Suicidal ideation and suicide attempts among students aged 12 to 24 after the lifting of COVID-19 restrictions in China: prevalence and associated factors.

Objective: To investigate the prevalence and associated factors of suicidal ideation and suicide attempts among adolescent and young adults in China from December 14, 2022 to February 28, 2023, when COVID-19 restrictions were lifted. Methods: Students in middle and high schools and colleges and universities in the province of Sichuan, China were asked to complete on-line cross-sectional surveys. Information was collected about sociodemographics, experiences related to the COVID-19 pandemic, suicidal ideation and suicide attempts. Participants also filled out the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 and the Social Support Rate Scale surveys. Factors associated with suicidal ideation or suicide attempts were explored using logistic regression. Results: Of the 82,873 respondents (aged 12 to 24 years), 21,292 (25.7%) reported having thought of suicide at least once in their lifetime, 10,382 (12.5%) reported having thought about suicide within the previous 12 months, and 1,123 (1.4%) reported having attempted it within the previous 12 months. Risk of lifetime suicidal ideation was higher among middle school students than among older students. Risk of suicidal ideation and risk of suicide attempts correlated directly with severity of symptoms of depression and anxiety, and inversely with level of social support. Greater risk of suicidal ideation and suicidal attempts was associated with: being female, living in an urban environment, attending a boarding school, currently being in love, having parents who divorced or remarried, having parents who exhibit non-authoritative parenting behavior, having higher family income, having been COVID-19 infected, having been quarantined for a long time, and being dissatisfied with one's education. Conclusions: Suicidal ideation and suicide attempts remain prevalent among young people in China. The potential associated factors identified in our study may be useful for targeting appropriate psychosocial interventions and developing mental health policies.

Leptin attenuates the osteogenic induction potential of BMP9 by increasing ß-catenin malonylation modification via Sirt5 down-regulation.

BMP9 has demonstrated significant osteogenic potential. In this study, we investigated the effect of Leptin on BMP9-induced osteogenic differentiation. Firstly, we found Leptin was decreased during BMP9-induced osteogenic differentiation and serum Leptin concentrations were increased in the ovariectomized (OVX) rats. Both in vitro and in vivo, exogenous expression of Leptin inhibited the process of osteogenic differentiation, whereas silencing Leptin enhanced. Exogenous Leptin could increase the malonylation of ß-catenin. However, BMP9 could increase the level of Sirt5 and subsequently decrease the malonylation of ß-catenin; the BMP9-induced osteogenic differentiation was inhibited by silencing Sirt5. These data suggested that Leptin can inhibit the BMP9-induced osteogenic differentiation, which may be mediated through reducing the activity of Wnt/ß-catenin signalling via down-regulating Sirt5 to increase the malonylation level of ß-catenin partly.

Clinical Observation and Cause Analysis of Perioperative Superior Cluneal Neuralgia in Vertebral Augmentation.

BACKGROUND: In our clinical practice, we observed that some osteoporotic vertebral compression fracture patients undergoing vertebral augmentation exhibited pain in the iliac crest region. This pain aligned with the diagnostic criteria for superior cluneal neuralgia (SCN) and affected treatment satisfaction. OBJECTIVE: This study aims to clinically observe patients undergoing vertebral augmentation in a hospital setting and analyze the etiology and risk factors associated with SCN. STUDY DESIGN: Retrospective cohort study. SETTING: Inpatient population of a single center. METHODS: We retrospectively analyzed clinical data from 630 patients who underwent vertebral augmentation in our hospital from March 2022 to March 2023. Fifty-two patients enrolled in the study experienced pain that met the diagnostic criteria for superior cluneal neuralgia during the perioperative period of the vertebral augmentation procedures. Those patients were divided into 2 subgroups according to the conditions involved in the occurrence of SCN: Group A (26 patients) had either no preoperative SCN but developed it postoperatively, or had preoperative SCN that worsened or did not alleviate postoperatively. Group B (26 patients) had preoperative SCN that was relieved postoperatively. Additionally, 52 consecutive patients in March 2022 to March 2023. who did not experience SCN during the perioperative period were selected as the control group (Group C). Variables such as surgical segment, age, height, weight, body mass index, duration of hospitalization, chronic low back pain (CLBP), duration of pain, anesthesia, surgical approach, fracture pattern, preoperative visual analog scale (pre-op VAS) score, intraoperative VAS score, one-day VAS score, one-month VAS score, lumbar sacral angle, and sacral tilt angle were statistically described and analyzed. RESULTS: In our hospital, the incidence of SCN during the perioperative period of vertebral augmentation procedures is 8.25% (52/630). Among all the segments of patients who developed SCN during the perioperative period, the L1 segment had the highest proportion, which was 29.03% and 35.14% in Groups A and B, respectively. Group B and Group C showed significant differences in duration of hospitalization (P = 0.012), pre-op VAS scores (P = 0.026), and CLBP (P < 0.001). Group A had significantly higher VAS scores preoperatively (P = 0.026) and intraoperatively (P = 0.004) and in CLBP (P = 0.001) than did Group C. LIMITATIONS: This is a retrospective study. Single-center noncontrolled studies may introduce selection bias. The small sample size in each group might have also led to bias. CONCLUSION: Perioperative SCN associated with vertebral augmentation is significantly correlated with preoperative VAS scores and CLBP. In addition, intraoperative VAS scores might be a factor contributing to the nonalleviation or exacerbation of postoperative SCN.

