Bone marrow lesion and 5-year incident joint surgery in patients with knee osteoarthritis: a retrospective cohort study.

BACKGROUND: It is beneficial for society to discover the risk factors associated with surgery and to carry out some early interventions for patients with these risk factors. Few studies specifically explored the relationship between bone marrow lesions (BMLs) and long-term incident joint surgery. OBJECTIVE: To investigate the association between BML severity observed in knee osteoarthritis (OA) patients' first MRI examination and incident knee surgery within 5 years. Additionally, to assess the predictive value of BMLs for the incident knee surgery. DESIGN: Retrospective cohort study. METHODS: We identified patients diagnosed with knee OA and treated at our institution between January 2015 and January 2018, and retrieved their baseline clinical data and first MRI examination films from the information system. Next, we proceeded to determine the Max BML grades, BML burden grades and Presence BML grades for the medial, lateral, patellofemoral, and total compartments, respectively. Multi-variable logistic regression models examined the association of the BML grades with 5-year incident knee surgery. Positive and negative predictive values (PPVs and NPVs) were determined for BML grades referring to 5-year incident knee surgery. RESULTS: Totally, 1011 participants (knees) were found eligible to form the study population. Within the 5 years, surgery was performed on 74 knees. Max BML grade 2 and grade 3 of medial, patellofemoral and total compartments were strongly and significantly associated with incident surgery. None of the BML grades from lateral compartment was associated with incident surgery. The PPV was low and NPV was high for BMLs. CONCLUSIONS: BMLs found in the first MRI examination were associated with 5-year incident joint surgery, except for those allocated in lateral compartments. The high NPVs imply that patients without BMLs have a low risk of requiring surgery within 5 years.

Mitochondrial dysfunction: mechanisms and advances in therapy.

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

A Pathologically Friendly Strategy for Determining the Organ-specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom-seq and Imaging Mass Cytometry.

Heterogeneous organ-specific responses to immunotherapy exist in lung cancer. Dissecting tumor microenvironment (TME) can provide new insights into the mechanisms of divergent responses, the process of which remains poor, partly due to the challenges associated with single-cell profiling using formalin-fixed paraffin-embedded (FFPE) materials. In this study, single-cell nuclei RNA sequencing and imaging mass cytometry (IMC) are used to dissect organ-specific cellular and spatial TME based on FFPE samples from paired primary lung adenocarcinoma (LUAD) and metastases. Single-cell analyses of 84 294 cells from sequencing and 250 600 cells from IMC reveal divergent organ-specific immune niches. For sites of LUAD responding well to immunotherapy, including primary LUAD and adrenal gland metastases, a significant enrichment of B, plasma, and T cells is detected. Spatially resolved maps reveal cellular neighborhoods recapitulating functional units of the tumor ecosystem and the spatial proximity of B and CD4+ T cells at immunogenic sites. Various organ-specific densities of tertiary lymphoid structures are observed. Immunosuppressive sites, including brain and liver metastases, are deposited with collagen I, and T cells at these sites highly express TIM-3. This study originally deciphers the single-cell landscape of the organ-specific TME at both cellular and spatial levels for LUAD, indicating the necessity for organ-specific treatment approaches.

Antibody Profiling of Pan-Cancer Viral Proteome Reveals Biomarkers for Nasopharyngeal Carcinoma Diagnosis and Prognosis.

Diagnosing, predicting disease outcome, and identifying effective treatment targets for virus-related cancers are lacking. Protein biomarkers have the potential to bridge the gap between prevention and treatment for these types of cancers. While it has been shown that certain antibodies against EBV proteins could be used to detect nasopharyngeal carcinoma (NPC), antibodies targeting are solely a tiny part of the about 80 proteins expressed by the EBV genome. Furthermore, it remains unclear what role other viruses play in NPC since many diseases are the result of multiple viral infections. For the first time, this study measured both IgA and IgG antibody responses against 646 viral proteins from 23 viruses in patients with NPC and control subjects using nucleic acid programmable protein arrays. Candidate seromarkers were then validated by ELISA using 1665 serum samples from three clinical cohorts. We demonstrated that the levels of five candidate seromarkers (EBV-BLLF3-IgA, EBV-BLRF2-IgA, EBV-BLRF2-IgG, EBV-BDLF1-IgA, EBV-BDLF1-IgG) in NPC patients were significantly elevated than controls. Additional examination revealed that NPC could be successfully diagnosed by combining the clinical biomarker EBNA1-IgA with the five anti-EBV antibodies. The sensitivity of the six-antibody signature at 95% specificity to diagnose NPC was comparable to the current clinically-approved biomarker combination, VCA-IgA, and EBNA1-IgA. However, the recombinant antigens of the five antibodies are easier to produce and standardize compared to the native viral VCA proteins. This suggests the potential replacement of the traditional VCA-IgA assay with the 5-antibodies combination to screen and diagnose NPC. Additionally, we investigated the prognostic significance of these seromarkers titers in NPC. We showed that NPC patients with elevated BLLF3-IgA and BDLF1-IgA titers in their serum exhibited significantly poorer disease-free survival, suggesting the potential of these two seromarkers as prognostic indicators of NPC. These findings will help develop serological tests to detect and treat NPC in the future.

