Targeting AGTPBP1 inhibits pancreatic cancer progression via regulating microtubules and ERK signaling pathway.

BACKGROUND: AGTPBP1 is a cytosolic carboxypeptidase that cleaves poly-glutamic acids from the C terminus or side chains of α/ß tubulins. Although its dysregulated expression has been linked to the development of non-small cell lung cancer, the specific roles and mechanisms of AGTPBP1 in pancreatic cancer (PC) have yet to be fully understood. In this study, we examined the role of AGTPBP1 on PC in vitro and in vivo. METHODS: Immunohistochemistry was used to examine the expression of AGTPBP1 in PC and non-cancerous tissues. Additionally, we assessed the malignant behaviors of PC cells following siRNA-mediated AGTPBP1 knockdown both in vitro and in vivo. RNA sequencing and bioinformatics analysis were performed to identify the differentially expressed genes regulated by AGTPBP1. RESULTS: We determined that AGTPBP1 was overexpressed in PC tissues and the higher expression of AGTPBP1 was closely related to the location of tumors. AGTPBP1 inhibition can significantly decrease cell progression in vivo and in vitro. Moreover, the knockdown of AGTPBP1 inhibited the expression of ERK1/2, P-ERK1/2, MYLK, and TUBB4B proteins via the ERK signaling pathway. CONCLUSION: Our research indicates that AGTPBP1 may be a putative therapeutic target for PC.

Strathclyde minor groove binders (S-MGBs) with activity against Acanthamoeba castellanii.

BACKGROUND: Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms. OBJECTIVES: To synthesize and evaluate the anti-Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development. METHODS: A panel of 12 S-MGBs was synthesized and anti-Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei, Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays. RESULTS AND DISCUSSION: S-MGB-241 has an IC50 of 6.6 µM against A. castellanii, comparable to the clinically used miltefosine (5.6 µM) and negligible activity against the other organisms. It was also found to have an IC50 > 100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a ΔTm = 1 ±â€Š0.1°C. CONCLUSIONS: Together, these data provide confidence that S-MGBs can be further optimized to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a 'hit' compound that is selectively active against A. castellanii, providing a starting point from which to begin optimization of DNA binding and potency.

Risk and Pathological Factors of Recurrence after Endoscopic Resection for Superficial Esophageal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: The risk and pathological factors of recurrence after endoscopic resection (ER) for superficial esophageal squamous cell carcinoma (ESCC) are inconsistent across studies. We evaluated this in a systematic review and meta-analysis. METHODS: The data of recurrence in such patients was extracted from all studies. Risk ratios (RRs) were combined using random-effects meta-analysis, to assess pooled recurrence rate and pathological risk factors. Relapse-free survival was combined using the Kaplan-Meier method to estimate the relationship between various pathological factors and recurrence time. RESULTS: We identified 26 studies, with a total of 5100 patients and 321 with recurrences (pooled rate, 6.2%). The risk of recurrence was significantly higher in positive vertical margin (VM) (RR [95% CI]: 4.51 [2.16 - 9.44]), positive horizontal margin (HM) (RR [95% CI]: 2.54 [1.57 - 4.13]), lymphovascular invasion (LVI) (RR [95% CI]: 2.33 [1.75 - 3.11], P < 0.001), lymphatic invasion (LI) (RR [95% CI]: 2.24 [1.24 - 4.06]), and tumor invading submucosa ≤200 µm (SM1) (RR [95% CI]: 1.71 [1.32 - 2.21], compared to muscularis mucosa). Patients with LI (HR 2.47; 95% CI 1.24 - 4.90; P = 0.02) and LVI (HR 2.36; 95% CI 2.22 - 4.59; P = 0.0006) tended to have earlier recurrence after ER. CONCLUSION: The recurrence rate of superficial ESCC after ER is acceptable. Patients with positive margins, LVI, LI and SM1 need to pay significant attention to the risk of recurrence. LI and VI should be evaluate separately. (PROSPERO CRD42023406309).

