Advancing mid-rectal cancer surgery: Unveiling the potential of natural orifice specimen extraction surgery in comparison to conventional laparoscopic-assisted resection.

BACKGROUND: Mid-rectal cancer treatment traditionally involves conventional laparoscopic-assisted resection (CLAR). This study aimed to assess the clinical and therapeutic advantages of Natural Orifice Specimen Extraction Surgery (NOSES) over CLAR. AIMS: To compare the clinical outcomes, intraoperative metrics, postoperative recovery, complications, and long-term prognosis between NOSES and CLAR groups. MATERIALS & METHODS: A total of 136 patients were analyzed, with 92 undergoing CLAR and 44 undergoing NOSES. Clinical outcomes were evaluated, and propensity score matching (PSM) was employed to control potential biases. RESULTS: The NOSES group exhibited significant improvements in postoperative recovery, including lower pain scores on days 1, 3, and 5 (p < .001), reduced need for additional analgesics (p = .02), shorter hospital stays (10.8 ± 2.3 vs. 14.2 ± 5.3 days; p < .001), and decreased intraoperative blood loss (48.1 ± 52.7 mL vs. 71.0 ± 55.0 mL; p = .03). Patients undergoing NOSES also reported enhanced satisfaction with postoperative abdominal appearance and better quality of life. Additionally, the NOSES approach resulted in fewer postoperative complications. CONCLUSION: While long-term outcomes (overall survival, disease-free survival, and local recurrence rates) were comparable between the two methods, NOSES demonstrated superior postoperative outcomes compared to CLAR in mid-rectal cancer treatment, while maintaining similar long-term oncological safety. These findings suggest that NOSES could serve as an effective alternative to CLAR without compromising long-term results.

Establishment of human hematopoietic organoids for evaluation of hematopoietic injury and regeneration effect.

BACKGROUND: Human hematopoietic organoids have a wide application value for modeling human bone marrow diseases, such as acute hematopoietic radiation injury. However, the manufacturing of human hematopoietic organoids is an unaddressed challenge because of the complexity of hematopoietic tissues. METHODS: To manufacture hematopoietic organoids, we obtained CD34+ hematopoietic stem and progenitor cells (HSPCs) from human embryonic stem cells (hESCs) using stepwise induction and immunomagnetic bead-sorting. We then mixed these CD34+ HSPCs with niche-related cells in Gelatin-methacryloyl (GelMA) to form a three-dimensional (3D) hematopoietic organoid. Additionally, we investigated the effects of radiation damage and response to granulocyte colony-stimulating factor (G-CSF) in hematopoietic organoids. RESULTS: The GelMA hydrogel maintained the undifferentiated state of hESCs-derived HSPCs by reducing intracellular reactive oxygen species (ROS) levels. The established hematopoietic organoids in GelMA with niche-related cells were composed of HSPCs and multilineage blood cells and demonstrated the adherence of hematopoietic cells to niche cells. Notably, these hematopoietic organoids exhibited radiation-induced hematopoietic cell injury effect, including increased intracellular ROS levels, γ-H2AX positive cell percentages, and hematopoietic cell apoptosis percentages. Moreover, G-CSF supplementation in the culture medium significantly improved the survival of HSPCs and enhanced myeloid cell regeneration in these hematopoietic organoids after radiation. CONCLUSIONS: These findings substantiate the successful manufacture of a preliminary 3D hematopoietic organoid from hESCs-derived HSPCs, which was utilized for modeling hematopoietic radiation injury and assessing the radiation-mitigating effects of G-CSF in vitro. Our study provides opportunities to further aid in the standard and scalable production of hematopoietic organoids for disease modeling and drug testing.

Satisfaction With and Adherence to Off-Label Corticosteroids in Adolescents and Adults With Eosinophilic Esophagitis: Results of a Web-Based Survey in the United States.

