ß1 integrins regulate cellular behavior and cardiomyocyte organization during ventricular wall formation.

AIMS: The mechanisms regulating the cellular behavior and cardiomyocyte organization during ventricular wall morphogenesis are poorly understood. Cardiomyocytes are surrounded by extracellular matrix (ECM) and interact with ECM via integrins. This study aims to determine whether and how ß1 integrins regulate cardiomyocyte behavior and organization during ventricular wall morphogenesis in the mouse. METHODS AND RESULTS: We applied mRNA deep sequencing and immunostaining to determine the expression repertoires of α/ß integrins and their ligands in the embryonic heart. Integrin ß1 subunit (ß1) and some of its ECM ligands are asymmetrically distributed and enriched in the luminal side of cardiomyocytes, and fibronectin surrounds cardiomyocytes, creating a network for them. Itgb1, which encodes the ß1, was deleted via Nkx2.5Cre/+ to generate myocardial-specific Itgb1 knockout (B1KO) mice. B1KO hearts display an absence of a trabecular zone but a thicker compact zone. The levels of hyaluronic acid and versican, essential for trabecular initiation, were not significantly different between control and B1KO. Instead, fibronectin, a ligand of ß1, was absent in the myocardium of B1KO hearts. Furthermore, B1KO cardiomyocytes display a random cellular orientation and fail to undergo perpendicular cell division, be organized properly, and establish the proper tissue architecture to form trabeculae. Mosaic clonal lineage tracing showed that Itgb1 regulates cardiomyocyte transmural migration and proliferation autonomously. CONCLUSIONS: ß1 is asymmetrically localized in the cardiomyocytes, and some of its ECM ligands are enriched along the luminal side of the myocardium, and fibronectin surrounds cardiomyocytes. ß1 integrins are required for cardiomyocytes to attach to the ECM network. This engagement provides structural support for cardiomyocytes to maintain shape, undergo perpendicular division, and establish cellular organization. Deletion of Itgb1 leads to loss of ß1 and fibronectin and prevents cardiomyocytes from engaging the ECM network, resulting in failure to establish tissue architecture to form trabeculae.

Unilateral Genital Tract Obstruction with Ipsilateral Renal Anomaly Syndrome: Classification, Clinical Manifestations, and Precise Diagnose.

Purpose: To recommend the classification of unilateral genital tract obstruction with ipsilateral renal anomaly (UGTOIRA) syndrome into five types based on the site of obstruction, and to analyze the clinical manifestations and precise diagnosis of the syndrome. Methods: The data, including demographic characteristics, symptoms, and precise diagnoses from 59 patients over the last decade, were retrospectively analyzed. Data analysis was conducted using the statistical software package SPSS 26.0. Results: All 59 patients diagnosed with UGTOIRA syndrome were classified into five types based on the site of obstruction: Type I (vaginal obstruction) (45, 76.3%), Type II (cervicovaginal obstruction) (7, 11.9%), Type III (cervical obstruction) (3, 5.1%), Type IV (unilateral partial cervical aplasia) (3, 5.1%), and Type V (Unilateral isthmus atresia) (1, 1.7%). Of these cases, there were 34 cases (57.6%) with communication and 25 cases (42.4%) without communication between the left and right genital tracts. The chief complaints included dysmenorrhea alone in 28 cases (47.5%), dysmenorrhea accompanied by blood dripping after menstruation in 12 cases (20.3%), blood dripping after menstruation alone in 14 cases (23.7%), purulent vaginal secretions in one case (1.7%), vaginal pain in one case (1.7%), irregular menstruation in one case (l.7%), and infertility in two cases (3.4%). The precise diagnostic criteria include the affected side, abnormalities in the kidney and ureter, the site of obstruction, the location of blood accumulation, the size of the ipsilateral genital tract, whether there is communication and its site, the type based on the site of obstruction, and the presence and type of complications. Conclusion: This classification of UGTOIRA syndrome encompasses the anatomical features of all cases reported in our study. Only by fully understanding the anatomical characteristics of this syndrome and identifying its clinical manifestations can clinicians make precise diagnoses as early as possible and provide individualized management.

Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1.

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies.

Towards prolonging ovarian reproductive life: Insights into trace elements homeostasis.

Ovarian aging is marked by a reduction in the quantity and quality of ovarian follicles, leading to a decline in female fertility and ovarian endocrine function. While the biological characteristics of ovarian aging are well-established, the exact mechanisms underlying this process remain elusive. Recent studies underscore the vital role of trace elements (TEs) in maintaining ovarian function. Imbalances in TEs can lead to ovarian aging, characterized by reduced enzyme activity, hormonal imbalances, ovulatory disorders, and decreased fertility. A comprehensive understanding of the relationship between systemic and cellular TEs balance and ovarian aging is critical for developing treatments to delay aging and manage age-related conditions. This review consolidates current insights into TEs homeostasis and its impact on ovarian aging, assesses how altered TEs metabolism affects ovarian aging, and suggests future research directions to prolong ovarian reproductive life. These studies are expected to offer novel approaches for mitigating ovarian aging.

WEE1 Inhibitors Mediate Antitumor Effects on Endometrial Cancer through Activation of Innate Immune Responses.

Introduction: Recurrence signifies the primary mortality factor in patients suffering from endometrial cancer, with few efficacious treatments currently available for recurrent cases. This research investigates the anti-tumoral capacities of WEE1 inhibitors within the context of endometrial cancer, aiming to establish a novel therapeutic avenue for high recurrence-risk patients. Materials and methods: We evaluated WEE1 expression in endometrial cancer patients utilizing immunohistochemistry on paraffin-embedded tissue sections. The cytotoxic potential of WEE1 inhibitors on endometrial cancer cells was assessed by CCK8 assay. Assays to gauge the influence of WEE1 inhibitors on cell proliferation and migration included clonal proliferation, wound healing, and transwell assays. We determined the impacts on apoptosis and cell cycle stages by flow cytometry. Employing qRT-PCR and western blotting, we investigated the mechanistic pathways underlying the anti-tumoral activity of WEE1 inhibitors. In vivo evaluations were executed to ascertain the inhibitory effect of WEE1 inhibitors on tumor growth in mice. Results: WEE1 exhibited high-level expression in endometrial cancer tissues, particularly pronounced in recurrent compared with non-recurrent patients. WEE1 inhibitors effectively eliminated endometrial cancer cells while inhibiting their proliferation and migration. Flow cytometric analyses revealed a significant promotion of apoptosis and an increase in G2/M phase cell proportion upon WEE1 inhibitor treatment. qRT-PCR and western blotting elucidated that WEE1 inhibitors activated the innate immune signaling pathway in endometrial cancer cells. Furthermore, in vivo assessments demonstrated substantial tumor growth suppression due to WEE1 inhibitors. Conclusions: WEE1 inhibitors initiated an innate immune response in endometrial cancer, exhibiting considerable anti-tumoral effects, which was promising for postoperative treatment of endometrial cancer, especially recurrent endometrial cancer patients.

Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-ß Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.

BACKGROUND: PRDM16 plays a role in myocardial development through TGF-ß (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans. METHODS: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR (clustered regularly interspaced short palindromic repeats)-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated and subjected to ECG, histological, and transcriptional analysis. RESULTS: We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy. One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study. Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including TGF-ß-associated transcripts. Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-ß expression. Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription. CONCLUSIONS: Novel loss-of-function PRDM16 variant impairs myocardial development resulting in noncompaction cardiomyopathy in humans and mice associated with altered TGF-ß signaling.

Diverse ultrasound image features of unilateral genital tract obstruction with ipsilateral renal anomaly syndrome on genitourinary system segmental sequential ultrasound screening and the accuracy of ultrasonic diagnosis.

