Deep ultraviolet laser at 223.8†nm with adjustable repetition rate and narrow pulse width.

We presented the first, to our knowledge, demonstration of an ultraviolet (UV) laser at 223.8 nm by six-harmonic generation of an electro-optic Q-switched cavity dumping 1342 nm Nd:YVO4 laser. It offers high power, constant short pulse duration, and adjustable pulse repetition rate. The pulse duration is independent of the pump power and repetition rate compared to classical Q-switched oscillators. The output efficiency of the UV laser is optimized by adjusting the focusing lens. With the incident pump power of 30 W, an maximum average output power of 249 mW was obtained at 13 kHz. The pulse width maintained 3.4-3.5 ns from 5 to 20 kHz. The maximum pulse energy of 28.1 µJ was obtained at 5 kHz, and the corresponding peak power was up to 8.1 kW.

Ni-B-PTFE Nanocomposite Co-Deposition on the Surface of 2A12 Aluminum Alloy.

The spinning cup, a crucial component of textile equipment, relies heavily on 2A12 aluminum alloy as its primary raw material. Commonly, electroplating and chemical nickel-phosphorus (Ni-P) plating are employed to improve the surface characteristics of the object. Nevertheless, due to the growing expectations for the performance of aluminum alloys, the hardness and wear resistance of Ni-P coatings are no longer sufficient to fulfill industry standards. This study primarily focuses on the synthesis of Ni-B-PTFE nanocomposite chemical plating and its effectiveness when applied to the surface of 2A12 aluminum alloy. We examine the impact of the composition of the plating solution, process parameters, and various other factors on the pace at which the coating is deposited, the hardness of the surface, and other indicators of the coating. The research findings indicate that the composite co-deposited coating achieves its optimal surface morphology when the following conditions are met: a nickel chloride concentration of 30 g/L, an ethylenediamine concentration of 70 mL, a sodium borohydride concentration of 0.6 g/L, a sodium hydroxide concentration of 90 g/L, a lead nitrate concentration of 30 mL, a pH value of 12, a temperature of 90 °C, and a PTFE concentration of 10 mL/L. The coating exhibits consistency, density, a smooth surface, and an absence of noticeable pores or fissures. The composite co-deposited coating exhibits a surface hardness of 1109 HV0.1, which significantly surpasses the substrate's hardness of 232.38 HV0.1. The Ni-B-PTFE composite coating exhibits an average friction coefficient of around 0.12. It has a scratch width of 855.18 µm and a wear mass of 0.05 mg. This coating demonstrates superior wear resistance when compared to Ni-B coatings. The Ni-B-PTFE composite coating specimen exhibits a self-corrosion potential of -6.195 V and a corrosion current density of 7.81 × 10-7 A/cm2, which is the lowest recorded. This enhances its corrosion resistance compared to Ni-B coatings.

Suppressing SENP1 inhibits esophageal squamous carcinoma cell growth via SIRT6 SUMOylation.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a prevalent tumor in the gastrointestinal tract, but our understanding of the molecular mechanisms underlying ESCC remains incomplete. Existing studies indicate that SUMO specific peptidase 1 (SENP1) plays a crucial role in the development and progression of various malignant tumors through diverse molecular mechanisms. However, the functional mechanism and clinical implications of SENP1 in the progression of ESCC remain unclear. METHODS: Bulk RNA-Sequencing (RNA-seq) was used to compare potential genes in the esophageal tissues of mice with ESCC to the control group. The up-regulated SENP1 was selected. The protein level of SENP1 in ESCC patient samples was analyzed by immunohistochemistry and western blot. The potential prognostic value of SENP1 on overall survival of ESCC patients was examined using tissue microarray analysis and the Kaplan-Meier method. The biological function was confirmed through in vitro and in vivo knockdown approaches of SENP1. The role of SENP1 in cell cycle progression and apoptosis of ESCC cells was analyzed by flow cytometry and western blot. The downstream signaling pathways regulated by SENP1 were investigated via using RNA-Seq. SENP1-associated proteins were identified through immunoprecipitation. Overexpression of Sirtuin 6 (SIRT6) wildtype and mutant was performed to investigate the regulatory role of SENP1 in ESCC progression in vitro. RESULTS: Our study discovered that SENP1 was upregulated in ESCC tissues and served as a novel prognostic factor. Moreover, SENP1 enhanced cell proliferation and migration of ESCC cell lines in vitro, as well as promoted tumor growth in vivo. Thymidine kinase 1 (TK1), Geminin (GMNN), cyclin dependent kinase 1(CDK1), and cyclin A2 (CCNA2) were identified as downstream genes of SENP1. Mechanistically, SENP1 deSUMOylated SIRT6 and subsequently inhibited SIRT6-mediated histone 3 lysine 56 (H3K56) deacetylation on those downstream genes. SIRT6 SUMOylation mutant (4KR) rescued the growth inhibition upon SENP1 depletion. CONCLUSIONS: SENP1 promotes the malignant progression of ESCC by inhibiting the deacetylase activity of SIRT6 pathway through deSUMOylation. Our findings suggest that SENP1 may serve as a valuable biomarker for prognosis and a target for therapeutic intervention in ESCC.