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study.

BACKGROUND: Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named "IEsohunter") for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance. METHODS: Participants with EC, high-grade intraepithelial neoplasia (HGIN), other malignancies, benign gastrointestinal lesions, or no abnormalities were prospectively enrolled from 5 tertiary referral centers across China. Peripheral blood samples were collected, followed by plasma cell-free DNA methylation analysis using the IEsohunter test based on multiplex quantitative polymerase chain reaction adopting an algorithm-free interpretation strategy. The primary outcome was the diagnostic accuracy of IEsohunter test for EC. RESULTS: We prospectively enrolled 1116 participants, including 334 patients with EC, 71 with HGIN, and 711 controls. The areas under the receiver operating characteristic curves of the IEsohunter test for detecting EC and HGIN were 0.903 (95% CI 0.880-0.927) and 0.727 (95% CI 0.653-0.801), respectively. IEsohunter test showed sensitivities of 78.5% (95% CI 69.1-85.6), 87.3% (95% CI 79.4-92.4), 92.5% (95% CI 85.9-96.2), and 96.9% (95% CI 84.3-99.8) for stage I-IV EC, respectively, with an overall sensitivity of 87.4% (95% CI 83.4-90.6) and specificity of 93.3% (95% CI 91.2-94.9) for EC detection. The IEsohunter test status turned negative (100.0%, 47/47) after surgical resection of EC. CONCLUSIONS: The IEsohunter test showed high diagnostic accuracy for EC detection, indicating that it could potentially serve as a tool for noninvasive early detection and surveillance of EC.

Association between physical activity and risk of gastroesophageal reflux disease: A systematic review and meta-analysis.

BACKGROUND: Lifestyle plays an important role in preventing and managing gastroesophageal reflux disease (GERD). In response to the conflicting results in previous studies, we performed a systematic review and meta-analysis to investigate this association. METHODS: Relevant studies published until January 2023 were retrieved from 6 databases, and the prevalence of symptomatic gastroesophageal reflux (GER) or GERD was determined from the original studies. A random effects model was employed to meta-analyze the association by computing the pooled relative risk (RR) with 95% confidence intervals (95%CIs). Furthermore, subgroup and dose-response analyses were performed to explore subgroup differences and the association between cumulative physical activity (PA) time and GERD. RESULTS: This meta-analysis included 33 studies comprising 242,850 participants. A significant negative association was observed between PA and the prevalence of symptomatic GER (RR = 0.74, 95%CI: 0.66-0.83; p < 0.01) or GERD (RR = 0.80, 95%CI: 0.76-0.84; p < 0.01), suggesting that engaging in PA might confer a protective benefit against GERD. Subgroup analyses consistently indicated the presence of this association across nearly all subgroups, particularly among the older individuals (RR<40 years:RR≥40 years = 0.85:0.69, p < 0.01) and smokers (RRsmoker:RRnon-smoker = 0.67:0.82, p = 0.03). Furthermore, a dose-response analysis revealed that individuals who engaged in 150 min of PA per week had a 72.09% lower risk of developing GERD. CONCLUSION: Maintaining high levels of PA decreased the risk of GERD, particularly among older adults and smokers. Meeting the recommended PA level of 150 min per week may significantly decrease the prevalence of GERD.