Background: Unilateral genital tract obstruction with ipsilateral renal anomaly (UGTOIRA) syndrome is a rare congenital urogenital anomaly, characterized by different combinations of uterine abnormalities, unilateral cervical-vaginal obstruction, and ipsilateral renal abnormalities. Timely and correct diagnosis is critical. In this study, we analyzed the diverse ultrasound image features of UGTOIRA syndrome on genitourinary system segmental sequential ultrasound screening (SSUS) and the accuracy of ultrasonic diagnosis. Methods: The data from 59 patients with UGTOIRA syndrome over the last decade were analyzed retrospectively, which included ultrasound presentations and diagnoses of abnormalities of the uterus, cervix, and vagina, as well as the conditions associated with the bilateral fallopian tubes, ovaries, pelvis, kidneys and ureters, bladder, and urethra. Results: All 59 patients (100%) were found to have ipsilateral renal agenesis, and the diagnostic accuracy of ultrasound was 100%. The uterus was correctively diagnosed as complete bicorporal uterus in 42 cases (71.2%), bicorporal septate uterus in 7 cases (11.9%), complete uterus septate in 8 cases (13.6%), partial uterus septate in 1 case (1.7%), and unilateral isthmus atresia in 1 case (1.7%). The cervix was correctively diagnosed as septate cervix in 28 cases (47.5%), double cervix in 17 cases (28.8%), unilateral small cervix in 5 cases (8.5%), unilateral obliterated cervical orifice in 5 cases (8.5%), partial development of the unilateral cervix with a blind end in 3 cases (5.1%), and unilateral completely undeveloped cervix appearing as a normal cervix in 1 case (1.7%). The vagina was correctively diagnosed as oblique vaginal septum (OVS) in 45 cases (76.3%), and normal vagina in 13 cases (22.0%) via preoperative ultrasound. In 1 case (1/59, 1.7%) of high OVS with ipsilateral obliterated external cervical orifice, the OVS was missed by preoperative ultrasound. The ultrasound diagnostic accuracy rates of uterine malformation, cervical malformation, vaginal malformation, hematoma location and volume, uterine communication, and cervical communication were respectively 100%, 100%, 98.3%, 100%, 100%, and 100%. The ultrasonic detection rate for a hole on the OVS was 0%, and the missed diagnosis rate was 100%. Conclusions: SSUS can be used to accurately evaluate uterine, cervical, and vaginal malformation, obstruction site, location and volume of keratocele, cervical or uterine communication, and ovarian endometriosis cyst in patients with UGTOIRA syndrome and ipsilateral urinary system malformation. However, ultrasound is unable to identify a hole on the OVS.

The role of blood pressure variability indicators combined with cerebral blood flow parameters in predicting intraventricular hemorrhage in very low birth weight preterm infants.

Background: Hemodynamic instability is the main factor responsible for the development of intraventricular hemorrhage (IVH) in premature newborns. Herein, we evaluated the predictive ability of blood pressure variability (BPV) and anterior cerebral artery (ACA) blood flow parameters in IVH in premature infants with gestational age (GA) ≤32 weeks and birth weight (BW) ≤ 1,500 g. Methods: Preterm infants with GA ≤32 weeks and BW ≤ 1,500 g admitted to the neonatal intensive care unit (NICU) of the hospital affiliated to Yangzhou University from January 2020 to January 2023 were selected as the research subjects. All preterm infants were admitted within 1 h after birth, and systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MABP) were monitored at 1-h intervals. The difference between maximum and minimum values (max-min), standard deviation (SD), coefficient of variation (CV), and successive variation (SV) were used as BPV indicators. On the 1st, 3rd, and 7th day after birth, transcranial ultrasound examination was performed to screen for the occurrence of IVH. On the 24 ± 1 h after birth, systolic velocity (Vs), diastolic velocity (Vd), and resistance index (RI) of the ACA were measured simultaneously. Preterm infants were divided into the IVH group and non-IVH group based on the results of transcranial ultrasound examination, and the correlation between BPV indicators, ACA blood flow parameters, and development of IVH was analyzed. Results: A total of 92 premature infants were enrolled, including 49 in the IVH group and 43 in the non-IVH group. There was no statistically significant difference in baseline characteristics such as BW, GA, sex, and perinatal medical history between the two groups of preterm infants (P > 0.05). The SBP SD (OR: 1.480, 95%CI: 1.020-2.147) and ACA-RI (OR: 3.027, 95%CI: 2.769-3.591) were independent risk factors for IVH in premature newborns. The sensitivity and specificity of combined detection of SBP SD and ACA-RI in predicting IVH were 61.2% and 79.1%, respectively. Conclusion: High BPV and ACA-RI are related to IVH in premature infants with GA ≤32 w and BW ≤1,500 g. Combined detection of SBP SD and ACA-RI has a certain predictive effect on early identification of IVH.

Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead.

Hypoplastic left heart syndrome (HLHS) is a lethal congenital heart disease (CHD) affecting 8-25 per 100,000 neonates globally. Clinical interventions, primarily surgical, have improved the life expectancy of the affected subjects substantially over the years. However, the etiological basis of HLHS remains fundamentally unclear to this day. Based upon the existing paradigm of studies, HLHS exhibits a multifactorial mode of etiology mediated by a complicated course of genetic and signaling cascade. This review presents a detailed outline of the HLHS phenotype, the prenatal and postnatal risks, and the signaling and molecular mechanisms driving HLHS pathogenesis. The review discusses the potential limitations and future perspectives of studies that can be undertaken to address the existing scientific gap. Mechanistic studies to explain HLHS etiology will potentially elucidate novel druggable targets and empower the development of therapeutic regimens against HLHS in the future.

Role of the Nrf2 Signaling Pathway in Ovarian Aging: Potential Mechanism and Protective Strategies.

The ovary holds a significant role as a reproductive endocrine organ in women, and its aging process bears implications such as menopause, decreased fertility, and long-term health risks including osteoporosis, cardiovascular disorders, and cognitive decline. The phenomenon of oxidative stress is tightly linked to the aging metabolic processes. More and more studies have demonstrated that oxidative stress impacts both physiologic and pathologic ovarian aging, and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating the antioxidant response. Furthermore, various therapeutic approaches have been identified to ameliorate ovarian aging by modulating the Nrf2 pathway. This review summarizes the important role of the Nrf2/ Kelch-like ECH-associated protein 1 (Keap1) signaling pathway in regulating oxidative stress and influencing ovarian aging. Additionally, it highlights the therapeutic strategies aimed at targeting the Nrf2/Keap1 pathway.

ß1 integrins regulate cellular behaviors and cardiomyocyte organization during ventricular wall formation.

Aims: The mechanisms regulating the cellular behavior and cardiomyocyte organization during ventricular wall morphogenesis are poorly understood. Cardiomyocytes are surrounded by extracellular matrix (ECM) and interact with ECM via integrins. This study aims to determine whether and how ß1 integrins regulate cardiomyocyte behavior and organization during ventricular wall morphogenesis in the mouse. Methods and Results: We applied mRNA deep sequencing and immunostaining to determine the expression repertoires of α/ß integrins and their ligands in the embryonic heart. Integrin ß1 subunit (ß1) and some of its ECM ligands are asymmetrically distributed and enriched in the luminal side of cardiomyocytes, while fibronectin surrounds cardiomyocytes, creating a network for them. Itgb1 , which encodes the ß1 integrin subunit, was deleted via Nkx2.5 Cre/+ to generate myocardial-specific Itgb1 knockout (B1KO) mice. B1KO hearts display an absence of trabecular zone but a thicker compact zone. The abundances of hyaluronic acid and versican are not significantly different. Instead, fibronectin, a ligand of ß1, was absent in B1KO. We examined cellular behaviors and organization via various tools. B1KO cardiomyocytes display a random cellular orientation and fail to undergo perpendicular cell division, be organized properly, and establish the proper tissue architecture to form trabeculae. The reduction of Notch1 activation was not the cause of the abnormal cellular organization in B1KO hearts. Mosaic clonal lineage tracing shows that Itgb1 regulates cardiomyocyte transmural migration and proliferation autonomously. Conclusions: ß1 is asymmetrically localized in the cardiomyocytes, and its ECM ligands are enriched in the luminal side of the myocardium and surrounding cardiomyocytes. ß1 integrins are required for cardiomyocytes to attach to the ECM network. This engagement provides structural support for cardiomyocytes to maintain shape, undergo perpendicular division, and establish cellular organization. Deletion of Itgb1 , leading to ablation of ß1 integrins, causes the dissociation of cardiomyocytes from the ECM network and failure to establish tissue architecture to form trabeculae.

