Pseudogene GSTM3P1 derived long non-coding RNA promotes ischemic acute kidney injury by target directed microRNA degradation of kidney-protective mir-668.

Long non-coding RNAs (lncRNAs) are a group of epigenetic regulators that have been implicated in kidney diseases including acute kidney injury (AKI). However, very little is known about the specific lncRNAs involved in AKI and the mechanisms underlying their pathologic roles. Here, we report a new lncRNA derived from the pseudogene GSTM3P1, which mediates ischemic AKI by interacting with and promoting the degradation of mir-668, a kidney-protective microRNA. GSTM3P1 and its mouse orthologue Gstm2-ps1 were induced by hypoxia in cultured kidney proximal tubular cells. In mouse kidneys, Gstm2-ps1 was significantly upregulated in proximal tubules at an early stage of ischemic AKI. This transient induction of Gstm2-ps1 depends on G3BP1, a key component in stress granules. GSTM3P1 overexpression increased kidney proximal tubular apoptosis after ATP depletion, which was rescued by mir-668. Notably, kidney proximal tubule-specific knockout of Gstm2-ps1 protected mice from ischemic AKI, as evidenced by improved kidney function, diminished tubular damage and apoptosis, and reduced kidney injury biomarker (NGAL) induction. To test the therapeutic potential, Gstm2-ps1 siRNAs were introduced into cultured mouse proximal tubular cells or administered to mice. In cultured cells, Gstm2-ps1 knockdown suppressed ATP depletion-associated apoptosis. In mice, Gstm2-ps1 knockdown ameliorated ischemic AKI. Mechanistically, both GSTM3P1 and Gstm2-ps1 possessed mir-668 binding sites and downregulated the mature form of mir-668. Specifically, GSTM3P1 directly bound to mature mir-668 to induce its decay via target-directed microRNA degradation. Thus, our results identify GSTM3P1 as a novel lncRNA that promotes kidney tubular cell death in AKI by binding mir-668 to inducing its degradation.

Dual-Activated H2O2-Responsive AIE Probes for Oocyte Quality Assessment.

Nonobstructive azoospermia (NOA) is an important cause of infertility, and intracytoplasmic sperm injection (ICSI) is the mainstay of treatment for these patients. In cases where a sufficient number of sperm (usually 1-2) is not available, the selection of oocytes for ICSI is a difficult problem that must be solved. Here, we constructed a dual-activated oxidative stress-responsive AIE probe, b-PyTPA. The strong donor-acceptor configuration of b-PyTPA leads to twisted intramolecular charge transfer (TICT) effect that quenches the fluorescence of the probe, however, H2O2 would specifically remove the boronatebenzyl unit and release a much weaker acceptor, which inhibits TICT and restores the fluorescence. In addition, the presence of a pyridine salt makes b-PyTPA more hydrophilic, whereas removal of the pyridine salt increases the hydrophobicity of PyTPA, which triggers aggregation and further enhances fluorescence. Thus, the higher the intracellular level of oxidative stress, the stronger the fluorescence. In vitro, this dual-activated fluorescent probe is capable of accurately detecting senescent cells (high oxidative stress). More importantly, b-PyTPA was able to characterize senescent oocytes, as assessed by the level of oxidative stress. It is also possible to identify high quality oocytes from those obtained for subsequent ICSI. In conclusion, this dual-activated oxidative stress-assessment probe enables the quality assessment of oocytes and has potential application in ICSI.

Deficiency of the Planar Cell Polarity Protein Intu Delays Kidney Repair and Suppresses Renal Fibrosis after Acute Kidney Injury.