Breast-conserving surgery is associated with a lower incidence of suicide among females with breast cancer in the United States: a population-based retrospective cohort study.

BACKGROUND: With comparable overall survival and local recurrence rates with mastectomy, breast-conserving surgery (BCS) has become the cornerstone of therapy for breast cancer; however, the difference in the incidence of suicide between BCS and mastectomy among breast cancer survivors remains unclear. This study evaluated the mortality risk from suicide among breast cancer survivors and compared suicide risk between BCS and mastectomy using a population-based cohort. MATERIALS AND METHODS: Female patients newly diagnosed with first primary breast cancer, recorded in the Surveillance, Epidemiology and End Results database, were included. Standardized mortality ratio (SMR) and cumulative mortality rate from suicide among those who underwent BCS and mastectomy were compared. RESULTS: A total of 1 190 991 patients with newly diagnosed first primary breast cancer were included in the study, of whom 56.5% underwent BCS and 36.1% underwent mastectomy. During the follow-up period, 667 suicides were recorded. Patients who underwent mastectomy exhibited significantly higher suicide mortality than the general population [mortality rate, 8.16 per 100 000 person-years; SMR 1.18 (95% CI 1.05-1.33)], while there was no significant difference in suicide rate between patients who underwent BCS and the general population [SMR 0.92 (95% CI 0.83-1.02)]. Multivariate Cox analysis revealed that BCS, compared with mastectomy, was associated with a significantly decreased risk of suicide among females with breast cancer [hazard ratio 0.80 (95% CI 0.68-0.95); P = 0.009]. CONCLUSION: BCS was associated with a significantly lower incidence of suicide among females with breast cancer. BCS offers a compelling option for improving the quality of life and self-esteem of patients with cancer and provides a novel perspective on cancer management.

HIPK3 maintains sensitivity to platinum drugs and prevents disease progression in gastric cancer.

In the realm of cancer therapeutics and resistance, kinases play a crucial role, particularly in gastric cancer (GC). Our study focused on platinum-based chemotherapy resistance in GC, revealing a significant reduction in homeodomain-interacting protein kinase 3 (HIPK3) expression in platinum-resistant tumors through meticulous analysis of transcriptome datasets. In vitro and in vivo experiments demonstrated that HIPK3 knockdown enhanced tumor proliferation and metastasis, while upregulation had the opposite effect. We identified the myocyte enhancer factor 2C (MEF2C) as a transcriptional regulator of HIPK3 and uncovered HIPK3's role in downregulating the morphogenesis regulator microtubule-associated protein (MAP7) through ubiquitination. Phosphoproteome profiling revealed HIPK3's inhibitory effects on mTOR and Wnt pathways crucial in cell proliferation and movement. A combined treatment strategy involving oxaliplatin, rapamycin, and IWR1-1-endo effectively overcame platinum resistance induced by reduced HIPK3 expression. Monitoring HIPK3 levels could serve as a GC malignancy and platinum resistance indicator, with our proposed treatment strategy offering novel avenues for reversing resistance in gastric cancer.

Spatial omics: An innovative frontier in aging research.