Development of a predictive model to predict postoperative bone metastasis in pathological I-II non-small cell lung cancer.

Background: Bone is a common metastatic site in postoperative metastasis, but related risk factors for early-stage non-small cell lung cancer (NSCLC) remain insufficiently investigated. Thus, the study aimed to identify risk factors for postoperative bone metastasis in early-stage NSCLC and construct a nomogram to identify high-risk individuals. Methods: Between January 2015 and January 2021, we included patients with resected stage I-II NSCLC at the Department of Thoracic Surgery, West China Hospital. Univariable and multivariable Cox regression analyses were used to identify related risk factors. Additionally, we developed a visual nomogram to forecast the likelihood of bone metastasis. Evaluation of the model involved metrics such as the area under the curve (AUC), C-index, and calibration curves. To ensure reliability, internal validation was performed through bootstrap resampling. Results: Our analyses included 2,106 eligible patients, with 54 (2.56%) developing bone metastasis. Multivariable Cox analyses showed that tumor nodules with solid component, higher pT stage, higher pN stage, and histologic subtypes especially solid/micropapillary predominant types were considered as independent risk factors of bone metastasis. In the training set, the developed model demonstrated AUCs of 0.807, 0.769, and 0.761 for 1-, 3-, and 5-year follow-ups, respectively. The C-index, derived from 1,000 bootstrap resampling, showed values of 0.820, 0.793, and 0.777 for 1-, 3-, and 5-year follow-ups. The calibration curve showed that the model was well calibrated. Conclusions: The predictive model is proven to be valuable in estimating the probability of bone metastasis in early-stage NSCLC following surgery. Leveraging four easy-to-acquire clinical parameters, this model effectively identifies high-risk patients and enables individualized surveillance strategies for better patient care.

"Nutrient-fungi-host" tripartite interaction in cancer progression.

The human microbiome exhibits a profound connection with the cancer development, progression, and therapeutic response, with particular emphasis on its components of the mycobiome, which are still in the early stages of research. In this review, we comprehensively summarize cancer-related symbiotic and pathogenic fungal genera. The intricate mechanisms through which fungi impact cancer as an integral member of both gut and tissue-resident microbiomes are further discussed. In addition, we shed light on the pivotal physiological roles of various nutrients, including cholesterol, carbohydrates, proteins and minerals, in facilitating the growth, reproduction, and invasive pathogenesis of the fungi. While our exploration of the interplay between nutrients and cancer, mediated by the mycobiome, is ongoing, the current findings have yet to yield conclusive results. Thus, delving into the relationship between nutrients and fungal pathogenesis in cancer development and progression would provide valuable insights into anticancer therapy and foster precision nutrition and individualized treatments that target fungi from bench to bedside.

Modified arthroscopic repair of a posterior cruciate ligament tibial avulsion fracture improves IKDC and Lysholm score compared to open reduction.

PURPOSE: The purpose of this study was to analyse the difference between arthroscopic fixation and open reduction internal fixation (ORIF) of posterior cruciate ligament (PCL) tibial avulsion fractures. METHODS: This retrospective study analysed patients with an acute PCL tibial avulsion fracture who underwent surgical treatment at our hospital and follow-up for at least 24 months. Variables based on sex, age, Meyers-McKeever type, surgical method, meniscus tear, external fixation, labour or sports, Lysholm knee score, IKDC score, and KT-1000 value were also recorded. Multifactor unconditional logistic regression and Student's t test with 1:1 propensity score matching (PSM) to remove confounding factors were used for analysis. RESULTS: Sixty-five cases achieved knee function graded as "good" or better, and 9 cases not. Single-factor analysis indicated that Meyers-McKeever type (χ2 = 4.669, P = 0.031) and surgical approach (χ2 = 9.428, P = 0.002) are related to functional outcomes. Multifactorial logistic regression analysis further confirmed that Meyers-McKeever typing (OR = 10.763, P = 0.036, [95% CI 1.174-98.693]) and surgical approach (OR = 9.274, P = 0.008, [95% CI 1.794-47.934]) are independent risk factors affecting prognosis. In addition, PSM verified significant differences in the Lysholm score (t = 3.195, P = 0.006), IKDC score (t = 4.703, P = 0.000) and A-KT/H-KT (t = 2.859, P = 0.012). However, the affected-side KT-1000 value (A-KT, mm, t = 1.225, P = 0.239) and healthy-side KT-1000 value (H-KT, mm, t = 1.436, P = 0.172) did not significantly differ between the two groups. The proportions of cases in which the Lysholm score, IKDC and A-KT/H-KT exceeded the minimal clinically important difference (MCID) were 62.5% (20/32), 62.5% (20/32) and 93.75% (30/32), respectively. CONCLUSION: Compared with ORIF, an arthroscopic approach for PCL tibial avulsion fractures achieves better results. LEVEL OF EVIDENCE: Retrospective cohort study; Level II.