Risk model based on genes regulating the response of tumor cells to T-cell-mediated killing in esophageal squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) represent a promising therapeutic approach for esophageal squamous cell carcinoma (ESCC). However, the subpopulations of ESCC patients expected to benefit from ICIs have not been clearly defined. The anti-tumor cytotoxic activity of T cells is an important pharmacological mechanism of ICIs. In this study, the prognostic value of the genes regulating tumor cells to T cell-mediated killing (referred to as GRTTKs) in ESCC was explored by using a comprehensive bioinformatics approach. Training and validation datasets were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. A prognostic risk scoring model was developed by integrating prognostic GRTTKs from TCGA and GEO datasets using a ridge regression algorithm. Patients with ESCC were divided into high- and low-risk groups based on eight GRTTKs (EIF4H, CDK2, TCEA1, SPTLC2, TMEM209, RGP1, EIF3D, and CAPZA3) to predict overall survival in the TCGA cohort. Using Kaplan-Meier curves, receiver operating characteristic curves, and C-index analysis, the high reliability of the prognostic risk-scoring model was certified. The model scores served as independent prognostic factors, and combining clinical staging with risk scoring improved the predictive value. Patients in the high-risk group exhibited abundant immune cell infiltration, including immune checkpoint expression, antigen presentation capability, immune cycle gene expression, and high tumor inflammation signature scores. The high-risk group exhibited a greater response to immunotherapy and neoadjuvant chemotherapy than the low-risk group. Drug sensitivity analysis demonstrated lower IC50 for AZD6244 and PD.0332991 in high-risk groups and lower IC50 for cisplatin, ATRA, QS11, and vinorelbine in the low-risk group. Furthermore, the differential expression of GRTTK-related signatures including CDK2, TCEA1, and TMEM209 were verified in ESCC tissues and paracancerous tissues. Overall, the novel GRTTK-based prognostic model can serve as indicators to predict the survival status and immunotherapy response of patients with ESCC, thereby providing guidance for the development of personalized treatment strategies.

Isorhynchophylline attenuates proliferation and migration of synovial fibroblasts via the FOXC1/ß-catenin axis.

Rheumatoid arthritis (RA) is a common type of chronic inflammatory disease. Elucidating the mechanism of fibroblast-like synovial (FLS) as a pathologic factor in RA may address the urgent medical requirement for the treatment of RA. Isorhynchophylline (IRN) is a tetracyclic hydroxyindole alkaloid isolated from uncinaria, which has multiple biological activities and affects the progression of osteoarthritis. However, the role of IRN in rheumatoid arthritis remains unclear. Herein, our study aimed to elucidate the potential effect of IRN on RA and reveal its mechanism. Human FLS cell line MH7A cells were stimulated with TNF-α for 24 h to construct a cell model. CCK-8, Edu, wound healing, as well as transwell assays were conducted to detect the effects of IRN on cell proliferation and motility. ELISA and Immunoblot assays were further performed to detect the production of pro-inflammatory factors and the expression levels of MMPs. Immunoblot and Immunostaining assays were conducted to uncover the mechanism. ELISA, H&E staining, and Immunoblot assays were used to confirm the effects of IRN on RA in a CIA rat model. We revealed that IRN restrained TNF-α-stimulated MH7A cell proliferation and motility. In addition, IRN blocked the production of pro-inflammatory factors and MMPs in TNF-α-stimulated-MH7A cells. We further found that IRN restrained FOXC1/ß-catenin axis, and improved MH7A cell proliferation as well as migration via the FOXC1/ß-catenin axis. IRN restores CIA by inhibiting pro-inflammatory cytokines in synovial tissues. In summary, IRN attenuates proliferation and migration of FLS in RA via the FOXC1 mediated ß-catenin axis.

Identification of hub genes associated with spermatogenesis by bioinformatics analysis.

Spermatogenesis is a complex process related to male infertility. Till now, the critical genes and specific mechanisms have not been elucidated clearly. Our objective was to determine the hub genes that play a crucial role in spermatogenesis by analyzing the differentially expressed genes (DEGs) present in non-obstructive azoospermia (NOA) compared to OA and normal samples using bioinformatics analysis. Four datasets, namely GSE45885, GSE45887, GSE9210 and GSE145467 were used. Functional enrichment analyses were performed on the DEGs. Hub genes were identified based on protein-protein interactions between DEGs. The expression of the hub genes was further examined in the testicular germ cell tumors from the TCGA by the GEPIA and validated by qRT-PCR in the testes of lipopolysaccharide-induced acute orchitis mice with impaired spermatogenesis. A total of 203 DEGs including 34 up-regulated and 169 down-regulated were identified. Functional enrichment analysis showed DEGs were mainly involved in microtubule motility, the process of cell growth and protein transport. PRM2, TEKT2, FSCN3, UBQLN3, SPATS1 and GTSF1L were identified and validated as hub genes for spermatogenesis. Three of them (PRM2, FSCN3 and TEKT2) were significantly down-regulated in the testicular germ cell tumors and their methylation levels were associated with the pathogenesis. In summary, the hub genes identified may be related to spermatogenesis and may act as potential therapeutic targets for NOA and testicular germ cell tumors.