Ovarian reserve in reproductive-aged patients with cancer before gonadotoxic treatment: a systematic review and meta-analysis.

STUDY QUESTION: Does cancer itself, before any gonadotoxic treatment, affect ovarian function in reproductive-aged patients? SUMMARY ANSWER: Our study revealed that women with cancer may have decreased ovarian reserve markers even before cancer therapy. WHAT IS KNOWN ALREADY: With the field 'oncofertility' improving rapidly, cancer therapy-mediated ovarian damage is well characterized. However, there is a controversy about whether cancer itself affects ovarian function before gonadotoxic treatment. STUDY DESIGN SIZE DURATION: We conducted a systematic meta-analysis investigating the association between cancer and ovarian function prior to gonadotoxic treatment. Titles or abstracts related to ovarian reserve (e.g. anti-Müllerian hormone (AMH), antral follicle count (AFC), or basal follicle-stimulating hormone (FSH)) combined with titles or abstracts related to the exposure (e.g. cancer*, oncolog*, or malignan*) were searched in PubMed, Embase, and Web of Science databases from inception to 1 February 2022. PARTICIPANTS/MATERIALS SETTING METHODS: We included cohort, case-control, and cross-sectional studies in English that examined ovarian reserve in reproductive-aged patients (18-45 years) with cancer compared to age-matched controls before cancer treatment. The quality of the included studies was assessed by ROBINS-I. Fixed or random effects were conducted to estimate standard or weighted mean difference (SMD or WMD, respectively) and CI. Heterogeneity was assessed by the Q test and I2 statistics, and publication bias was evaluated by Egger's and Begg's tests. MAIN RESULTS AND THE ROLE OF CHANCE: The review identified 17 eligible studies for inclusion. The results showed that cancer patients had lower serum AMH levels compared to healthy controls (SMD = -0.19, 95% CI = -0.34 to -0.03, P = 0.001), especially women with hematological malignancies (SMD = -0.62, 95% CI = -0.99 to -0.24, P = 0.001). The AFC was also decreased in patients with cancer (WMD = -0.93, 95% CI = -1.79 to -0.07, P = 0.033) compared to controls, while inhibin B and basal FSH levels showed no statistically significant differences. LIMITATIONS REASONS FOR CAUTION: Serum AMH and basal FSH levels in this meta-analysis showed high heterogeneity, and the small number of studies contributing to most subgroup analyses limited the heterogeneity analysis. Moreover, the studies for specific cancer subtypes may be too small to draw conclusions; more studies are needed to investigate the possible impact of cancer type and stage on ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Our study confirmed the findings that cancer per se, especially hematological malignancies, negatively affects serum AMH level, and AFC values of reproductive-aged women. However, the lower AMH levels and AFC values may also be due to the changes in ovarian physiology under oncological conditions, rather than actual lower ovarian reserves. Based on the meta-analysis, clinicians should raise awareness about the possible need for personalized approaches for young women with cancer who are interested in pursuing fertility preservation strategies before anticancer treatments. STUDY FUNDING/COMPETING INTERESTS: This work was financially supported by the National Natural Science Foundation of China (nos 81873824, 82001514, and 81902669) and the Applied Basic Research Program of Wuhan Municipal Bureau of Science and Technology (2019020701011436). The authors declare that they have no conflicts of interest. REGISTRATION NUMBER: PROSPERO (CRD42021235954).