Comparison between intramedullary nail and conventional plate for displaced intra-articular calcaneal fractures: A meta-analysis.

OBJECTIVES: This study aimed to compare the efficacy and safety of the intramedullary nail and conventional plate for the treatment of displaced intra-articular calcaneal fractures from clinical comparative trials. MATERIALS AND METHODS: A comprehensive search of English databases was carried out in the Springer, PubMed, ScienceDirect, Web of Science, and Cochrane Library databases until September 2023. Studies on calcaneal fractures treated by an intramedullary nail or a plate were considered for inclusion. Endpoints included duration of operation, length of hospital stay, the Visual Analog Scale (VAS) score, postoperative functional score, radiological parameters, and complications. The mean difference (MD) and risk difference (RD) as the combined variables, as well as the 95% confidence intervals, (CIs) were calculated. RESULTS: Five retrospective controlled studies covering 473 feet at the one-year follow-up met the inclusion criteria. The meta-analysis demonstrated that there were significant differences in the duration of operation (MD: -10.81; 95% CI: -16.32, -5.31; p=0.0001), length of hospital stay (MD: -3.65; 95% CI: -4.35, -2.95; p<0.00001). No significant differences were found regarding postoperative American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale (MD: 0.36; 95% CI: -3.89, 4.61; p=0.87), VAS (MD: 1.95; 95% CI: -0.30, 4.21; p=0.09), or postoperative Böhler angle (MD: 0.94; 95% CI: -0.04, 1.92; p=0.06) between the two groups. The incidence of total complications (RD: -0.31; 95% CI: -0.46, -0.17; p<0.0001) and wound-healing complications (RD: -0.16; 95% CI: -0.30, -0.03; p=0.02) were lower in the intramedullary nail group. There were no significant differences in the incidences of revision surgery, implant removal, superficial wound infection, deep infection, and nonunion. CONCLUSION: Compared to conventional plates, the intramedullary nail showed a shorter duration of operation, reduced length of hospital stay, and fewer postoperative total complications and wound-healing complications in treating displaced intra-articular calcaneal fractures.

Unilateral Biplanar Screw-Rod Fixation Technique for the Treatment of Odontoid Fractures in Patients with Atlantoaxial Bone or Vascular Abnormalities.

OBJETIVE: This study aims to introduce the unilateral biplanar screw-rod fixation (UBSF) technique (a hybrid fixation technique: 2 sets of atlantoaxial screws were placed on the same side), which serves as a salvage method for traditional posterior atlantoaxial fixation. To summarize the indications of this technique and to assess its safety, feasibility, and clinical effectiveness in the treatment of odontoid fractures. METHODS: Patients with odontoid fractures were enrolled according to special criteria. Surgical duration and intraoperative blood loss were documented. Patients were followed up for a minimum of 12 months. X-ray and computerized tomography scans were conducted and reviewed at 1 day, and patients were asked to return for computerized tomography reviews at 3, 6, 9, and 12 months after surgery until fracture union. Recorded and compared the Neck Visual Analog Scale and Neck Disability Index presurgery and at 1 week and 12 months postsurgery. RESULTS: Between January 2016 and December 2022, our study enrolled 7 patients who were diagnosed with odontoid fractures accompanied by atlantoaxial bone or vascular abnormalities. All 7 patients underwent successful UBSF surgery, and no neurovascular injuries were recorded during surgery. Fracture union was observed in all patients, and the Neck Visual Analog Scale and Neck Disability Index scores improved significantly at 1 week and 12 months postoperative (P < 0.01). CONCLUSIONS: The UBSF technique has been demonstrated to be safe, feasible, and effective in treating odontoid fractures. In cases where the atlantoaxial bone or vascular structure exhibits abnormalities, it can function as a supplementary or alternative approach to the conventional posterior C1-2 fixation.