Planar cell polarity (PCP), a process of coordinated alignment of cell polarity across the tissue plane, may contribute to the repair of renal tubules after kidney injury. Intu is a key effector protein of PCP. Herein, conditional knockout (KO) mouse models that ablate Intu specifically from kidney tubules (Intu KO) were established. Intu KO mice and wild-type littermates were subjected to unilateral renal ischemia/reperfusion injury (IRI) or unilateral ureteral obstruction. Kidney repair was evaluated by histologic, biochemical, and immunohistochemical analyses. In vitro, scratch wound healing was examined in Intu-knockdown and control renal tubular cells. Ablation of Intu in renal tubules delayed kidney repair and ameliorated renal fibrosis after renal IRI. Intu KO mice had less renal fibrosis during unilateral ureteral obstruction. Mechanistically, Intu KO kidneys had less senescence but higher levels of cell proliferation and apoptosis during kidney repair after renal IRI. In vitro, Intu knockdown suppressed scratch wound healing in renal tubular cells, accompanied by the abnormality of centrosome orientation. Together, the results provide the first evidence for the involvement of PCP in tubular repair after kidney injury, shedding light on new strategies for improving kidney repair and recovery.

Global, regional, and national burden of infertility attributable to PCOS, 1990-2019.

STUDY QUESTION: What is the current burden of infertility attributable to PCOS at global, regional, and national levels by age and socio-demographic index (SDI) across 21 regions and 204 countries and territories? SUMMARY ANSWER: The burden of infertility attributable to PCOS increased from 6.00 million prevalent cases in 1990 to 12.13 million in 2019 globally and increased sharply in most regions and nations. WHAT IS KNOWN ALREADY: PCOS is the most common cause of anovulatory infertility, affecting up to 80% of women with anovulation. No comprehensive and detailed epidemiological estimates of infertility attributable to PCOS in reproductive women aged 15-49 years by age and SDI, at the global, regional, and national level, have been reported. STUDY DESIGN, SIZE, DURATION: An age- and SDI-stratified systematic analysis of the prevalence and years lived with disability (YLD) of infertility attributable to PCOS across 21 regions and 204 countries and territories from 1990 to 2019 has been performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: The prevalence and YLD of female infertility attributable to PCOS in reproductive women aged 15-49 years from 1990 to 2019 were retrieved directly from the Global Burden of Diseases 2019. The number, rates per 100 000 persons, and average annual percentage changes (AAPCs) of prevalence and YLD were estimated at the global, regional, and national levels. MAIN RESULTS AND THE ROLE OF CHANCE: Globally, the prevalent cases of infertility attributable to PCOS among women of reproductive age (15-49 years) doubled from 1990 to 2019, with 6.00 million prevalent cases in 1900 and 12.13 million in 2019. The global age-standardized prevalence rates (ASPRs) of infertility attributable to PCOS were 223.50/100 000 persons in 1990 and 308.25/100 000 persons in 2019. At global level, the YLDs of infertility attributable to PCOS increased by 98.0% from 35.20 thousand in 1990 to 69.70 thousand in 2019. The burden of infertility attributable to PCOS in the high SDI region was significantly higher than that in the other four SDI regions. The greatest annual increases in rates of ASPR and age-standardized YLD rate were observed in the middle SDI region (AAPC 1.96 [95% CI 1.87-2.06], 1.94 [1.87-2.00], respectively) and the low-middle SDI region (AAPC 1.96 [1.90-2.03], 1.90 [1.85-1.94], respectively). The regional highest ASPR and the age-standardized YLD rate of infertility were observed in High-income Asia Pacific. The national highest ASPR and the age-standardized YLD rate of infertility were observed in Italy. Positive associations were observed between these burden estimates and the SDI level (all P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Although the Global Burden of Diseases 2019 has tried its best to collect all available data, some countries have limited data, which may result in an underestimation of the burden of infertility attributable to PCOS. The diagnostic criteria of PCOS are constantly changing, which may induce bias in infertility attributable to PCOS. No information on the PCOS phenotype is provided in the Global Burden of Diseases 2019, so we cannot estimate the infertility attributable to a specific PCOS phenotype. Detection bias would lead to a higher prevalence of PCOS and infertility attributable to PCOS in developed countries with well-established medical systems and greater willingness of the populace to seek medical attention. Thus, health resource allocation for infertility attributable to PCOS in low-prevalence areas should not be ignored. WIDER IMPLICATIONS OF THE FINDINGS: The global burden of infertility attributable to PCOS increased sharply from 1990 to 2019. Effective health interventions and efficient preventative and managerial strategies should be established to reduce the burden of infertility attributable to PCOS. Weight control is suggested to reduce the burden of infertility attributable to PCOS, especially in the high SDI region. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (grant number, 2022YFC2704100) and the National Natural Science Foundation of China (Nos 82001498 and 82371648). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Global, regional, and national burden of premenstrual syndrome, 1990-2019: an analysis based on the Global Burden of Disease Study 2019.