Disentangling the impact of aging on health and disease has become critical as population aging progresses rapidly. Studying aging at the molecular level is complicated by the diverse aging profiles and dynamics. However, the examination of cellular states within aging tissues in situ is hampered by the lack of high-resolution spatial data. Emerging spatial omics technologies facilitate molecular and spatial analysis of tissues, providing direct access to precise information on various functional regions and serving as a favorable tool for unraveling the heterogeneity of aging. In this review, we summarize the recent advances in spatial omics application in multi-organ aging research, which has enhanced the understanding of aging mechanisms from multiple standpoints. We also discuss the main challenges in spatial omics research to date, the opportunities for further developing the technology, and the potential applications of spatial omics in aging and aging-related diseases.

Anti-depressant medication use is a risk factor for incident knee surgery and opioid use in patients with knee osteoarthritis.

Objective: To investigate whether depression and exposure to anti-depressant medication are independent risk factors for incident knee surgery and opioid use in knee osteoarthritis (KOA) patients. Methods: We identified all patients who visited our outpatient department and were clinically diagnosed with KOA between January 2010 and January 2018. We retrieved their demographic, clinical, and radiographic data from the database of our hospital. Next, we analyzed the effect of depression and anti-depressant medication on the incident knee surgery and opioid use in KOA patients. Results: A total of 4,341 KOA patients were found eligible to form the study population. Incident knee surgery and opioid use for the purpose of treating osteoarthritis were observed in 242 and 568 patients, respectively. Incident knee surgery was significantly associated with age (OR [95%CI], 1.024 [1.009-1.039], P = 0.002), BMI (OR [95%CI], 1.090 [1.054-1.128], P < 0.001), baseline K-L grade 3 (OR [95%CI], 1.977 [1.343-2.909], P = 0.001), baseline K-L grade 4 (OR [95%CI], 1.979 [1.241-3.157], P = 0.004), depression (OR [95%CI], 1.670 [1.088-2.563], P = 0.019), and exposure to anti-depressant medication (OR [95%CI], 2.004 [1.140-3.521], P = 0.016). Incident opioid use was significantly associated with depression (OR [95%CI], 1.554 [1.089-2.215], P = 0.015) and exposure to anti-depressant medication (OR [95%CI], 1.813 [1.110-2.960], P = 0.017). Conclusion: Depression and anti-depressant drug exposure were independently associated with incident knee surgery, highlighting the need for more attention on comorbid depression in KOA management.

Endoscopic excision versus radical nephroureterectomy for non-muscle invasive upper tract urothelial carcinoma: A population-based large cohort study.

Background: As an important kidney-sparing treatment for upper urothelial carcinoma (UTUC), whether endoscopic excision can be performed without sacrificing oncologic outcomes remains indefinite. This study aimed to investigate the prevalence and efficacy of endoscopic excision, in patients with non-muscle invasive UTUC (NMIUTUC) and compare them to those of radical nephroureterectomy (RNU). Methods: Using the Surveillance, Epidemiology, and End Results database, we reviewed 4347 cases with NMIUTUC (cTis/Ta/T1-N0-M0,≤ 5.0 cm) between 2004 and 2020. Surgical treatment modalities included endoscopic excision and RNU. Propensity score matching analysis was used to minimize the selection bias between endoscopic excision and RNU, selecting 1:1 matched patients in the two group. Results: A total of 794 patients with NMIUTUC were included after matching (397:397). Patients who underwent endoscopic excision had worse survival outcomes compared with those of patients who underwent RNU (5-year OS: 65.3 % vs. 80.3 %, p < 0.0001; 5-year DSS: 83.2 % vs. 94.0 %, p = 0.00021). After stratification by anatomical sites, the effect of endoscopic excision for NMI renal pelvis cancer was worse than RNU (5-year OS, 62.9 % vs. 82.8 %; 5-year DSS, 78.8 % vs. 91.6 %), while in NMI ureteral cancer, there is no statistically significant difference in OS and DSS between endoscopic excision and RNU. Further stratification according to tumor grade revealed equivalent tumor control effects of endoscopic excision and RNU in low-grade NMI ureteral cancer (5-year OS: 67.7 % vs. 72.5 %, p = 0.23; 5-year DSS: 87.2 % vs. 93.1 %, p = 0.17); while for renal pelvis tumor and high-grade ureteral tumor, endoscopic excision was related with significantly inferior prognosis. Conclusions: Only for low-grade NMI ureteral cancer, endoscopic excision and RNU are oncologically equivalent, indicating that endoscopic excision might be an effective option for low-grade NMI ureteral cancer. This result needs to be further verified in randomized controlled trials.