Differential pathogenic and molecular features in neurological infection of SARS-CoV-2 Omicron BA.5.2 and BA.2.75 and Delta.

The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global threat, exacerbated by the emergence of viral variants. Two variants of SARS-CoV-2, Omicron BA.2.75 and BA.5, led to global infection peaks between May 2022 and May 2023, yet their precise characteristics in pathogenesis are not well understood. In this study, we compared these two Omicron sublineages with the previously dominant Delta variant using a human angiotensin-converting enzyme 2 knock-in mouse model. As expected, Delta exhibited higher viral replication in the lung and brain than both Omicron sublineages which induced less severe lung damage and immune activation. In contrast, the Omicron variants especially BA.5.2 showed a propensity for cellular proliferation and developmental pathways. Both Delta and BA.5.2 variants, but not BA.2.75, led to decreased pulmonary lymphocytes, indicating differential adaptive immune response. Neuroinvasiveness was shared with all strains, accompanied by vascular abnormalities, synaptic injury, and loss of astrocytes. However, Immunostaining assays and transcriptomic analysis showed that BA.5.2 displayed stronger immune suppression and neurodegeneration, while BA.2.75 exhibited more similar characteristics to Delta in the cortex. Such differentially infectious features could be partially attributed to the weakened interaction between Omicron Spike protein and host proteomes decoded via co-immunoprecipitation followed by mass spectrometry in neuronal cells. Our present study supports attenuated replication and pathogenicity of Omicron variants but also highlights their newly infectious characteristics in the lung and brain, especially with BA.5.2 demonstrating enhanced immune evasion and neural damage that could exacerbate neurological sequelae.

The mutual overlapping impact of stress and infection on mental health problems in adolescents and youths during and after COVID-19 pandemic in China.

BACKGROUND: It is unclear about the mutual impact of COVID-19 related psychological stress and infection on mental health of adolescent and youth students. This study aimed to explore the mutual impact of COVID-19 related psychological stress and infection on mental health problems among students. METHODS: This study was conducted from December 14, 2022 to February 28, 2023 in Sichuan, China. Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, PTSD Checklist for DSM-5, Insomnia Severity Index, and Internet Addiction Test were used. Participants were grouped by COVID-19 infection and psychological stress level. The differences among groups were compared, and logistic regression analysis was used to investigate risk factors for depression, anxiety, PTSD and insomnia among groups. RESULTS: Of 90,118 participants, 82,873 (92.0 %) finished the questionnaires and were included in the study. Of 82,873 participants, 33,314 (40.2 %) reported to be infected with COVID-19. Participants had depression symptoms (38.1 %), anxiety symptoms (31.8 %), PTSD (33.9 %), insomnia (34.0 %), and internet addiction (60.3 %). Compared with participants uninfected with low psychological stress level, the risk for symptoms of depression, anxiety, PTSD and insomnia increased by 9.6 %, 12.3 %, 6.6 %, and 12.0 % in participants infected with low psychological stress level (p < 0.001), 106.8 %, 125.9 %, 125.2 %, and 95.7 % in participants uninfected with high psychological stress level (p < 0.001), and 147.3 %, 161.1 %, 158.7 %, and 141.0 % in participants infected with high psychological stress level (p < 0.001). LIMITATION: This study is a cross-sectional design, and no causal associations should be inferred. Infection status was based on self-report of participants with infectious symptoms. CONCLUSION: COVID-19 related psychological stress and infection per se have mutually overlapping impacts on mental health problems among students. Further health policies and psychosocial interventions should be developed to reduce mutually overlapping impact and improve the long-term mental health among students.

Effects of internet addiction and academic satisfaction on mental health among college students after the lifting of COVID-19 restrictions in China.