STUDY QUESTION: What is the burden of premenstrual syndrome (PMS) at the global, regional, and national levels across 21 regions and 204 countries and territories? SUMMARY ANSWER: Over the past few decades, the global prevalent cases of PMS have grown significantly from 652.5 million in 1990 to 956.0 million in 2019, representing a 46.5% increase. WHAT IS KNOWN ALREADY: PMS, which affects almost half of reproductive women worldwide, has substantial social, occupational, academic, and psychological effects on women's lives. However, no comprehensive and detailed epidemiological estimates of PMS by age and socio-demographic index (SDI) at global, regional, and national levels have been reported. STUDY DESIGN, SIZE, DURATION: An age- and SDI-stratified systematic analysis of the prevalence and years lived with disability (YLD) of PMS by age and SDI across 21 regions and 204 countries and territories has been performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: The prevalence and YLD of PMS from 1990 to 2019 were retrieved directly from the Global Burden of Diseases (GBD) 2019 study. The number, rates per 100 000 persons, and average annual percentage changes (AAPCs) of prevalence and YLD were estimated at the global, regional, and national levels. MAIN RESULTS AND THE ROLE OF CHANCE: Globally, the prevalent cases of PMS increased by 46.5% from 652.5 million in 1990 to 956.0 million in 2019; in contrast, however, the age-standardized prevalence rate was approximately stable at 24 431.15/100 000 persons in 1990 and 24 406.51/100 000 persons in 2019 (AAPC, 0[95% CI: -0.01 to 0.01]). Globally, the YLD was 8.0 million in 2019 and 5.4 million in 1990, with a sizable increase over the past 30 years. The age-standardized YLD rate was stable (AAPC 0.01, P = 0.182), at 203.45/100 000 persons in 1990 and 203.76/100 000 persons in 2019. The age-standardized burden estimates were the highest in the low-middle SDI regions and the lowest in the high SDI regions. Peaks in burden rate estimates were all observed in the 40-44 years age group. Regional age-standardized burden estimates were the highest in South Asia and the lowest in Western Sub-Saharan Africa. The national age-standardized burden estimates were the highest in Pakistan and the lowest in Niger. LIMITATIONS, REASONS FOR CAUTION: The accuracy of the results depended on the quality and quantity of the GBD 2019 data. Fortunately, the GBD study endeavoured to retrieve data globally and applied multiple models to optimize the completeness, accuracy, and reliability of the data. In addition, the GBD study took the country as its basic unit and neglected the influence of race. Further study is warranted to compare differences in PMS burden associated with race. Finally, no data are available on the aetiology and risk information related to PMS, which might help us to better understand the trends and age distribution of PMS and help local governments formulate more detailed policies and comprehensive interventions. WIDER IMPLICATIONS OF THE FINDINGS: Although the age-standardized prevalence/YLD rate has been stable over the past 30 years, the absolute number of prevalent cases and YLD grew significantly worldwide from 1990 to 2019. Public health-related policies should be implemented to reduce the prevalence and alleviate the symptoms of PMS. Lifestyle changes and cognitive-behavioral therapy are critical in helping to reduce the burden of PMS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (grant number 2022YFC2704100) and the National Natural Science Foundation of China (No. 82001498, No. 82371648). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

An important oversight in WHO diagnostic classification: chronic myeloid leukemia with PML::RARA fusion clone.