Alcoholic drink produced by pea is a risk factor for incident knee surgery in patients with knee osteoarthritis.

Objective: The objective of this study is to investigate whether alcohol exposure and specific alcoholic drinks are independent risk factors for incident knee surgery in knee osteoarthritis (KOA) patients. Methods: We identified all patients who were clinically diagnosed as KOA between January 2010 and January 2018 in our outpatient department. Demographic, clinical, and radiographic data were collected from the database of our hospital. Next, we analyzed the association between alcohol consumption and incident knee surgery. Results: A total of 4,341 KOA patients completed the current study and were included in the final analysis. Incident knee surgery for the purpose of treating osteoarthritis was observed in 242 patients. Incident knee surgery was significantly associated with age (OR [95%CI], 1.023 [1.009-1.039], P = 0.002), BMI (OR [95%CI], 1.086 [1.049-1.123], P < 0.001), baseline K-L grade 3 (OR [95%CI], 1.960 [1.331-2.886], P = 0.001), baseline K-L grade 4 (OR [95%CI], 1.966 [1.230-3.143], P = 0.005), 7.1-14 drinks per week (OR [95%CI], 2.013 [1.282-3.159], P = 0.002), >14 standard drinks per week (OR [95%CI], 2.556 [1.504-4.344], P = 0.001), and the most common alcoholic drink produced by pea (OR [95%CI], 3.133 [1.715-5.723], P < 0.001). Conclusion: KOA patients who consumed more than seven standard drinks per week were at substantial risk of incident knee surgery. In addition, alcoholic drink produced by pea is also an independent risk factor.

The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer.

Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1ß in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.

Cancer-Erythrocyte Membrane-Mimicking Fe3O4 Nanoparticles and DHJS for Ferroptosis/Immunotherapy Synergism in Tumors.

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.

Local excision as a viable alternative to hysterectomy for early-stage cervical cancer in women of reproductive age: a population-based cohort study.

BACKGROUND: Local excision as the main alternative for fertility-sparing surgery (FSS) has been widely used in patients with early-stage cervical cancer to achieve fertility preservation, but its safety and practicability are still questioned. Therefore, The authors evaluated the current application of local excision in early-stage cervical cancer with this population-based study and compared its efficacy with hysterectomy. MATERIALS AND METHODS: Women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I cervical cancer at childbearing age (18-49 years) recorded in the Surveillance, Epidemiology and End Results (SEER) database from 2000 to 2017 were included. Overall survival (OS) and disease-specific survival (DSS) rates were compared between local excision and hysterectomy. RESULTS: A total of 18 519 patients of reproductive age with cervical cancer were included, and 2268 deaths were observed. 17.0% of patients underwent FSS via local excision, and 70.1% underwent hysterectomy. Among patients younger than 39 years, OS and DSS of local excision were comparable to those of hysterectomy, whereas, in patients older than 40 years, OS and DSS of local excision were significantly worse than those of hysterectomy. In addition, OS and DSS of local excision were similar to hysterectomy in patients with stage IA cervical cancer, but OS and DSS were inferior to hysterectomy in patients with stage IB cervical cancer who underwent local excision. CONCLUSION: For patients without fertility requirements, hysterectomy remains the best therapeutic option. However, for patients under 40 years of age diagnosed with stage IA cervical cancer, FSS via local excision is a viable option that can achieve a well-balanced outcome between tumour control and fertility preservation.

Change in onset age of first primary colorectal cancer in the USA.

PURPOSE: Identifying the onset age of cancer is essential for its early intervention. The aim of this study was to characterize the features and investigate the variation tendency of first primary colorectal cancer (CRC) onset age in the USA. METHODS: For this retrospective population-based cohort analysis, data on patients diagnosed with first primary CRC (n = 330,977) between 1992 and 2017 were obtained from the Surveillance, Epidemiology, and End Results dataset. Annual percent changes (APC) and average APCs were calculated to examine the changes in average age at CRC diagnosis using the Joinpoint Regression Program. RESULTS: From 1992 to 2017, the average age at CRC diagnosis decreased from 67.0 to 61.2 years, declining by 0.22% and 0.45% annually before and after 2000. The age at diagnosis was lower in the distal than in the proximal CRC cases and the age has the downward trends in all subgroups of sex, race, and stage. Over one-fifth of CRC patients were initially diagnosed with distantly metastatic CRC, with the age lower than that in localized CRC cases (63.5 vs 64.8 years). CONCLUSIONS: The first primary CRC onset age has decreased significantly in the USA over the last 25 years and the modern lifestyle may be responsible for the decline. Specifically, the age of proximal CRC is invariably higher than that of distal CRC. Moreover, the age of advanced stage is lower than that of the early stage. Clinicians should adopt earlier screening age and more effective screening techniques for CRC.