Background: Internet addiction (IA) among students, worsened by Coronavirus disease 2019 (COVID-19) pandemic, has become a social problem with the digitalization of school learning and many aspects of daily life. However, few studies on IA have been conducted among students after the lifting of COVID-19 restrictions in China. Method: This large-sample, cross-sectional, online survey was conducted to explore the characteristics of IA and the association among IA, academic satisfaction, and mental health problems from December 14, 2022 to February 28, 2023 in Sichuan, China. All participants (N = 22,605) were students in colleges and universities, recruited via their teachers and professors. Results: Of all the participants, 14,921 (66.0%) participants had IA. Participants with IA were more likely to have depression symptom, anxiety symptom, insomnia, and lifetime suicidal ideation. In addition, participants with severe IA had significantly higher rates of mental health problems (e.g., depression, anxiety, insomnia, and suicidal ideation) than those with mild IA. A significant IA-by-academic satisfactory-interaction on mental health was identified: participants with higher level of IA showed particularly severe symptom of depression, anxiety and insomnia when affected by low satisfactory of academy (p < 0.001). Conclusion: This study reveals that IA has a significantly negative impact on mental health among college students after the lifting of COVID-19 restrictions in China. IA and academic satisfaction have interactive impacts on mental health problems among students. Further educational and health policies and psychosocial interventions should be developed to reduce IA and enhance academic satisfaction for improving students' mental health.

Academic performance and mental health among Chinese middle and high school students after the lifting of COVID-19 restrictions.

Background: Although the COVID-19 pandemic has greatly changed the way students studied, it is still unknown about the impact of the COVID-19 pandemic on students' academic performance and mental health. Objective: To explore the academic performance and mental health status of middle and high school students after the lifting of COVID-19 restrictions in China. Methods: An online survey was conducted in Sichuan province, China from Dec 14, 2022 to Feb 28, 2023. All participants were students in middle and high schools, recruited via their teachers. The general information, COVID-19-related information, and academic performance were collected. The Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Internet Addiction Test (IAT) were used to assess the mental health problems. Results: Of 60,268 participants, 36,247 (60.2%) middle and high school students reported that their studies were affected by the COVID-19 pandemic, and 24,864 (41.2%) reported that their academic performance had worsened. The prevalence of depression and anxiety symptoms was 38.4 and 32.7%, respectively. There was a significant association between academic performance change and mental health problems. The logistic regression analysis showed that improved academic performance was a protective factor for depression, and declined academic performance was a risk factor for depression and anxiety. Being COVID-19 infected, family members being infected, with quarantine experience, and with COVID-19-related stigma were risk factors for depression and anxiety. Conclusion: Academic studies and mental health status of middle and high school students in Sichuan, China have been negatively impacted by the COVID-19 pandemic, even after the lifting of COVID-19 restrictions. Students' academic performance, academic concerns, and mental health status should be considered for educational policymakers and institutions to improve students' academic studies and mental well-being.

Nomogram for predicting coronary artery lesions in patients with Kawasaki disease.

BACKGROUND: Coronary artery lesions are the most important complications of Kawasaki disease. Approximately 25-30% of untreated patients develop coronary artery disease, which can lead to long-term cardiovascular sequelae. AIM: The aim of this study is to evaluate the risk factors for coronary artery lesions in Kawasaki disease and to construct a nomogram for predicting the likelihood of developing such lesions. METHODS: Data from 599 patients between January 2012 and June 2020 were reviewed retrospectively. Patients were randomly assigned to the training set (n = 450) and the validation set (n = 149). A comparison of clinical features and laboratory data was performed, followed by multivariate logistic regression analysis to identify independent risk factors and develop the nomogram. The predictive efficiency of the nomogram was evaluated using the calibration curve, area under the receiver operating characteristic curve (AUC), C-index, and decision curve analysis (DCA). RESULTS: Intravenous immunoglobulin (IVIG) resistance, delayed IVIG treatment, C-reactive protein, and neutrophil/lymphocyte ratio were identified as independent risk factors for the development of coronary artery lesions. The nomogram was constructed based on these four variables. The calibration curve of the nomogram showed a high degree of agreement between the predicted probability and the actual probability. The AUC of the nomogram in the training and validation set was 0.790 and 0.711, respectively. In addition, DCA revealed that the nomogram provided a significant net benefit, further supporting its clinical utility. CONCLUSIONS: The constructed nomogram demonstrates a strong and reliable performance in predicting coronary artery lesions, which enables clinicians to make timely and tailored clinical decisions.

cdh23 affects congenital hearing loss through regulating purine metabolism.