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

Danshensu reduces neuronal excitability by enhancing potassium currents in bushy cells in the mouse cochlear nucleus.

Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1 h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100 µm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7 mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50 µm and Danshensu of 200 µm failed to cause significantly more enhancement on K+ currents when compared to that of 100 µm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.

Enhancing the acidic oxygen evolution reaction performance of RuO2-TiO2by a reduction-oxidation process.

As a promising alternative to Ir based acidic oxygen evolution reaction (OER) catalysts, Ru suffers from severe fading issues. Supporting it on robust oxides such as TiO2is a simple and effective way to enhance its lifetime. Here, we find that a simple reduction-oxidation process can further improve both activity and stability of RuO2-TiO2composites at high potentials. In this process, the degree of oxidation was carefully controlled to form Ru/RuO2heterostructure to improve OER activity. Moreover, due to the oxophilicity difference of Ru and Ti, the structure of catalysts was changed from supported to embedded, which enhanced the protective effect of TiO2and mitigated the dissolution of Ru element in acidic electrolyte, making as-prepared Ru/RuO2-TiO2with better durability at all tested potentials.

Suction versus non-suction drainage strategy after uniportal thoracoscopic lung surgery: a prospective cohort study.

Background: The postoperative outcomes of suction drainage versus non-suction drainage after uniportal video-assisted thoracoscopic surgery (UniVATS) come with little consensus. This study aimed to prospectively compare the postoperative outcomes of suction drainage versus non-suction drainage in patients who underwent UniVATS. Methods: Between October 2022 and January 2023, patients undergoing UniVATS were prospectively enrolled. The choice of drainage strategy (suction or non-suction) was at the surgeon's discretion. The primary outcome was chest tube duration, with secondary outcomes including postoperative drainage volume, pain scores, postoperative complications, length of hospital stay, and hospitalization cost. Baseline characteristics and postoperative outcomes were compared. Univariable and multivariable analyses were used to identify risk factors for postoperative outcomes. Results: A total of 206 patients were enrolled in this study, with 103 patients in each group. Baseline characteristics were well-balanced. The chest tube duration did not significantly differ between the two groups. However, suction drainage exhibited a significantly lower total drainage volume compared to non-suction drainage (280.00 vs. 400.00 mL, P=0.03). Suction drainage was associated with a significantly shorter postoperative hospital stay (3.00 vs. 4.00 days, P<0.001) and lower pain score on the second postoperative day (POD). Multivariable analyses also confirmed that suction drainage was significantly correlated with a lower total drainage volume and a shorter postoperative hospital stay. Conclusions: These findings suggested that the suction drainage was superior to non-suction drainage in terms of postoperative drainage volume and length of hospital stay in patients undergoing UniVATS.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma: A case report.

BACKGROUND: Multiple primary carcinomas (MPCs) are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual. Synchronous MPCs are rarer than solitary cancers or metachronous MPCs. Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases. CASE SUMMARY: A 64-year-old patient presented with dysphagia, without obvious cause. A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results. After multi-disciplinary consultations, combination chemotherapy (a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14) and esophageal cancer radiotherapy were initiated. Based on the results of genetic testing, we switched to a regimen of leucovorin + fluorouracil + oxaliplatin and cetuximab regimen for 8 cycles. Subsequently, capecitabine and bevacizumab were administered until the most recent follow-up, at which the tumor remained stable. CONCLUSION: Successful cetuximab chemotherapy treatment provides a reference for the non-operative and homogeneous treatment of different pathological types of synchronous MCPs.

THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.

Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain-containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain-containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.

Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related fatalities globally. In this study, we observed a significant increase in the expression level of the YEATS2 gene in HCC patients, and it is negatively correlated with the patients' survival rate. While we have previously identified the association between YEATS2 and the survival of pancreatic cancer cells, the regulatory mechanisms and significance in HCC are still to be fully elucidated. Our study shows that knockdown (KD) of YEATS2 expression leads to DNA damage, which in turn results in an upregulation of γ-H2A.X expression and activation of the canonical senescence-related pathway p53/p21Cip1. Moreover, our transcriptomic analysis reveals that YEATS2 KD cells can enhance the expression of p21Cip1 via the c-Myc/miR-93-5p pathway, consequently fostering the senescence of HCC cells. The initiation of cellular senescence through dual-channel activation suggests that YEATS2 plays a pivotal regulatory role in the process of cell proliferation. Ultimately, our in vivo research utilizing a nude mouse tumor model revealed a notable decrease in both tumor volume and weight after the suppression of YEATS2 expression. This phenomenon is likely attributable to the attenuation of proliferative cell activity, coupled with a concurrent augmentation in the population of natural killer (NK) cells. In summary, our research results have supplemented the understanding of the regulatory mechanisms of HCC cell proliferation and indicated that targeting YEATS2 may potentially inhibit liver tumor growth.

DNA methylation clocks for estimating biological age in Chinese cohorts.

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation at specific CpG sites. However, available DNA methylation (DNAm) age predictors are based on datasets with limited ethnic representation. Moreover, a systematic comparison between DNAm data and other omics datasets has not yet been performed. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation (DNAm) aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing basis for evaluating aging intervention strategies.

Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration.

Intense inflammatory response impairs bone marrow mesenchymal stem cell (BMSC)-mediated bone regeneration, with transforming growth factor (TGF)-ß1 being the most highly expressed cytokine. However, how to find effective and safe means to improve bone formation impaired by excessive TGF-ß1 remains unclear. In this study, we found that the expression of orphan nuclear receptor Nr4a1, an endogenous repressor of TGF-ß1, was suppressed directly by TGF-ß1-induced Smad3 and indirectly by Hdac4, respectively. Importantly, Nr4a1 overexpression promoted BMSC osteogenesis and reversed TGF-ß1-mediated osteogenic inhibition and pro-fibrotic effects. Transcriptomic and histologic analyses confirmed that upregulation of Nr4a1 increased the transcription of Wnt family member 4 (Wnt4) and activated Wnt pathway. Mechanistically, Nr4a1 bound to the promoter of Wnt4 and regulated its expression, thereby enhancing the osteogenic capacity of BMSCs. Moreover, treatment with Nr4a1 gene therapy or Nr4a1 agonist Csn-B could promote ectopic bone formation, defect repair, and fracture healing. Finally, we demonstrated the correlation of NR4A1 with osteogenesis and the activation of the WNT4/ß-catenin pathway in human BMSCs and fracture samples. Taken together, these findings uncover the critical role of Nr4a1 in bone formation and alleviation of inflammation-induced bone regeneration disorders, and suggest that Nr4a1 has the potential to be a therapeutic target for accelerating bone healing.

Immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus.

OBJECTIVES: We evaluated the immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus (adoSLE) receiving either high- or low-dose immunosuppressant (High-IS and Low-IS). METHODS: Patients aged 12-18 years diagnosed with SLE were enrolled. High-IS was defined as >7.5 mg/day prednisolone or with other immunosuppressant, while Low-IS was defined as only ≤7.5 mg/day of prednisolone and no immunosuppressant. Two doses of BNT162b2 vaccination were given 4 weeks apart, followed by a booster (third) dose at 4-6 months later. Anti-spike receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NT) against Wuhan and Omicron variants, and cellular immune response by IFN-γ-ELISpot assay were evaluated following vaccination. Adverse events (AEs) and SLE flare were monitored. RESULTS: A total of 73 participants were enrolled, 40 and 33 in the High-IS and Low-IS group, respectively. At 4 weeks following the 2nd dose, overall anti-RBD IgG seropositivity was 97.3%, with no difference between the groups (p = .498). AdoSLE on High-IS had lower anti-RBD IgG (p < .001), Wuhan NT (p < .001), and IFN-γ-ELISpot (p = .022) than those on Low-IS. A 3rd dose induced significantly higher antibody responses than after the 2nd dose (p < .001) in both groups and established seroconversion against Omicron variants, with persistent lower antibody levels in High-IS group. SELENA-SLEDAI scores within 12 weeks after 2-dose vaccination was higher than before vaccination (3.1 vs 2.5; p < .036); however, the occurrence of disease flare by SELENA-SLEDAI flare index was not different after vaccination compared to before vaccination, consistent across groups. Non-severe AEs occurred similarly in both groups. CONCLUSION: AdoSLE on High-IS induced lower SARS-CoV-2 vaccine immune responses than Low-IS. Vaccination can increase disease activity and requires close monitoring for disease flare.