Genome-wide methylation profiling identified methylated KCNA3 and OTOP2 as promising diagnostic markers for esophageal squamous cell carcinoma.

BACKGROUND: Early detection of esophageal squamous cell carcinoma (ESCC) can considerably improve the prognosis of patients. Aberrant cell-free DNA (cfDNA) methylation signatures are a promising tool for detecting ESCC. However, available markers based on cell-free DNA methylation are still inadequate. This study aimed to identify ESCC-specific cfDNA methylation markers and evaluate the diagnostic performance in the early detection of ESCC. METHODS: We performed whole-genome bisulfite sequencing (WGBS) for 24 ESCC tissues and their normal adjacent tissues. Based on the WGBS data, we identified 21,469,837 eligible CpG sites (CpGs). By integrating several methylation datasets, we identified several promising ESCC-specific cell-free DNA methylation markers. Finally, we developed a dual-marker panel based on methylated KCNA3 and OTOP2, and then, we evaluated its performance in our training and validation cohorts. RESULTS: The ESCC diagnostic model constructed based on KCNA3 and OTOP2 had an AUC of 0.91 [95% CI: 0.85-0.95], and an optimal sensitivity and specificity of 84.91% and 94.32%, respectively, in the training cohort. In the independent validation cohort, the AUC was 0.88 [95% CI: 0.83-0.92], along with an optimal sensitivity of 81.5% and specificity of 92.9%. The model sensitivity for stage I-II ESCC was 78.4%, which was slightly lower than the sensitivity of the model (85.7%) for stage III-IV ESCC. CONCLUSIONS: The dual-target panel based on cfDNA showed excellent performance for detecting ESCC and might be an alternative strategy for screening ESCC.

A Retrospective, Long-term Follow-up of the Clinical Outcomes and Cost-effectiveness of Single-anesthetic Multiple Total Joint Procedures in Hemophilic Arthropathy.

OBJECTIVE: Although total joint replacement (TJR) procedures are efficacious, perioperative high-dose factors replacement therapy (FRT) to avoid catastrophic bleeding represents a significant hurdle, particularly for patients with multiple joint affection. Double simultaneous bilateral TJRs were reported as safe and cost-effective. However, little is known about multiple TJRs. The feasibility and effects remain debatable. Surgeons need to weigh the high cost of FRT against safety. Accordingly, we aimed to evaluate the clinical outcomes and cost-effectiveness of single-anesthetic multiple-joint procedures of lower limbs in end-stage hemophilic arthropathy. METHODS: Our retrospective cohort study retrieved data from an inpatient database of patients with hemophilia who underwent total knee arthroplasty (TKA), total hip arthroplasty (THA), and/or ankle arthrodesis from January 2000 to April 2016. Complications, hospital stays, transfusion, doses of clotting factor, medical costs, range of motion (ROM), Harris hip scores (HHSs) and Hospital for special surgery knee scores (HSSs) were recorded. A P value < 0.05 was considered significant. RESULTS: A total number of 81 patients were included in this study, among which 89 TKAs and 52 THAs were performed. Compared to the single TJR group, the simultaneous multiple TJR group showed a significantly higher rate of blood transfusions (P < 0.05). But no significant differences were found in the length of hospital stays, factor consumption, hospitalization costs excluding prosthesis expenses, and total complication rates. Finally, similar postoperative ROM, HHS, and HSS were witnessed in two groups (P value > 0.05). CONCLUSION: Our data indicated that simultaneous multiple TJRs are a safe and cost-effective choice for treating hemophilic patients with multiple HA-affected lower limb joints.