Not available.

Room-temperature efficient and tunable interlayer exciton emissions in WS2/WSe2 heterobilayers at high generation rates.

Transition metal dichalcogenide (TMDC) heterobilayers (HBs) have been intensively investigated lately because they offer novel platforms for the exploration of interlayer excitons (IXs). However, the potentials of IXs in TMDC HBs have not been fully studied as efficient and tunable emitters for both photoluminescence (PL) and electroluminescence (EL) at room temperature (RT). Also, the efficiencies of the PL and EL of IXs have not been carefully quantified. In this work, we demonstrate that IX in WS2/WSe2 HBs could serve as promising emitters at high generation rates due to its immunity to efficiency roll-off. Furthermore, by applying gate voltages to balance the electron and hole concentrations and to reinforce the built-in electric fields, high PL quantum yield (QY) and EL external quantum efficiency (EQE) of ∼0.48% and ∼0.11% were achieved at RT, respectively, with generation rates exceeding 1021 cm-2·s-1, which confirms the capabilities of IXs as efficient NIR light emitters by surpassing most of the intralayer emissions from TMDCs.

Surface-engineered erythrocyte membrane-camouflage fluorescent bioprobe for precision ovarian cancer surgery.

PURPOSE: Fluorescence imaging-guided surgery has been used in oncology. However, for tiny tumors, the current imaging probes are still difficult to achieve high-contrast imaging, leading to incomplete resection. In this study, we achieved precise surgical resection of tiny metastatic cancers by constructing an engineering erythrocyte membrane-camouflaged bioprobe (AR-M@HMSN@P). METHODS: AR-M@HMSN@P combined the properties of aggregation-induced emission luminogens (AIEgens) named PF3-PPh3 (P), with functional erythrocyte membrane modified by a modular peptide (AR). Interestingly, AR was composed of an asymmetric tripodal pentapeptide scaffold (GGKGG) with three appended modulars: KPSSPPEE (A6) peptide, RRRR (R4) peptide and cholesterol. To verify the specificity of the probe in vitro, SKOV3 cells with overexpression of CD44 were used as the positive group, and HLF cells with low expression of CD44 were devoted as the control group. The AR-M@HMSN@P fluorescence imaging was utilized to provide surgical guidance for the removal of micro-metastatic lesions. RESULTS: In vivo, the clearance of AR-M@HMSN@P by the immune system was reduced due to the natural properties inherited from erythrocytes. Meanwhile, the A6 peptide on AR-M@HMSN@P was able to specifically target CD44 on ovarian cancer cells, and the electrostatic attraction between the R4 peptide and the cell membrane enhanced the firmness of this targeting. Benefiting from these multiple effects, AR-M@HMSN@P achieved ultra-precise tumor imaging with a signal-to-noise ratio (SNR) of 15.2, making it possible to surgical resection of tumors < 1 mm by imaging guidance. CONCLUSION: We have successfully designed an engineered fluorescent imaging bioprobe (AR-M@HMSN@P), which can target CD44-overexpressing ovarian cancers for precise imaging and guide the resection of minor tumors. Notably, this work holds significant promise for developing biomimetic probes for clinical imaging-guided precision cancer surgery by exploiting their externally specified functional modifications.

Rare case of simultaneous occurrence of chronic neutrophil leukemia and T lymphoblastic lymphoma: case report and literature review.

Chronic neutrophil leukemia (CNL) is a rare and life-threatening disease. Cases of CNL combined with lymphoma are rare. Here, we report a case of CNL with T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in a 28-year-old male. After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

Nonparametric predictive model for sparse and irregular longitudinal data.