Androgen Signaling Contributes to Sex Differences in Cancer by Inhibiting NF-κB Activation in T Cells and Suppressing Antitumor Immunity.

Sex is known to be an important factor in the incidence, progression, and outcome of cancer. A better understanding of the underlying mechanisms could help improve cancer prevention and treatment. Here, we demonstrated a crucial role of antitumor immunity in the sex differences in cancer. Consistent with observations in human cancers, male mice showed accelerated tumor progression compared with females, but these differences were not observed in immunodeficient mice. Androgen signaling suppressed T-cell immunity against cancer in males. Mechanistically, androgen-activated androgen receptor upregulated expression of USP18, which inhibited TAK1 phosphorylation and the subsequent activation of NF-κB in antitumor T cells. Reduction of testosterone synthesis by surgical castration or using the small-molecular inhibitor abiraterone significantly enhanced the antitumor activity of T cells in male mice and improved the efficacy of anti-PD-1 immunotherapy. Together, this study revealed a novel mechanism contributing to sex differences in cancer. These results indicate that inhibition of androgen signaling is a promising approach to improve the efficacy of immunotherapy in males. SIGNIFICANCE: Androgen signaling induces immunosuppression in cancer by blocking T-cell activity through upregulation of USP18 and subsequent inhibition of NF-κB activity, providing a targetable axis to improve antitumor immunity in males.

Issues of Elder Care among Migrant Workers in Contemporary Rural China: Filial Piety Redefined from a Foucauldian Perspective.

This article reports on research that explored rural migrant workers' experiences of returning to their hometown to provide care for elderly parents diagnosed with cancer. The authors used a culturally integrated approach to Foucauldian discourse analysis to consider how 24 participants narrated their experiences of care in China. The discourse of care demonstrated a strong commitment to filial piety despite their unique care challenges, and this commitment was bolstered by discourses that emphasized how much parents had sacrificed, as well as by a persistent forgetting of experiences or background details that suggested any lack of parental sacrifice in recent Chinese history. Policy implications related to enhancing filial care are discussed.

qPTM: an updated database for PTM dynamics in human, mouse, rat and yeast.

Post-translational modifications (PTMs) are critical molecular mechanisms that regulate protein functions temporally and spatially in various organisms. Since most PTMs are dynamically regulated, quantifying PTM events under different states is crucial for understanding biological processes and diseases. With the rapid development of high-throughput proteomics technologies, massive quantitative PTM proteome datasets have been generated. Thus, a comprehensive one-stop data resource for surfing big data will benefit the community. Here, we updated our previous phosphorylation dynamics database qPhos to the qPTM (http://qptm.omicsbio.info). In qPTM, 11 482 553 quantification events among six types of PTMs, including phosphorylation, acetylation, glycosylation, methylation, SUMOylation and ubiquitylation in four different organisms were collected and integrated, and the matched proteome datasets were included if available. The raw mass spectrometry based false discovery rate control and the recurrences of identifications among datasets were integrated into a scoring system to assess the reliability of the PTM sites. Browse and search functions were improved to facilitate users in swiftly and accurately acquiring specific information. The results page was revised with more abundant annotations, and time-course dynamics data were visualized in trend lines. We expected the qPTM database to be a much more powerful and comprehensive data repository for the PTM research community.

SRSF10 stabilizes CDC25A by triggering exon 6 skipping to promote hepatocarcinogenesis.