[Effect of stump-preserving repair on rotator cuff healing and shoulder function for degenerative total rotator cuff tears].

Objective: To analyze the effect of stump-preserving repair on rotator cuff healing and shoulder function for degenerative total rotator cuff tears. Methods: A clinical data of 152 patients with degenerative total rotator cuff tears, who underwent arthroscopic repair between April 2019 and May 2022, was retrospectively analyzed. There were 76 males and 76 females with an average age of 55.4 years (range, 24-78 years). MRI was performed at 6 months postoperatively to evaluate the rotator cuff healing according to the Sugaya classification. Pre- and intra-operative related factors were included for univariate analysis, including age (≥60 years/<60 years), gender (male/female), passive activity disorder (yes/no), disease duration (≤3 months/>3 months), stump-preserving repair (yes/no), use of suture bridge technique (yes/no), shoulder joint abduction angle at knotting (<45°/≥45°), acromioplasty (yes/no), glucocorticoid injection (yes/no), time for patients to start postoperative passive exercise (≤2 weeks/>2 weeks), and time for patients to start postoperative active exercise (≤3 months/>3 months). The influencing factors of tendon healing were screened; further logistic regression was used to conduct multivariate analysis to screen for risk factors. Two sets of data were balanced by propensity score matching. The American Shoulder and Elbow Surgeons (ASES) score and Constant-Murley score of shoulder joint function at 6 and 12 months postoperatively, as well as rotator cuff healing rate at 6 months postoperatively, were compared between groups based on whether or not stump-preserving repair was used. Results: All patients were followed up 12-33 months (mean, 23.8 months). MRI at 25-31 weeks postoperatively showed the 121 cases of rotator cuff healing and 31 cases of non healing. Univariate analysis showed that the disease duration, stump-preserving repair, shoulder joint abduction angle at knotting, and the time for patients to start postoperative active exercise were the influencing factors of rotator cuff healing ( P<0.05). Multivariate analysis showed that non-stump-preserving repair, shoulder abduction angle more than 45° at knotting, and the time to start active exercise within 3 months postoperatively were risk factors affecting rotator cuff healing ( P<0.05). A total of 51 pairs of cases were matched based on the grouping criteria of whether the disease duration exceeded 3 months, whether the shoulder abduction angle at knotting exceeded 45°, and whether the time to start postoperative active exercise exceeded 3 months. The rotator cuff healing rate, ASES score, and Constant-Murley score of the preserving repair group at 6 months postoperatively were superior to those of the non-preserving repair group, and the differences were significant ( P<0.05). There was no significant difference in ASES score and Constant-Murley score between the two groups at 12 months postoperatively ( P>0.05). Conclusion: For degenerative total rotator cuff tears, the stump-preserving repair can shorten the healing time and promote the shoulder function recovery, but has no significant effect on shoulder function at 1 year postoperatively.

Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs.

BACKGROUND & AIMS: Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. METHODS: A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. RESULTS: The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. CONCLUSIONS: Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

Molecular subtypes of disulfidptosis-regulated genes and prognosis models for predicting prognosis, tumor microenvironment infiltration, and therapeutic response in hepatocellular carcinoma.

Disulfidptosis, a recently identified mode of cellular demise marked by excess SLC7A11-reliant cystine, has been proved to affect the development and resilience of tumor cells through the production of glutathione from cystine. Glutathione synthesis plays a crucial role in chemotherapy resistance and the survival of liver cancer cells. Thus, understanding the relationship between disulfidptosis and hepatocellular carcinoma (HCC) is imperative. A molecular typing approach was employed to classify patients with HCC into two distinct subtypes, namely disulfidptosis and disulfide-homeostasis, based on the expression of genes associated with disulfidptosis. Patients with disulfidptosis exhibited a longer survival time, improved immune status, and heightened sensitivity to conventional chemotherapeutic drugs and immunotherapy. Patients with disulfide-homeostasis demonstrated an immunosuppressive microenvironment, drug resistance, and unfavorable prognosis. A prognostic model was constructed utilizing the significant prognostic variables of the disulfidptosis-regulated genes. A real-world cohort was subjected to multiplex immunofluorescence to validate the clinical outcomes and immune context. Ultimately, our study delved into the prognostic relevance of disulfidptosis in HCC and provides insights into potential avenues for future research.