Association Between Constipation and a Reduction in Lower Limb Muscle Strength in Preoperative Patients with Thoracic Spinal Tumors.

Objective To investigate the clinical symptoms experienced by patients with thoracic spinal tumors and verify the associated symptoms that are predictive of a decline in muscle strength in the lower limbs. Methods A single-center, retrospective cross-sectional study was conducted on in-patients diagnosed with epidural thoracic spinal tumors between January 2011 and May 2021. The study involved a review of electronic medical records and radiographs and the collection of clinical data. The differences in clinical manifestations between patients with constipation and those without constipation were analyzed. Binary logistic regression analyses were performed to identify risk factors associated with a decline in muscle strength in the lower limbs.Results A total of 227 patients were enrolled, including 131 patients with constipation and 96 without constipation. The constipation group had a significantly higher proportion of patients who experienced difficulty walking or paralysis compared to those without constipation prior to surgery (83.2% vs. 17.7%, χ2 = 99.035,P < 0.001). Constipation (OR = 9.522, 95%CI: 4.150-21.849, P < 0.001) and urinary retention (OR = 14.490, 95%CI: 4.543-46.213, P < 0.001) were independent risk factors for muscle strength decline in the lower limbs. Conclusions The study observed that patients with thoracic spinal tumors who experienced constipation symptoms had a higher incidence of lower limb weakness. Moreover, the analysis revealed that constipation and urinary retention were independent risk factors associated with a preoperative decline in muscle strength of lower limbs.

LncRNA Gm16638-201 Inhibits the 14-3-3Ɛ Pathway in the Murine Prefrontal Cortex to Induce Depressive Behaviors.

The dysregulation of certain long non-coding RNAs (lncRNAs) has been considered to be involved in neuropsychiatric disorders such as depression, implying the vital role of these transcripts. We have previously identified many differentially expressed lncRNAs in chronic unpredictable mild stress (CUMS) induced mice. Among them, lncRNA Gm16638-201 was highly expressed in the hippocampus (HIP) of CUMS, but the specific role and the underlying mechanisms remain unclear. Here, we reported that lncRNA Gm16638-201 was highly expressed in the prefrontal cortex (PFC) of CUMS induced depressive mice. Bioinformatic analysis shows that Gm16638-201 is mainly located in the cytoplasm. Nine neurological-related genes (Elmo2, Satb1, Hnrnpul1, Sipa1l3, Mapt, Tada3, Sgip1, IL-16, and StarD5) were predicted to be regulated in cis or trans by Gm16638-201 and involved into the 14-3-3Ɛ neurotrophic signaling pathway. We further confirmed the down-regulation of 14-3-3Ɛ and the nine predicted target genes in the PFC of CUMS mice except for Sgip1 and IL-16. In addition, they were also down-regulated in the primary cortical cell cultures with overexpression of Gm16638-201 constructed using an adenoviral-medicated gene expression system. In conclusion, we found that overexpression of Gm16638-201 negatively regulated several target genes and inhibited the 14-3-3Ɛ pathway in the PFC of CUMS induced depressive mice. This promising result suggests that Gm16638-201 may be a potential novel therapeutic target for depression.

The Effect of a Local Injection of Flurbiprofen Ester Microspheres on Systemic Inflammatory Model Rats With a Closed Femoral Shaft Fracture.