BACKGROUND: Alternative splicing (AS) events are extensively involved in the progression of diverse tumors, but how serine/arginine-rich splicing Factor 10 (SRSF10) behaves in hepatocellular carcinoma (HCC) has not been sufficiently studied. We aimed to determine SRSF10 associated AS mechanisms and their effects on HCC progression. METHODS: The expression of SRSF10 in HCC tissues was examined, and the in vitro and in vivo functions of SRSF10 were investigated. The downstream AS targets were screened using RNA sequencing. The interaction between SRSF10 protein and exclusion of cell division cycle 25 A (CDC25A) mRNA was identified using RNA immunoprecipitation and crosslinking immunoprecipitation q-PCR. The effects of SRSF10 on CDC25A posttranslational modification, subcellular distribution, and protein stability were verified through coimmunoprecipitation, immunofluorescence, and western blotting. RESULTS: SRSF10 was enriched in HCC tissues and facilitated HCC proliferation, cell cycle, and invasion. RNA sequencing showed that SRSF10 promotes exon 6 exclusion of CDC25A pre-mRNA splicing. As a crucial cell cycle mediator, the exon-skipped isoform CDC25A(△E6) was identified to be stabilized and retained in the nucleus due to the deletion of two ubiquitination (Lys150, Lys169) sites in exon 6. The stabilized isoform CDC25A(△E6) derived from AS had stronger cell cycle effects on HCC tumorigenesis, and playing a more significant role than the commonly expressed longer variant CDC25A(L). Interestingly, SRSF10 activated the carcinogenesis role of CDC25A through Ser178 dephosphorylation to cause nuclear retention. Moreover, CDC25A(△E6) was verified to be indispensable for SRSF10 to promote HCC development in vitro and in vivo. CONCLUSIONS: We reveal a regulatory pattern whereby SRSF10 contributes to a large proportion of stabilized CDC25A(△E6) production, which is indispensable for SRSF10 to promote HCC development. Our findings uncover AS mechanisms such as CDC25A that might serve as potential therapeutic targets to treat HCC.

A novel method of manual positioning based on anatomical mark (shoulder-to-shoulder) to prevent postoperative leg-length discrepancy for femoral neck fractures in hip arthroplasty.

Objective: To determine whether the two lower extremities are of equal length after hip arthroplasty for femoral neck fractures, we developed a novel method of manual positioning based on anatomical mark (shoulder-to-shoulder) in hip arthroplasty. Methods: Patients with femoral neck fractures requiring hip arthroplasty from July 2020 to March 2022 in the orthopedic department of Jinjiang Municipal Hospital, Fujian Province, China were recruited. Hip arthroplasty was performed using the proposed "shoulder-to-shoulder" method of manual positioning based on anatomical mark in 52 patients with femoral neck fractures who met the inclusion criteria. "Shoulder-to-shoulder" was achieved by alignment of the marked femoral "shoulder" and the "shoulder" of prosthesis stem. There were 16 male and 36 female patients, with 27 undergoing total hip arthroplasty (THA) and 25 undergoing hip hemiarthroplasty (HA). The fractures were categorized according to the Garden classification: type II, type III, and type IV in 5, 11, and 36 patients, respectively. The vertical distance from the apex of the medial margin of the femoral trochanter to the tear drop line on both sides which was regarded as the length of both limbs were compared via postoperative imaging, and the apex-shoulder distance on the ipsilateral side measured via postoperative imaging was compared with those measured intraoperatively. Results: All patients completed the surgery successfully. The measurement results for the lower extremities after THA were as follows: contralateral group, 43.87 ± 5.59 mm; ipsilateral group, 44.64 ± 5.43 mm. The measurement results for the lower extremities after HA were as follows: contralateral group, 45.18 ± 7.82 mm; ipsilateral group, 45.16 ± 6.43 mm. The measurement results for the lower extremities after all arthroplasties were as follows: contralateral group, 44.50 ± 6.72 mm; ipsilateral group, 44.89 ± 5.90 mm. The results for the apex-shoulder distance were as follows: postoperative imaging, 19.44 ± 3.54 mm; intraoperative apex-shoulder distance, 27.28 ± 2.84 mm. Statistical analysis results indicated no statistically significant difference in the postoperative bilateral lower extremity length after hip arthroplasty (P = 0.75), while a statistically significant difference was found between the intraoperative and postoperative imaging measurements of the apex-shoulder distance (P < 0.01). Conclusion: The novel method of manual positioning based on anatomical mark (shoulder-to-shoulder) for femoral neck fractures in hip arthroplasty is simple and accurate, making it effective for preventing postoperative bilateral leg length discrepancy.