We propose a kernel-based estimator to predict the mean response trajectory for sparse and irregularly measured longitudinal data. The kernel estimator is constructed by imposing weights based on the subject-wise similarity on L2 metric space between predictor trajectories, where we assume that an analogous fashion in predictor trajectories over time would result in a similar trend in the response trajectory among subjects. In order to deal with the curse of dimensionality caused by the multiple predictors, we propose an appealing multiplicative model with multivariate Gaussian kernels. This model is capable of achieving dimension reduction as well as selecting functional covariates with predictive significance. The asymptotic properties of the proposed nonparametric estimator are investigated under mild regularity conditions. We illustrate the robustness and flexibility of our proposed method via extensive simulation studies and an application to the Framingham Heart Study.

Efficacy and Safety of Ibrutinib as Monotherapy or Combination Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL): A Systematic Review and Meta-analysis.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease group. Ibrutinib's monotherapy or combination therapy is effective in relapsed/refractory (R/R) DLBCL. However, the treatment response in R/R DLBCL varies from 15% to 90% with different regimens, and the tolerance remains controversial. AREAS OF UNCERTAINTY: The efficacy and safety of ibrutinib monotherapy or combination therapy in patients with R/R DLBCL remain uncertain. DATA SOURCES: The PubMed, CBM, MEDLINE, Cochrane Library, and Embase databases were searched from their inception to July 2021. THERAPEUTIC ADVANCES: The total complete remission rate (CRR) and overall response rate in R/R DLBCL patients treated with ibrutinib were 26% and 49%, respectively. The CRR of ibrutinib combination therapy was significantly higher than the ibrutinib monotherapy (45% vs. 19%). Moreover, the CRR of patients was 40% in double expressing lymphoma, 35% in central nervous system lymphoma, and 33% in nongerminal center B-cell-like (non-GCB) DLBCL, which was higher than the 8% in those with the GCB subtype. The pooled median PFS and overall survival were 5.57 and 10.17 months, respectively. GCB-DLBCL had the worst overall survival (5.1 months). Nevertheless, we found that combination regimens had no survival advantage compared with monotherapy (P > 0.05), indicating that combination therapy was only a transitional treatment and bridge for chimeric antigen receptor T cells or other treatments. Moreover, 12% of patients on ibrutinib combination therapy had ≥grade 3 adverse events compared with 9% on ibrutinib monotherapy. CONCLUSIONS: Ibrutinib monotherapy or combination therapy was safe and effective in treating R/R DLBCL with tolerable adverse reactions.

Reactive oxygen species-scavenging nanomaterials for the prevention and treatment of age-related diseases.

With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications.

Solar-powered detection of organic dyes using nitrogen-doped N-TiO2/Ag2O nanorod arrays.

Organic pollutant detection has caused widespread concern regarding due to their potential environmental and human health risks. In this work, a nitrogen-doped titanium dioxide/silver oxide (N-TiO2/Ag2O) composite has been designed as a sensitive photoelectrochemical (PEC) monitoring platform of organic dyes. Sensitive determination relies on the outstanding PEC performance of N-TiO2/Ag2O. The improved PEC performance stems from the effective separation of photocarriers and the extended light response range provided by the narrowing bandgap and a p-n junction with N-TiO2/Ag2O. The N-TiO2/Ag2O electrode exhibits a photocurrent density of up to 2.2 mA/cm2, demonstrating three times increase compared with the photocurrent density observed with the pure TiO2 film. The linear detection range for rhodamine B (RhB), methylene blue (MB), and methyl orange (MO) is 0.2 ng/mL to 10 µg/mL with an ultrasensitive detection limit of 0.2 ng/mL without bias voltage. Due to the outstanding photocurrent density and sensitive response to organic pollutants, the N-TiO2/Ag2O PEC sensor provided a promising analytical method to detect environmental organic dyes.

A Fuzzy-PI Clock Servo with Window Filter for Compensating Queue-Induced Delay Asymmetry in IEEE 1588 Networks.