Background: Periarticular injections with a combination of local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDs), and epinephrine are becoming increasingly popular in the perioperative analgesia of artificial joint replacement. However, data on the efficacy and safety of local injection NSAIDs are still scarce. The purpose of this study was to investigate the efficacy and safety of a local injection of Flurbiprofen Ester Lipid microspheres into the inflammatory model of femoral shaft closed fractures in rats. Methods: A systemic inflammatory model was induced in SD rats (60) by closed femoral shaft fracture; 12 non-fractured rats were used as the blank control group (group A). The systemic inflammation model of 60 rats was divided into 5 groups (12 in each group); Group B: intramuscular injectionof the same amount of normal saline at different time points as a negative control; Group C: intravenous injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group D: intramuscular injection of Flurbiprofen Ester microspheres (2.25 mg/kg) at different time points; Group E: intramuscular injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group F: intramuscular injection of Flurbiprofen Ester microspheres (9 mg/kg) at different time points. The behavioral test observed the behavior of the rats. Then, the inflammation factors of CRP, IL-6, COX-1, COX-2 and TNF-αby ELISA were recorded. Results: Through the behavioral test it could be found that the effect of the intramuscular and intravenous injections of Flurbiprofen Ester microspheres was similar. Fracture rats with a local injection of Flurbiprofen Ester microspheres showed lower inflammation levels measured by COX-1, CRP, and TNF-α compared with the control group. Pathological sections at 24, 48, and 96 h after surgery did not display any local muscle necrosis at the local injection site. These findings suggested that a Flurbiprofen Ester microsphere muscular injection exhibited a similar effect to an intravenous injection. Conclusion: The local injection of Flurbiprofen Ester microspheres significantly reduced the inflammatory response in fracture rats and did not increase the risk of muscle necrosis, suggesting its feasibility in local injection analgesia.

Molecular pathways associated with oxidative stress and their potential applications in radiotherapy (Review).

Radiotherapy is an essential and effective treatment modality for cancer. Excessive levels of reactive oxygen species (ROS) induced by ionizing radiation disrupt the redox homeostasis and lead to oxidative stress that may result in cell death. However, the tumor cell microenvironment is dynamic and responds to radiotherapy by activating numerous cellular signaling pathways. By scavenging excess ROS, the activity levels of the endogenous antioxidant enzymes result in radioresistance and worsen the clinical outcomes. To assess the full potential of radiotherapy, it is essential to explore the underlying mechanisms of oxidative stress in radiotherapy for potential target identification. The present review article summarized recent data demonstrating nuclear factor­erythroid factor 2­related factor 2 (Nrf2) as a powerful transcription factor and one of the major cellular defense mechanisms that protect against oxidative stress in response to radiotherapy; the glutathione (GSH) and thioredoxin (Trx) systems complement each other and are effective antioxidant mechanisms associated with the protection of cancer cells from radiation damage. In addition, it is suggested that dual targeting to inhibit GSH and Trx enzymes may be a potential strategy for the development of radiosensitive and radioprotective drugs.

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions.

Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. Resveratrol is gaining attention for its cancer preventive and suppressive properties. The mechanisms of resveratrol in cancer suppression by inducing cancer cell senescence are unclear. Our results showed that resveratrol induced cell senescence along with an increase of SA-ß-Gal activity and inhibition of colony formation in breast and lung cancer cells. The underlying mechanisms were that resveratrol induced ER-stress by increasing SIRT1 to promote p38MAPK expression and by reducing NO level to up-regulate DLC1 expression, and ER-stress further resulted in DNA damage and mitochondrial dysfunction, eventually leading to cancer cell senescence. Our findings on resveratrol's induction of cancer cell senescence via activating ER-stress through the SIRT1/p38MAPK and NO/DLC1 pathways provide a solid base for its clinical application and its preventive application as a food additive.

Knowledge mapping of alternative splicing of cancer from 2012 to 2021: A bibliometric analysis.