Introduction: The pathogenic gene CDH23 plays a pivotal role in tip links, which is indispensable for mechanoelectrical transduction in the hair cells. However, the underlying molecular mechanism and signal regulatory networks that influence deafness is still largely unknown. Methods: In this study, a congenital deafness family, whole exome sequencing revealed a new mutation in the pathogenic gene CDH23, subsequently; the mutation has been validated using Sanger sequencing method. Then CRISPR/Cas9 technology was employed to knockout zebrafish cdh23 gene. Startle response experiment was used to compare with wide-type, the response to sound stimulation between wide-type and cdh23-/-. To further illustrate the molecular mechanisms underlying congenital deafness, comparative transcriptomic profiling and multiple bioinformatics analyses were performed. Results: The YO-PRO-1 assay result showed that in cdh23 deficient embryos, the YO-PRO-1 signal in inner ear and lateral line neuromast hair cells were completely lost. Startle response experiment showed that compared with wide-type, the response to sound stimulation decreased significantly in cdh23 mutant larvae. Comparative transcriptomic showed that the candidate genes such as atp1b2b and myof could affect hearing by regulating ATP production and purine metabolism in a synergetic way with cdh23. RT-qPCR results further confirmed the transcriptomics results. Further compensatory experiment showed that ATP treated cdh23-/- embryos can partially recover the mutant phenotype. Conclusion: In conclusion, our study may shed light on deciphering the principal mechanism and provide a potential therapeutic method for congenital hearing loss under the condition of CDH23 mutation.

Drying kinetics and quality dynamics of ultrasound-assisted dried selenium-enriched germinated black rice.

Black rice is a functional food due to its higher protein, fiber, iron, antioxidant compounds, and other health benefits than traditional rice. The ultrasonic (US) pretreatments (10, 20, and 50 min) followed by hot-air drying (50, 60, and 70 °C) were applied to study the drying kinetics, mathematical modeling, thermodynamics, microstructure, bioactive profile, volatile compounds and to lock the nutritional composition of selenium-enriched germinated black rice (SeGBR). Ultrasonic-treated samples exhibited a 20.5% reduced drying time than control ones. The Hii model accurately describes the drying kinetics of SeGBR with the highest R2 (>0.997 to 1.00) among the fifteen studied models. The activation energy values in US-SeGBR varied from 3.97 to 13.90 kJ/mol, while the specific energy consumption ranged from 6.45 to 12.32 kWh/kg, which was lower than untreated. The obtained thermodynamic attributes of dried black rice revealed that the process was endothermic and non-spontaneous. Gallic acid, kaempferol, and cyanidin 3-glucoside were present in high concentrations in phenolics, flavonoids, and anthocyanins, respectively. The HS-SPME-GC-MS investigation detected and quantified 55 volatile compounds. The US-treated SeGBR had more volatile compounds, which may stimulate the release of more flavorful substances. The scanning electronic micrograph shows that the US-treated samples absorbed high water through several micro-cavities. Selenium concentration was significantly higher in US-treated samples at 50 °C than in control samples. In conclusion, ultrasound-assisted hot-air drying accelerated drying and improved SeGBR quality, which is crucial for the food industry and global promotion of this healthiest rice variety.

The anatomic study and surgical technique for canal decompression with "pedicle-plasty" strategy in lumbar burst fractures with pedicle rupture.

In the treatment of lumbar burst fractures with nerve injury, fusion is often required to rebuild spinal stability, but it can lead to the loss of motor units and increase the occurrence of adjacent segment diseases. Thus, a novel approach of lumbar canal decompression with "pedicle-plasty" strategy (DDP) was needed in clincal treatment. Firstly, image measurement analysis, the images of 60 patients with lumbar spine CT examinations were selected to measure osteotomy angle (OA), distance from the intersection of osteotomy plane and skin to the posterior midline (DM),transverse length of the osteotomy plane (TLOP), and sagittal diameter of the outer edge of superior articular process (SD). Secondary, cadaver study, distance between the intermuscular space and midline (DMSM), anterior and posterior diameters of the decompression (APDD), and lateral traction distance of the lumbosacral plexus (TDLP) were measured on 10 cadaveric specimens. Finally, procedure of DDP was demonstrated on cadaver specimens. OA ranged from 27.68°+4.59° to 38.34°+5.97°, DM ranged from 43.44+6.29 to 68.33+12.06 mm, TLOP ranged from 16.84+2.19 to 19.64+2.36 mm, and SD ranged from 22.49+1.74 to 25.53+2.21 mm. DMSM ranged from 45.53+5.73 to 65.46+6.43 mm. APDD were between 10.51+3.59 and 12.12+4.54 mm, and TDLP were between 3.28+0.81 and 6.27+0.62 mm.DDP was successfully performed on cadaveric specimens. DDP, as a novel approach of decompression of burst fractures with pedicle rupture, can fully relieve the occupation and at the same time preserve the spinal motor unit because of no resection of intervertebral discs and no destruction of facet joints,and has certain developmental significance.

Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility.

DNA double-strand breaks (DSBs) are functionally linked to genomic instability in spermatocytes and to male infertility. The heavy metal cadmium (Cd) is known to induce DNA damage in spermatocytes by unknown mechanisms. Here, we showed that Cd ions impaired the canonical non-homologous end-joining (NHEJ) repair pathway, but not the homologous recombination (HR) repair pathway, through stimulation of Ser2056 and Thr2609 phosphorylation of DNA-PKcs at DSB sites. Hyper-phosphorylation of DNA-PKcs led to its premature dissociation from DNA ends and the Ku complex, preventing recruitment of processing enzymes and further ligation of DNA ends. Specifically, this cascade was initiated by the loss of PP5 phosphatase activity, which results from the dissociation of PP5 from its activating ions (Mn), that is antagonized by Cd ions through a competitive mechanism. In accordance, in a mouse model Cd-induced genomic instability and consequential male reproductive dysfunction were effectively reversed by a high dosage of Mn ions. Together, our findings corroborate a protein phosphorylation-mediated genomic instability pathway in spermatocytes that is triggered by exchange of heavy metal ions.

Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

A phase III randomized, double-blind, placebo-controlled trial of the denosumab biosimilar QL1206 in postmenopausal Chinese women with osteoporosis and high fracture risk.

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.

Encapsulation of Platinum Prodrugs into PC7A Polymeric Nanoparticles Combined with Immune Checkpoint Inhibitors for Therapeutically Enhanced Multimodal Chemotherapy and Immunotherapy by Activation of the STING Pathway.

Tumor immunotherapy has emerged as one of the most promising therapeutic methods to treat cancer. Despite its clinical application, the immunosuppressive tumor microenvironment compromises the therapeutic efficiency of this technique. To overcome this limitation, many research efforts have been devoted to the development of agents that reprogram the immunosuppressive tumor microenvironment through novel mechanisms. Over the last decade, compounds that intervene through the immunogenic stimulator of interferon genes (STING) pathway have emerged with potential for clinical development. Herein, the encapsulation of chemotherapeutic platinum complexes with a polymer with a cyclic seven-membered ring (PC7A)-based polymer into pH-responsive nanoparticles for multimodal therapeutically enhanced chemotherapy and immunotherapy is presented. This study represents the first nanomaterial with a dual activation mechanism of the STING pathway through DNA fragmentation as well as PC7A binding. The combination of these nanoparticles with immune checkpoint inhibitors demonstrates to nearly fully eradicate a colorectal tumor inside the mouse model by chemotherapy and immunotherapy using the STING pathway.

Feedforward loop between IMP1 and YAP/TAZ promotes tumorigenesis and malignant progression in glioblastoma.

YAP/TAZ have been identified as master regulators in malignant phenotypes of glioblastoma (GBM); however, YAP/TAZ transcriptional disruptor in GBM treatment remains ineffective. Whether post-transcriptional dysregulation of YAP/TAZ improves GBM outcome is currently unknown. Here, we report that insulin-like growth factor 2 (IGF2) mRNA-binding protein 1 (IGF2BP1 or IMP1) is upregulated in mesenchymal GBM compared with proneural GBM and correlates with worse patient outcome. Overexpression of IMP1 in proneural glioma stem-like cells (GSCs) promotes while IMP1 knockdown in mesenchymal GSCs attenuates tumorigenesis and mesenchymal signatures. IMP1 binds to and stabilizes m6A-YAP mRNA, leading to activation of YAP/TAZ signaling, depending on its m6A recognition and binding domain. On the other hand, TAZ functions as enhancer for IMP1 expression. Collectively, our data reveal a feedforward loop between IMP1 and YAP/TAZ maintaining GBM/GSC tumorigenesis and malignant progression and a promising molecular target in GBM.