Clock synchronization is one of the popular research topics in Distributed Measurement and Control Systems (DMCSs). In most industrial fields, such as Smart Grid and Flight Test, the highest requirement for synchronization accuracy is 1 µs. IEEE 1588 Precision Time Protocol-2008 (PTPv2) can theoretically achieve sub-microsecond accuracy, but it relies on the assumption that the forward and backward delays of PTP packets are symmetrical. In practice, PTP packets will experience random queue delays in switches, making the above assumption challenging to satisfy and causing poor synchronization accuracy. Although using switches supporting the Transparent Clock (TC) can improve synchronization accuracy, these dedicated switches are generally expensive. This paper designs a PTP clock servo for compensating Queue-Induced Delay Asymmetry (QIDA), which can be implemented based on ordinary switches. Its main algorithm comprises a minimum window filter with drift compensation and a fuzzy proportional-integral (PI) controller. We construct a low-cost hardware platform (the cost of each node is within USD 10) to test the performance of the clock servo. In a 100 Mbps network with background (BG) traffic of less than 70 Mbps, the maximum absolute time error (max |TE|) does not exceed 0.35 µs, and the convergence time is about half a minute. The accuracy is improved hundreds of times compared with other existing clock servos.

Study on the Mechanisms of Glrα3 in Pain Sensitization of Endometriosis.

Endometriosis, often associated with chronic pelvic pain, can lead to anxiety and depression. This study investigates the role and mechanism of Glycine receptor alpha 3 (Glrα3) in the central sensitization of pain in endometriosis, aiming to identify new therapeutic targets. Using a Glrα3 knockout mouse model of endometriosis, we employed behavioral tests, qPCR, immunofluorescence, Nissl staining, MRI, and Western blot to assess the involvement of Glrα3 in central pain sensitization. Our results indicate that endometriosis-induced hyperalgesia and anxiety-depressive-like behaviors are linked to increased Glrα3 expression. Chronic pain in endometriosis leads to gray matter changes in the sensory and insular cortices, with Glrα3 playing a significant role. The inhibition of Glrα3 alleviates pain, reduces neuronal abnormalities, and decreases glial cell activation. The absence of Glrα3 effectively regulates the central sensitization of pain in endometriosis by inhibiting glial cell activation and maintaining neuronal stability. This study offers new therapeutic avenues for the clinical treatment of endometriosis-related pain.

IL-1R8 expression in DLBCL regulates NK cell recruitment and influences patient prognosis.

The precise biological function of Interleukin-1 receptor 8 (IL-1R8) in diffuse large B-cell lymphoma (DLBCL) is still not well understood. Our goal is to decipher the profile of IL-1R8 expression status in DLBCL and to explore how IL-1R8 is involved in DLBCL progression. Utilizing a tissue microarray consisting of 70 samples of DLBCL tumors alongside 15 samples of tonsillitis, our investigation revealed a parallel expression profile of IL-1R8 between the tumor tissues and tonsillitis samples (p > 0.05). Nevertheless, an intriguing association emerged, as heightened expression of IL-1R8 correlated significantly with unfavorable survival outcomes in patients with DLBCL (p < 0.05). The status of IL-1R8 expression did not directly regulate proliferation (p > 0.05) and apoptosis (p > 0.05) in DLBCL cells via CCK8 and apoptotic assays. Subsequent chemotaxis analysis indicated that natural killer (NK) cell recruitment could be suppressed by IL-1R8 signaling in DLBCL, at least partially through CXCL1 inhibition (p < 0.05). The status of IL-1R8 expression in tumor tissues exhibited a negative correlation with the density of CD57+ NK cell infiltration (p < 0.05), while it did not demonstrate a significant association with CD3+ T cells (p > 0.05), CD68+ macrophages (p > 0.05), or S-100+ dendritic cells (p > 0.05). In line with this observation, elevated levels of NK cell infiltration demonstrated a significant positive correlation with improved overall survival (OS) among patients diagnosed with DLBCL (p < 0.05). Our data suggests the immuno-regulating potential of IL-1R8 through NK cell recruitment in DLBCL, providing novel insights into future immuno-modulating therapies.