Background: As a processing method of RNA precursors, alternative splicing (AS) is critical to normal cellular activities. Aberrant AS events are associated with cancer development and can be promising targets to treat cancer. However, no detailed and unbiased study describes the current state of AS of cancer research. We aim to measure and recognize the current state and trends of AS cancer research in this study. Methods: The Web of Science Core Collection was used to acquire the articles. Utilizing three bibliometric tools (CiteSpace, VOSviewer, R-bibliometrix), we were able to measure and recognize the influence and collaboration data of individual articles, journals, and co-citations. Analysis of co-occurrence and burst information helped us identify the trending research areas related to AS of cancer. Results: From 2012 to 2021, the total number of papers on AS of cancer published in 766 academic journals was 3,507, authored by 20,406 researchers in 405 institutions from 80 countries/regions. Research involving AS of cancer genes was primarily conducted in the United States and China; simultaneously, the Chinese Academy of Sciences, Fudan University, and National Cancer Institute were the institutions with strong research capabilities. Scorilas Andreas is the scholar with the most publications, while the most co-citations were generated by Wang, Eric T. Plos One published the most papers on AS of cancer, while J Biol Chem was the most co-cited academic journal in this field. The results of keyword co-occurrence analysis can be divided into three types: molecular (P53, CD44, androgen receptor, srsf3, esrp1), pathological process (apoptosis, EMT, metastasis, angiogenesis, proliferation), and disease (breast cancer, colorectal cancer, prostate cancer, hepatocellular carcinoma, gastric cancer). Conclusion: Research on AS of cancer has been increasing in intensity over the past decade. Current AS of cancer studies focused on the hallmarks of AS in cancer and AS signatures including diagnostic and therapeutic targets. Among them, the current trends are splicing factors regulating epithelial-mesenchymal transition and other hallmarks, aberrant splicing events in tumors, and further mechanisms. These might give researchers interested in this field a forward-looking perspective and inform further research.

LINC00261 Inhibits Esophageal Cancer Radioresistance by Down-Regulating microRNA-552-3p and Promoting DIRAS1.

OBJECTIVE: Esophageal cancer (EC) represents a life-threatening tumor with an ever-increasing incidence rate. Long intergenic non-protein coding RNAs (LINCs) have also become a topic of interest in EC. In a similar light, the current study aimed to investigate the role of LINC00261 in EC radioresistance. METHODS: Firstly, radioresistant EC cell lines TE-1-R and TE-5-R were established using TE-1 and TE-5 cells. Subsequently, LINC00261, microRNA (miR)-552-3p, and DIRAS1 expression patterns in EC tissues and adjacent normal tissues and EC cells were evaluated. In addition, survival fraction (SF), colony formation, apoptosis, and γ-H2AX levels were analyzed, followed by the detection of the binding relation between LINC00261 and miR-552-3p and between miR-552-3p and DIRAS1. Lastly, xenograft transplantation was carried out to confirm the effects of LINC00261 on EC radioresistance in vivo. RESULTS: LINC00261 and DIRAS1 were poorly-expressed in EC tissues and cells, but miR-552-3p was over-expressed. In EC cells with X-ray radiation, over-expression of LINC00261 reduced SF and cell viability, strengthened γ-H2AX levels, and promoted apoptosis, while all these trends were counteracted by miR-522-3p over-expression or DIRAS1 silencing. Mechanistic investigation further validated the binding relation between LINC00261 and miR-552-3p, and between miR-552-3p and DIRAS1. Moreover, LINC00261 over-expression suppressed tumor growth and reduced EC radioresistance in vivo. CONCLUSION: Altogether, our findings indicated that LINC00261 exerts a suppressive effect on EC radioresistance via the competing endogenous RNA network to sponge miR-552-3p and up-regulate DIRAS1 transcription.

Risk-Stratified Venous Thromboembolism Prophylaxis after Total Joint Arthroplasty: Low Molecular Weight Heparins and Sequential Aspirin vs Aggressive Chemoprophylaxis.

