BAP1 regulates HSF1 activity and cancer immunity in pancreatic cancer.

BACKGROUND: The vast majority of pancreatic cancers have been shown to be insensitive to single-agent immunotherapy. Exploring the mechanisms of immune resistance and implementing combination therapeutic strategies are crucial for PDAC patients to derive benefits from immunotherapy. Deletion of BAP1 occurs in approximately 27% of PDAC patients and is significantly correlated with poor prognosis, but the mechanism how BAP1-deletion compromises survival of patients with PDAC remain a puzzle. METHODS: Bap1 knock-out KPC (KrasG12D/+; LSLTrp53R172H/+; Pdx-1-Cre) mice and control KPC mice, syngeneic xenograft models were applied to analysis the correlation between BAP1 and immune therapy response in PDAC. Immunoprecipitation, RT-qPCR, luciferase and transcriptome analysis were combined to revealing potential mechanisms. Syngeneic xenograft models and flow cytometry were constructed to examine the efficacy of the inhibitor of SIRT1 and its synergistic effect with anti-PD-1 therapy. RESULT: The deletion of BAP1 contributes to the resistance to immunotherapy in PDAC, which is attributable to BAP1's suppression of the transcriptional activity of HSF1. Specifically, BAP1 competes with SIRT1 for binding to the K80 acetylated HSF1. The BAP1-HSF1 interaction preserves the acetylation of HSF1-K80 and promotes HSF1-HSP70 interaction, facilitating HSF1 oligomerization and detachment from the chromatin. Furthermore, we demonstrate that the targeted inhibition of SIRT1 reverses the immune insensitivity in BAP1 deficient PDAC mouse model. CONCLUSION: Our study elucidates an unrevealed mechanism by which BAP1 regulates immune therapy response in PDAC via HSF1 inhibition, and providing promising therapeutic strategies to address immune insensitivity in BAP1-deficient PDAC.

Lumbar osteopathic manipulative treatment can improve KOA symptoms: short-term efficacy observation and mechanism analysis.

Background: Manipulative treatment can effectively improve knee pain and function, but no previous studies have shown that lumbar osteopathic manipulative treatment can improve knee symptoms. To explore the influence of lumbar manipulation on KOA and analyze its principlerelationship between coronal position of lumbar spine and KOA. Methods: Patients were divided into OMT group and DT group according to treatment. WOMAC scores were compared between the two groups, and X-ray examinations before and after treatment were performed in OMT group to analyze the imaging changes. Results: Both OMT group and DT group showed significant improvement in WOMAC score after treatment, and the improvement in OMT group was better than that in DT group. After OMT treatment, cTMI(P = 0.034), mL-SOD (P < 0.001), mΔL-KOD (P = 0.001), LL (P = 0.036), and FTA(P = 0.026) were significantly changed. Conclusion: Compared with drug therapy, lumbar manipulation can better improve WOMAC scores in KOA patients. It relives symptoms by loosening muscles and correcting small joint disorders to improve local knee alignment.

[Effect of oblique insertion at ashi point with long needle on joint function in female patients with knee osteoarthritis of early and middle stages].

OBJECTIVE: To compare the improvement of joint function in female patients with early-middle-stage knee osteoarthritis (KOA) treated by oblique insertion at ashi point with long needle and oral celecoxib capsule. METHODS: A total of 105 female patients with early-middle-stage KOA were randomly divided into an observation group (65 cases, 6 cases dropped out, 3 cases were discontinued) and a control group (40 cases, 6 cases dropped out, 2 cases were discontinued). Patients in the observation group were treated with oblique insertion at ashi point (hard knots of quadriceps femoris, hamstring muscle, popliteal muscle, etc.) with long needle, once every other 3 days, twice a week, for a total of 2 weeks. Patients in the control group were treated with oral celecoxib capsules, 0.2 g each time, once a day for 2 weeks. Both groups started functional exercise after 2 weeks of treatment. The joint function score of Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and pain visual analogue scale (VAS) score of the two groups were observed before and after treatment and after 6 weeks of treatment completion (follow-up), the 12-item short-form health survey (SF-12) score was compared between the two groups before treatment and in follow-up, and the safety of the two groups was evaluated. RESULTS: After treatment and during the follow-up, the joint function scores of WOMAC and VAS scores of the two groups were lower than those before treatment (P<0.05). During the follow-up, the joint function scores of WOMAC and VAS scores were lower than those after treatment (P<0.05), and the SF-12 scores were higher than those before treatment (P<0.05) in the two groups. After treatment, the joint function score of WOMAC of the observation group was lower and the VAS score was higher than those of the control group (P<0.001, P<0.01). During the follow-up, the SF-12 score of the observation group was higher than that of the control group (P<0.05). No serious adverse reactions occurred in both groups. CONCLUSION: The treatment of oblique insertion at ashi point with long needle can improve the knee joint function and quality of life of female patients with early-middle-staqe KOA, which is better than oral celecoxib capsule.