Cancer-Associated Fibroblast Mimetic AIE Probe for Precision Imaging-Guided Full-Cycle Management of Ovarian Cancer Surgery.

Fluorescence imaging can improve surgical accuracy in ovarian cancer, but a high signal-to-noise ratio is crucial for tiny metastatic cancers. Meanwhile, intraoperative fluorescent surgical navigation modalities alone are still insufficient to completely remove ovarian cancer lesions, and the recurrence rate remains high. Here, we constructed a cancer-associated fibroblasts (CAFs)-mimetic aggregation-induced emission (AIE) probe to enable full-cycle management of surgery that eliminates recurrence. AIE molecules (P3-PPh3) were packed in hollow mesoporous silica nanoparticles (HMSNs) to form HMSN-probe and then coated with a CAFs membrane to prepare CAF-probe. First, due to the negative potential of the CAF-probe, the circulation time in vivo is elevated, which facilitates passive tumor targeting. Second, the CAF-probe avoids its clearance by the immune system and improves the bioavailability. Finally, the fibronectin on the CAF-probe specifically binds to integrin α-5 (ITGA5), which is highly expressed in ovarian cancer cells, enabling fluorescence imaging with a contrast of up to 8.6. CAF-probe-based fluorescence imaging is used to evaluate the size and location of ovarian cancer before surgery (preoperative evaluation), to guide tumor removal during surgery (intraoperative navigation), and to monitor tumor recurrence after surgery (postoperative monitoring), ultimately significantly improving the efficiency of surgery and completely eliminating tumor recurrence. In conclusion, we constructed a CAFs mimetic AIE probe and established a full-cycle surgical management model based on its precise imaging properties, which significantly reduced the recurrence of ovarian cancer.

Semaphorin 4C regulates ovarian steroidogenesis through RHOA/ROCK1-mediated actin cytoskeleton rearrangement.

Semaphorins are a family of evolutionarily conserved morphogenetic molecules that were initially found to be associated with axonal guidance. Semaphorin 4C (Sema4C), a member of the fourth subfamily of semaphorins, has been demonstrated to play multifaceted and important roles in organ development, immune regulation, tumor growth, and metastasis. However, it is completely unknown whether Sema4C is involved in the regulation of ovarian function. We found that Sema4C was widely expressed in the stroma, follicles, and corpus luteum of mouse ovaries, and its expression was decreased at distinct foci in ovaries of mice of mid-to-advanced reproductive age. Inhibition of Sema4C by the ovarian intrabursal administration of recombinant adeno-associated virus-shRNA significantly reduced oestradiol, progesterone, and testosterone levels in vivo. Transcriptome sequencing analysis showed changes in pathways related to ovarian steroidogenesis and the actin cytoskeleton. Similarly, knockdown of Sema4C by siRNA interference in mouse primary ovarian granulosa cells or thecal interstitial cells significantly suppressed ovarian steroidogenesis and led to actin cytoskeleton disorganization. Importantly, the cytoskeleton-related pathway RHOA/ROCK1 was simultaneously inhibited after the downregulation of Sema4C. Furthermore, treatment with a ROCK1 agonist after siRNA interference stabilized the actin cytoskeleton and reversed the inhibitory effect on steroid hormones described above. In conclusion, Sema4C may play an important role in ovarian steroidogenesis through regulation of the actin cytoskeleton via the RHOA/ROCK1 signaling pathway. These findings shed new light on the identification of dominant factors involved in the endocrine physiology of female reproduction.

Inhibition of checkpoint kinase prevents human oocyte apoptosis induced by chemotherapy and allows enhanced tumour chemotherapeutic efficacy.