OBJECTIVE: Venous thromboembolism (VTE) is a significant concern post total joint arthroplasty (TJA). However, the optimal prevention method of VTE remains controversial at present. This study aims to evaluate a risk-stratified VTE prophylaxis protocol for patients undergoing TJA. METHODS: A total of 891 TJA patients from January 2011 to November 2019 were retrospectively investigated. The study was divided into two cohorts. In cohort 1, 410 patients (250 females and 160 males, mean age 64.32 years) were treated with an aggressive VTE chemoprophylaxis protocol. In cohort 2, 481 patients were treated with a risk-stratified protocol that utilized low molecular weight heparins (LMWH) and sequential aspirin (ASA) for standard-risk patients (a total of 288 containing 177 females and 111 males, mean age 65.4 years), and targeted anticoagulation for high-risk patients (a total of 193 containing 121 females and 72 males, mean age 66.8 years). The patients were followed up at 2-4 weeks for an initial visit and at 6-10 weeks for a subsequent visit after surgery. A chart review of all patient medical records was performed to record the demographics, comorbidities, deep vein thrombosis, pulmonary embolus, superficial infection, deep infection, bleeding complications, and 90-day readmissions. RESULTS: The VTE rate was 1.71% (7/410) in cohort 1 and 1.46% (7/481) in cohort 2 respectively. For cohort 2, the VTE rate was 2.07% (4/193) in high-risk group and 1.04% (3/288) in standard-risk group. The readmission rate was 2.44% (10/410) in cohort 1 and 2.08% (10/481) in cohort 2. For cohort 2, the readmission rate was 2.07% (4/193) in high-risk group and 2.08% (6/288) in standard-risk group. The reasons for readmission were as follows: infection, 1.3% (5/410) in cohort 1 and 1.3% (6/481) in cohort 2; wound or bleeding complications, 0.48% (2/410) in cohort 1 and 0.2% (1/481) in cohort 2; trauma, 0.2% (1/410) in cohort 1 and 0.2% (1/481) in cohort 2; VTE, 0.2% (1/410) in cohort 1 and 0.2% (1/481) in cohort 2; others, 0.2% (1/410) in cohort 1 and 0.6% (3/481) in cohort 2. There was a decrease in VTE events and readmissions in the risk-stratified cohort, although this did not reach statistical significance. However, it was found that there was a significant reduction in costs (P < 0.001) with the use of LMWH/ASA, when compared with aggressive anticoagulation agents in the risk-stratified cohort. CONCLUSION: The use of LMWH/ASA in a risk-stratified TJA population is a safe and cost-effective method of VTE prophylaxis.

The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation.

Radiotherapy is one of the most important treatments for breast cancer. Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, whether ionizing radiation (IR) could induce ferroptosis in breast cancer and how it works remain unknown. Bioinformatics analysis were performed to screen ferroptosis-related genes differentially expressed in breast tumor tissue and normal tissue. Then, breast cancer cell lines with different estrogen receptor (ER) phenotypes were used for studies in vitro, including ER-positive (MCF-7 and ZR-75-1) and ER-negative (MDA-MB-231) cells. The dynamic changes of mRNA and protein levels were examined after x-ray of 8 Gy by qRT-PCR and Western blotting, respectively. Immunoprecipitation (IP) was used to explore the interaction between proteins. Luciferase assay was used to analyze the transcriptional regulation effect of ESR1 on SLC7A11. BODIPY C11 and trypan blue dyes were used to determine lipid peroxidation and cell death, respectively. The result showed that the ferroptosis-related gene SLC7A11 was higher in breast cancer tissues compared with normal tissues and associated with poor survival. A positive correlation exists between ESR1 and SLC7A11 expression. ESR1 promoted SLC7A11 expression at the early stage after IR. ESR1/SLC7A11 knockdown significantly enhanced IR-induced ferroptosis in ER-positive cells. At 12 h after IR, the IP data showed the interaction between E3 ubiquitin ligase NEDD4L and SLC7A11 increased, followed by the ubiquitylation and degradation of SLC7A11. Thus, SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, we elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.