PER2 binding to PDK1 enhances the cisplatin sensitivity of oral squamous cell carcinoma through inhibition of the AKT/mTOR pathway.

Cisplatin (CDDP) is a cornerstone chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC) and many solid cancers. However, the mechanisms underlying tumor resistance to CDDP obscure the enhancement of its therapeutic efficacy. In this study, we unveil diminished expression of the biological clock gene PER2 in OSCC, negatively correlated with the expression of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). The overexpression of PER2 suppressed MDR1 and MRP1 expression and increased intracellular CDDP levels and DNA damage, thereby bolstering OSCC cell sensitivity to CDDP. In vivo tumorigenic assays corroborated that PER2 overexpression notably increased OSCC sensitivity to CDDP, augmenting the suppression of OSCC tumorigenesis. Co-immunoprecipitation, GST pull-down, and cycloheximide tracking assays revealed that PER2, via its C-terminal domain, bound to and diminishes PDK1 stability. The degradation of PDK1 was further dependent on the suppression of the AKT/mTOR pathway to enhance the sensitivity of OSCC cells to CDDP. Our study supports PER2 as a target for improving CDDP sensitivity in OSCC, and the combination of PER2 and CDDP is a novel strategy with potential clinical therapeutic value.

Correlation Between Coronal Position Sequence of Lumbar and WOMAC Score in Knee Osteoarthritis (KOA) in Standard Standing Position.

INTRODUCTION: Sagittal sequences of the spine have been shown to correlate with knee osteoarthritis (KOA), but coronal sequences and KOA have never been studied before. The study required patients to use a standard standing posture and aimed to explore the relationship between coronal position of lumbar spine and WOMAC score in KOA. METHODS: This is a cross-sectional observational study. Data on a total of 268 patients with KOA were collected. Patients were photographed in a standard standing position and lumbar-sacrum offset distance (L-SOD) and lumbar-knee offset distance (ΔL-KOD) were calculated. Patients were then divided into different groups according to different critical values and differences were compared. RESULTS: In the L-SOD of L1-3, WOMAC function (P = 0.021, P = 0.032, P = 0.001) and total score (P = 0.039, P = 0.034, P < 0.001) were different. In the L-SOD of L3-4, WOMAC pain score were different (P = 0.001, P = 0.032). At a cutoff of 13 mm, ΔL-KOD of L1-2 showed significant differences in pain part (P = 0.025, P = 0.039) and total score (P = 0.036, P = 0.050). There were significant differences in pain (P = 0.023, P = 0.027, P = 0.022), function (P = 0.048, P = 0.038, P = 0.047), and total score (P = 0.030, P = 0.027, P = 0.029) of L3-5. In the 18-mm cutoff group, only L1 and L2 have differences in the pain part (P = 0.050, P = 0.038). CONCLUSION: Coronal balance of the lumbar spine is associated with knee pain and function. The pelvis plays an important role in maintaining the coronal balance. Both the lumbar spine and the knee joint should be considered when developing the surgical strategy.

As a result of population aging, the number of patients suffering from both knee osteoarthritis (KOA) and degenerative diseases of the lumbar spine is increasing. It has been reported that patients with KOA have less symptomatic recovery after lumbar surgery, and that patients with lumbar degenerative disease have less symptomatic improvement after knee surgery than those without lumbar disease. So the knee and lumbar must be interacting in some way. Previous studies have confirmed the correlation between lumbar sagittal position sequence and KOA. However, no studies have been conducted on coronal sequences and KOA of the lumbar spine. We believe that it is because patients are required to stand naturally when taking coronal x-rays, and natural standing will lead to individual differences in the distance between the feet of patients, thereby preventing analysis. In our study, for the first time, we used a uniform stance to avoid this effect. The advantage of uniform stance is that individual differences can be excluded, and the same patient can be compared before and after treatment (because the natural stance of the patient's feet will be different before and after treatment), which is greatly conducive to the study. Our research found that the offset of the lumbar spine in the coronal position and the distance between the central vertical line of the lumbar spine and the bilateral knee joint are significantly correlated with knee pain and function. This may have some guiding significance for lumbar and knee surgery. For lumbar surgery (such as degenerative scoliosis), previous studies have suggested that short segment fixation is sufficient for patients with small Cobb angle. However, according to our conclusion, this may cause accelerated knee joint degeneration in the patient's later stages, which requires the surgeon to comprehensively evaluate the condition of the patient's knee and lumbar spine, and then formulate surgical strategies. The same is true for knee surgery: previous studies have shown no significant correlation between knee deformity and pain. Therefore, for patients with knee deformity and accompanying pain, knee surgery may not be the best choice, and it is more important to correct the deviation of the spine.

Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.

BACKGROUND: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression.

BACKGROUND: Programmed death-ligand 1 (PD-L1) contributes to the immune escape of tumor cells and is a critical target for antitumor immunotherapy. However, the molecular mechanisms regulating PD-L1 expression remain unclear, hindering the development of effective therapies. Here we investigate the role and molecular mechanism of the core clock gene Period2 (PER2) in regulating PD-L1 expression and its role in the combination therapy of oral squamous cell carcinoma (OSCC). METHODS: Quantitative real-time PCR, western blotting or immunohistochemistry to detect expression of PER2 and PD-L1 in OSCC tissues and cells. Overexpression and knockdown of PER2 detects the function of PER2. Bioinformatics, immunoprecipitation, GST pull-down, CHX chase assay and western blot and strip to detect the mechanism of PER2 regulation for PD-L1. A humanized immune reconstitution subcutaneous xenograft mouse model was established to investigate the combination therapy efficacy. RESULTS: In OSCC tissues and cells, PER2 expression was reduced and PD-L1 expression was increased, the expression of PER2 was significantly negatively correlated with PD-L1. In vitro and in vivo experiments demonstrated that PER2 inhibited PD-L1 expression and enhanced T-cell-mediated OSCC cell killing by suppressing the IKK/NF-κB pathway. Mechanistically, PER2 binds to heat shock protein 90 (HSP90) through the PAS1 domain and reduces the interaction of HSP90 with inhibitors of kappa B kinase (IKKs), promoting the ubiquitination of IKKα/ß and p65 nuclear translocation to inhibit IKK/NF-κB pathway, thereby suppressing PD-L1 expression. In humanized immune reconstitution subcutaneous xenograft mouse model, it was demonstrated that PER2 targeting combined with anti-PD-L1 treatment improved the inhibition of OSCC growth by promoting CD8+ T-cell infiltration into the tumor. CONCLUSIONS: Our findings reveal the role and mechanism of PD-L1 regulation by PER2 and support the potential clinical application of PER2 targeting in combination with anti-PD-L1 in OSCC immunotherapy.

The biological clock gene PER1 affects the development of oral squamous cell carcinoma by altering the circadian rhythms of cell proliferation and apoptosis.

Circadian rhythms expressed by the biological clock gene PER1 are aberrantly altered in a variety of tumor cells, including oral squamous cell carcinoma (OSCC); however, their functions and mechanisms are unclear. Here, we found that compared with normal oral epithelial HOK cells, OSCC cells showed altered circadian rhythm characteristics of proliferation, apoptosis and PER1 expression, exhibiting abnormal changes in the 3 dimensions of mesor, amplitude and acrophase. It was further found that in OSCC cells overexpressing PER1 (OE-PER1-SCC15), the circadian rhythm characteristics of cell proliferation, apoptosis, p-AKT and p-mTOR expression were abnormally altered. After adding the AKT activator SC79 to OE-PER1-SCC15 cells, the circadian rhythm characteristics of cell proliferation, apoptosis and p-AKT and p-mTOR expression were altered in opposite ways. In vivo tumorigenic assays demonstrated that overexpression of PER1 inhibited OSCC growth. The circadian rhythm characteristics of cell proliferation and apoptosis, PER1, p-AKT and p-mTOR expression were altered similarly to those observed in vitro. Our findings demonstrate for the first time that PER1 regulates the circadian rhythm of OSCC cell proliferation and apoptosis by altering the circadian rhythm characteristics of the AKT/mTOR pathway. The results have the potential to provide a new strategy for circadian rhythm-based treatment of OSCC.

Prevalence of depression symptoms and its influencing factors among pregnant women in late pregnancy in urban areas of Hengyang City, Hunan Province, China: a cross-sectional study.