STUDY QUESTION: Could inhibition of the checkpoint kinase (CHEK) pathway protect human oocytes and even enhance the anti-tumour effects, during chemotherapy? SUMMARY ANSWER: CHEK inhibitors prevented apoptosis of human oocytes induced by chemotherapy and even enhanced the anti-tumour effects. WHAT IS KNOWN ALREADY: CHEK inhibitors showed ovarian protective effects in mice during chemotherapy, while their role in human oocytes is unclear. STUDY DESIGN, SIZE, DURATION: This experimental study evaluated the ovarian reserve of young patients (120 patients) with cancer, exposed or not exposed to taxane and platinum (TP)-combined chemotherapy. Single RNA-sequencing analysis of human primordial oocytes from 10 patients was performed to explore the mechanism of oocyte apoptosis induced by TP chemotherapy. The damaging effects of paclitaxel (PTX) and cisplatin on human oocytes were also evaluated by culturing human ovaries in vitro. A new mouse model that combines human ovarian xenotransplantation and patient-derived tumour xenografts was developed to explore adjuvant therapies for ovarian protection. The mice were randomly allocated to four groups (10 mice for each group): control, cisplatin, cisplatin + CK1 (CHEK1 inhibitor, SCH 900776), and cisplatin + CK2 (CHEK2 inhibitor, BML277). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the prospective cohort study, human ovarian follicles were counted and serum AMH levels were evaluated. RNA-sequencing analysis was conducted, and staining for follicular damage (phosphorylated H2AX histone; γH2AX), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) assays and assessments of apoptotic biomarkers (western blot and immunofluorescence) were conducted in human ovaries. After the treatments, histological analysis was performed on human ovarian samples to investigate follicular populations, and oocyte damage was measured by γH2AX staining, BAX staining, and TUNEL assays. At the same time, the tumours were evaluated for volume, weight, and apoptosis levels. MAIN RESULTS AND THE ROLE OF CHANCE: Patients who received TP chemotherapy showed decreased ovarian reserves. Single RNA-sequencing analysis of human primordial oocytes indicated that TP chemotherapy induced apoptosis of human primordial oocytes by causing CHEK-mediated TAp63α phosphorylation. In vitro culture of human ovaries showed greater damaging effects on oocytes after cisplatin treatment compared with that after PTX treatment. Using the new animal model, CHEK1/2 inhibitors prevented the apoptosis of human oocytes induced by cisplatin and even enhanced its anti-tumour effects. This protective effect appeared to be mediated by inhibiting DNA damage via the CHEK-TAp63α pathway and by generation of anti-apoptotic signals in the oocytes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was a preclinical study performed with human ovarian samples, and clinical research is required for validation. WIDER IMPLICATIONS OF THE FINDINGS: These findings highlight the therapeutic potential of CHEK1/2 inhibitors as a complementary strategy for preserving fertility in female cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by the National Natural Science Foundation of China (nos. 82001514 and 81902669) and the Fundamental Research Funds for the Central Universities (2021yjsCXCY087). The authors declare no conflict of interest.

DDX04+ Stem Cells in the Ovaries of Postmenopausal Women: Existence and Differentiation Potential.

Ovarian aging is a pacemaker with multiple organ dysfunction. Recently, stem cells with the ability to generate new oocytes have been identified, which provides the possibility of stem cell therapy for ovarian aging. Several studies have revealed the existence of stem cells in the human postmenopausal ovary. In this study, we describe a new method using magnetic-activated cell sorting combined with differential adhesion to isolate DDX4+ stem cells from ovaries of postmenopausal women and show that the cells exhibit similar gene expression profiles and growth characteristics with primitive germ cells. Furthermore, the DDX4+ stem cells could enter the meiosis stage and differentiation into oocytes. The RNA-seq data of the differentiated oocytes shows that mitochondrial metabolism may play an important role in the oogenesis process of the DDX4+ stem cells. Through using the human ovarian cortical fragments transplantation model, we indicated that the GFP-DDX4+ stem cells differentiated into some GFP positive oocyte-like structure in vivo. Our study provided a new method for the isolation of DDX4+ stem cells from the ovaries of postmenopausal women and confirmed the ability of these stem cells to differentiate into oocytes.