyzing the topological properties of resting-state brain function network connectivity based on graph theoretical methods in patients with high myopia.

AIM: Recent imaging studies have found significant abnormalities in the brain's functional or structural connectivity among patients with high myopia (HM), indicating a heightened risk of cognitive impairment and other behavioral changes. However, there is a lack of research on the topological characteristics and connectivity changes of the functional networks in HM patients. In this study, we employed graph theoretical analysis to investigate the topological structure and regional connectivity of the brain function network in HM patients. METHODS: We conducted rs-fMRI scans on 82 individuals with HM and 59 healthy controls (HC), ensuring that the two groups were matched for age and education level. Through graph theoretical analysis, we studied the topological structure of whole-brain functional networks among participants, exploring the topological properties and differences between the two groups. RESULTS: In the range of 0.05 to 0.50 of sparsity, both groups demonstrated a small-world architecture of the brain network. Compared to the control group, HM patients showed significantly lower values of normalized clustering coefficient (γ) (P = 0.0101) and small-worldness (σ) (P = 0.0168). Additionally, the HM group showed lower nodal centrality in the right Amygdala (P < 0.001, Bonferroni-corrected). Notably, there is an increase in functional connectivity (FC) between the saliency network (SN) and Sensorimotor Network (SMN) in the HM group, while the strength of FC between the basal ganglia is relatively weaker (P < 0.01). CONCLUSION: HM Patients exhibit reduced small-world characteristics in their brain networks, with significant drops in γ and σ values indicating weakened global interregional information transfer ability. Not only that, the topological properties of the amygdala nodes in HM patients significantly decline, indicating dysfunction within the brain network. In addition, there are abnormalities in the FC between the SN, SMN, and basal ganglia networks in HM patients, which is related to attention regulation, motor impairment, emotions, and cognitive performance. These findings may provide a new mechanism for central pathology in HM patients.

N6-methyladenosine modification of circMARK2 enhances cytoplasmic export and stabilizes LIN28B, contributing to the progression of Wilms tumor.

BACKGROUND: The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression. METHODS: We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. RESULTS: CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. CONCLUSIONS: Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.