OBJECTIVES: To evaluate the prevalence of depressive symptoms and its influencing factors in late pregnancy. DESIGN: Cross-sectional study. SETTING: Fourteen community in urban areas of Hengyang City. PARTICIPANTS: The study conducted from July to October 2019, and surveyed 813 women in late pregnancy who lived in urban areas of Hengyang for more than 6 months, signed an informed consent and were without cognitive disorders, severe mental illnesses or other serious diseases. MEASURES: Perinatal depression symptoms were evaluated using the Patient Health Questionnaire-9, and perinatal anxiety symptoms were evaluated using the Generalised Anxiety Disorder-7 Scale. Sociodemographic variables, obstetric characteristics, lifestyle behaviours, family factors, social support, sleep quality and self-efficacy were obtained through structured questionnaires. RESULTS: The prevalence of depression symptoms among pregnant women in late pregnancy was 9.2% (95% CI 7.2%-11.2%). Protective factor: age between 25 and 29 years (OR=0.398; 95% CI 0.16-0.991). RISK FACTORS: a normal relationship with her mother-in-law (OR=5.309; 95% CI 1.122-4.184), artificial insemination (OR=4.339; 95% CI 1.492-12.623), no exercise during pregnancy (OR=2.666; 95% CI 1.177-6.039), low self-efficacy (OR=4.253; 95% CI 1.518-11.916), low social support (OR=2.371; 95% CI 1.206-4.661), poor sleep quality (OR=2.134; 95% CI 1.131-4.027), existence of anxiety symptoms (OR=17.654; 95% CI 8.494-36.689). CONCLUSION: The prevalence of depression symptoms is lower than that in developing countries, but due to the large population base of China, the problem should still be taken seriously. To prevent mental disorders of pregnant women, early screening for mental disorders, promotion of healthy lifestyles, mental healthcare during pregnancy and improved family and social support should be implemented during pregnancy nursing.

Association between family functions and antenatal depression symptoms: a cross-sectional study among pregnant women in urban communities of Hengyang city, China.

OBJECTIVE: To explore the prevalence of depressive symptoms among women in late pregnancy, and assess mediating effect of self-efficacy in the association between family functions and the antenatal depressive symptoms. DESIGN: Community-based, cross-sectional study was conducted among women during the third trimester of pregnancy. SETTING: This study was conducted among pregnant women registered at community health service centres of urban Hengyang City, China from July to October 2019. PARTICIPANTS: 813 people were selected from 14 communities by multi-staged cluster random sampling method. MAIN OUTCOME MEASURES: The Family Adaptation Partnership Growth Affection and Resolve Index, the General Self-efficacy Scale and Patient Health Questionnaire were used to access family functions, self-efficacy and antenatal depression symptoms, respectively. RESULTS: In this study, 9.2% pregnant women reported the symptoms of antenatal depression (95 CI% 7.2% to 11.2%). After adjustment, the results showed that severe family dysfunction (adjusted OR, AOR 3.67; 95% CI 1.88 to 7.14) and low level of self-efficacy (AOR 3.16; 95% CI 1.37 to 7.27) were associated with antenatal depressive symptoms (p<0.05). Furthermore, self-efficacy level partially mediated the association between family functions and antenatal depressive symptoms(ß=-0.05, 95% CI -0.07 to -0.03, p<0.05) and the mediating effect accounted for 17.09% of the total effect. CONCLUSIONS: This study reported 9.2% positive rates of antenatal depression symptoms among women in the third trimester of pregnancy in Hengyang city, China. The mediating effect of self-efficacy on the association between family functions and antenatal depression symptoms among women in the third trimester of pregnancy was found in this study, which provide a theoretical basis to maternal and child health personnel to identify high-risk pregnant women and take targeted intervention for them.

The prevalence of domestic violence and its association with family factors: a cross-sectional study among pregnant women in urban communities of Hengyang City, China.

BACKGROUND: With the increased vulnerability during pregnancy, domestic violence (DV) is a serious threat to the physical and mental health of pregnant women, making it a significant issue in public health initiatives. In China, family is of great significance to pregnant women, but few scholars have focused specifically on the relationship between the family factors of pregnant women and DV. This study aimed to explore the prevalence and association between family factors and DV among women in late pregnancy, to provide evidence for the prevention of domestic violence during pregnancy. METHODS: A cross-sectional survey was conducted from July-October, 2019 among pregnant women in urban communities of Hengyang City, Hunan Province, China. A total of 813 participants were included by a multi-staged cluster random sampling method. DV was assessed by the Abuse Assessment Screen Questionnaire (AAS). A multivariate binary logistic regression model was used to evaluate the relationship between family factors and DV. RESULTS: Ultimately, 127 (15.62%) participants were identified as victims of DV. After adjustment, the potential risk factors of DV were tensions between their mother-in-law and other family members (OR: 2.85; 95% CI: 1.29 to 6.30 and OR: 3.30; 95% CI: 1.57 to 6.93), medium household debt (OR: 2.17; 95% CI: 1.18 to 4.00), middle and low family APGARI (OR: 2.01; 95% CI: 1.30 to 3.13 and OR: 4.01; 95% CI: 2.09 to 7.69). CONCLUSIONS: In summary, women in late pregnancy were at higher risk of DV in the family with tensions, medium household debt and family dysfunction, which may help medical personnel intervene in cases of domestic violence against pregnant women in a reasonable and timely manner.