Tumor microenvironment promotes lymphatic metastasis of cervical cancer: its mechanisms and clinical implications.

Although previous studies have shed light on the etiology of cervical cancer, metastasis of advanced cervical cancer remains the main reason for the poor outcome and high cancer-related mortality rate. Cervical cancer cells closely communicate with immune cells recruited to the tumor microenvironment (TME), such as lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells. The crosstalk between tumors and immune cells has been clearly shown to foster metastatic dissemination. Therefore, unraveling the mechanisms of tumor metastasis is crucial to develop more effective therapies. In this review, we interpret several characteristics of the TME that promote the lymphatic metastasis of cervical cancer, such as immune suppression and premetastatic niche formation. Furthermore, we summarize the complex interactions between tumor cells and immune cells within the TME, as well as potential therapeutic strategies to target the TME.

Short-time mortality and severe complications of very premature infants-a multicenter retrospective cohort study from Jiangsu Province during 2019-2021.

Background: The short-term and long-term severe complications of preterm infants have brought serious psychological and economic burdens to the society and family. Therefore, our study aimed to investigate the risk factors for the mortality and serious complications in very premature infants less than 32 weeks of gestational age (GA), so as to guide the antenatal and postnatal care of very premature. Methods: The very premature infants from 1 January 2019 to 31 December 2021 from 15 member hospitals of the Neonatal Intensive Care Unit (NICU) Multi-center Clinical Research Collaboration Group in Jiangsu Province were recruited. In accordance with the plan of the intensive care unit for unified management, recruitment of premature infants is carried out on the day of admission, and discharge or death is the outcome indicator in 1-2 months by telephone follow-up. The research content mainly includes three aspects: clinical information of mother and infant, outcomes and complications. According to the final outcomes, very premature infants were divided into two categories: survival without severe complications, survival with severe complications and death. Then, univariate and multivariate logistic regression model and receiver operating characteristic (ROC) analyses were used to analyze the independent risk factors. Results: A total of 3,200 very premature infants with GA less than 32 weeks were recruited. The median GA is 30.00 (28.57, 31.14) weeks, the average birth weight is 1,350 (1,110, 1,590) g, among whom 375 premature infants survived with severe complications, and 2,391 premature infants survived without severe complications. Then, it was found that GA at birth was a protective factor for death and severe complications, whereas severe neonatal asphyxia and persistent pulmonary hypertension of the newborn (PPHN) were independent risk factors for death and severe complications in very premature infants born at less than 32 weeks of gestation. Conclusions: The prognosis of very premature infants in NICU treatment depends not only on GA, but also on various perinatal factors and their clinical management, such as preterm asphyxia and PPHN occurrence, so the next step is necessary for multicenter continuous quality improvement to improve outcomes in very preterm infants.

Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model.

Muscular dystrophies make up a group of genetic neuromuscular disorders that involve severe muscle wasting. TGF-ß-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeletal muscle of adult mice. However, the role of TAK1 in muscle diseases remains poorly understood. In the present study, we have investigated how TAK1 affects the progression of dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). TAK1 is highly activated in the dystrophic muscle of mdx mice during the peak necrotic phase. While targeted inducible inactivation of TAK1 inhibits myofiber injury in young mdx mice, it results in reduced muscle mass and contractile function. TAK1 inactivation also causes loss of muscle mass in adult mdx mice. By contrast, forced activation of TAK1 through overexpression of TAK1 and TAB1 induces myofiber growth without having any deleterious effect on muscle histopathology. Collectively, our results suggest that TAK1 is a positive regulator of skeletal muscle mass and that targeted regulation of TAK1 can suppress myonecrosis and ameliorate disease progression in DMD.

Recent progress of second near-infrared (NIR-II) fluorescence microscopy in bioimaging.

Visualizing biological tissues in vivo at a cellular or subcellular resolution to explore molecular signaling and cell behaviors is a crucial direction for research into biological processes. In vivo imaging can provide quantitative and dynamic visualization/mapping in biology and immunology. New microscopy techniques combined with near-infrared region fluorophores provide additional avenues for further progress in vivo bioimaging. Based on the development of chemical materials and physical optoelectronics, new NIR-II microscopy techniques are emerging, such as confocal and multiphoton microscopy, light-sheet fluorescence microscopy (LSFM), and wide-field microscopy. In this review, we introduce the characteristics of in vivo imaging using NIR-II fluorescence microscopy. We also cover the recent advances in NIR-II fluorescence microscopy techniques in bioimaging and the potential for overcoming current challenges.

Effect of hysterectomy on ovarian function: a systematic review and meta-analysis.

BACKGROUND: Hysterectomy is one of the most frequently gynecologic surgeries performed in premenopausal women. Many premenopausal patients are unwilling to undergo hysterectomy due to the probable decreased ovarian function. The aim of this study is to determine the effect of hysterectomy on ovarian function. METHODS: A meta-analysis has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) guidelines. We mainly searched the Embase, PubMed and Web of Science databases for eligible studies. The outcomes were the levels of common indicators of ovarian function, such as anti-müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, estradiol (E2) and luteinizing hormone (LH). The evidence was synthesized using meta-analysis via fixed or random effect model according to heterogeneity. Subgroup analyses were performed to examine the potential sources of heterogeneity. RESULTS: The 14 included studies were conducted between 1989 and 2021, involving a total of 1,457 premenopausal women with 760 and 697 in the hysterectomy and control group, respectively. We found that hysterectomy damage ovarian function compared to the control group, with lower AMH level [Weighted mean difference (WMD) = -0.56, 95% confidence interval (95% CI): -0.72 to -0.39, P = 0.000], higher FSH levels (WMD = 2.96, 95% CI: 1.47 to 4.44, P = 0.000), lower inhibin B levels (WMD = -14.34, 95% CI: -24.69 to -3.99, P = 0.000) and higher LH levels (WMD = 4.07, 95% CI: 1.78 to 6.37, P = 0.000). In addition, E2 levels have a decreasing trend (WMD = -17.13, 95% CI: -35.10 to 0.85, P = 0.631) in the hysterectomy group but were not statistically significant. CONCLUSION: Hysterectomy has a negative impact on ovarian function, especially in female patients over 40 years old. So, the older patients should closely monitor their ovarian function for early diagnosis and treatment of menopausal symptoms.

Primary cesarean scar choriocarcinoma: A case series and literature review.

OBJECTIVES: To provide clinical guidance for early diagnosis and effective management of primary cesarean scar choriocarcinoma, which is an extremely rare but highly malignant trophoblastic tumor. METHODS: This retrospective case series summarized the clinical courses of seven patients diagnosed with cesarean scar choriocarcinoma. RESULTS: We identified two patients in our institution with cesarean scar choriocarcinoma. In addition, details of the previous five patients were extracted from databases and analyzed to provide more clinical information. The seven patients had an average age of 31.14 years, their tumor sizes ranged from 2.0 to 6.5 cm, and their pretreatment serum ß-human chorionic gonadotropin (ß-hCG) levels ranged from 3664 to 312 468 mIU/mL. All the patients were categorized as having FIGO Stage I disease, with four patients at low risk and three at high risk. Six of the seven were misdiagnosed with ectopic pregnancy before pathologic examination. CONCLUSIONS: Clinicians should pay attention to masses in cesarean scar and to continuous elevation of serum ß-hCG levels after treatment. When cesarean scar choriocarcinoma is suspected, diagnostic surgery can be chosen for tentative treatment and pathologic sampling. Salvage EMA-CO chemotherapy (etoposide, actinomycin D, methotrexate, cyclophosphamide and vincristine) should be performed as early as possible to prevent metastasis and recurrence after pathologic diagnosis.

Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self-Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy.

Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co-delivery micelles (BML@PMP) are developed, which are composed of a reduction-sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2-TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor-based co-delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy-associated fertility damage.