GOALS: We assessed satisfaction with and adherence to off-label corticosteroids in patients with eosinophilic esophagitis (EoE) in the United States. BACKGROUND: EoE is a chronic inflammatory disease for which there are currently no US Food and Drug Administration-approved swallowed topical corticosteroids. STUDY: This noninterventional, cross-sectional, web-based survey included caregivers of adolescents (aged 11 to 17 y) and adults (aged 18 years or older) with a self-reported [or caregiver-reported (adolescents)] physician diagnosis of EoE who were receiving corticosteroids. Participants were recruited through 2 nonprofit, patient advocacy groups. The 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) was used to assess satisfaction across effectiveness, convenience, and global satisfaction domains (scale: 1 to 100 per domain); higher scores indicated greater satisfaction. The 4-item Morisky Green Levine Medication Adherence Scale (MGL-4) was used to assess adherence; an MGL-4 score of <3 indicated adherence. Participants also reported reasons for nonadherence. RESULTS: Overall, 201 participants (caregivers of adolescents, n=98; adults, n=103) were included in this study. Mean TSQM-9 scores indicated low satisfaction with off-label corticosteroids across all 3 satisfaction domains in adolescents (≤61.1) and adults (≤55.7). Slightly fewer adolescents (37.1%) than adults (40.8%) were considered adherent. Forgetfulness was the most frequently reported reason for nonadherence; some patients chose not to take their medications, owing to poor palatability (adolescents), difficulty taking medications at specific times (adults), or feeling depressed/overwhelmed (adolescents and adults). CONCLUSIONS: Satisfaction with and adherence to off-label corticosteroids were low in this web-based survey of adolescents and adults with EoE in the United States.

Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA.

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Low Initial Cell Density Promotes the Differentiation and Maturation of Human Pluripotent Stem Cells into Erythrocytes.

Human pluripotent stem cell (hPSC)-derived red blood cells (RBCs) possess great potential for compensating shortages in transfusion medicine. For better RBC generation from hPSCs, we compared the cell seeding density in the embryoid body formation-based hPSC induction protocol. In the selection of low- and high-density inoculation conditions, we found that low-density culture performed better in the final RBC product with more cell output and increased average cellular hemoglobin content. An elaborate study using flow cytometry demonstrated that low inoculation density promoted endothelial-to-hematopoietic transition, followed by improved hematopoietic progenitor formation and erythrocyte generation. The improved transformation from glycolysis to mitochondrial oxidation and reduced apoptosis might be responsible for this effect. Hints from RNA sequencing suggested that molecules involved in microenvironment interaction and metabolic regulation might respond for the different developmental potential. The possible mediators between outer message and intracellular response could be the nutrition sensors FOXO, PRKAA1 (AMPK), and MTOR genes. It is possible that low inoculation density triggered metabolic regulation signals, promoted mitochondrial oxidation, and resulted in enhanced cell amplification and hematopoietic differentiation. The low cell culture density will improve RBC generation from hPSCs.

Real-world clinical outcomes and healthcare costs in patients with Crohn's disease treated with vedolizumab versus ustekinumab in the United States.

OBJECTIVE: To compare real-world treatment persistence, dose escalation, rates of opportunistic or serious infections, and healthcare costs in patients with Crohn's disease (CD) receiving vedolizumab (VDZ) vs ustekinumab (UST) in the United States. METHODS: A retrospective observational study in adults with CD initiated on VDZ or UST on/after 26 September 2016, was performed using the IBM Truven Health MarketScan databases (1 January 2009-30 September 2018). Rates of treatment persistence, dose escalation, opportunistic or serious infection-related encounters, and healthcare costs per patient per month (PPPM) were evaluated. Entropy balancing was used to balance patient characteristics between cohorts. Event rates were assessed using weighted Kaplan-Meier analyses and compared between cohorts using log-rank tests. Healthcare costs were compared between cohorts using weighted 2-part models. RESULTS: 589 VDZ and 599 UST patients were included (172 [29.2%] and 117 [19.5%] were bio-naïve, respectively). After weighting, baseline characteristics were comparable between cohorts. No significant difference in rates of treatment persistence (12-month: VDZ, 76.5%; UST, 82.1%; p = .17), dose escalation (12-month: VDZ, 29.3%; UST, 32.7%; p = .97), or opportunistic or serious infection-related encounters were observed between VDZ and UST. Total mean healthcare costs were significantly lower for patients treated with VDZ vs UST (mean cost difference = -$5051 PPPM; p < .01). Findings were consistent in bio-naïve patients. CONCLUSIONS: In this real-world study, similar treatment persistence, dose escalation, and rates of opportunistic or serious infections were observed with VDZ- and UST-treated patients with CD. However, VDZ was associated with a significantly lower cost outlay for healthcare systems.

Crohn's disease (CD) causes inflammation in the digestive system. Vedolizumab (VDZ) and ustekinumab (UST) are therapies for patients with CD. Little is known about the clinical outcomes and healthcare costs of VDZ versus UST in the real world in the United States. We used health claims data and found that VDZ and UST had comparable real-world clinical outcomes. After 12 months of treatment, the proportions of patients with CD who stayed on treatment and those who needed to increase therapy dose were similar with VDZ and UST. The rate of infection was also similar between the two groups of patients. However, the monthly healthcare costs were $5051 less for patients treated with VDZ than with UST. This was mainly due to the lower cost of VDZ, which was almost half of that of UST. The lower treatment costs with VDZ may provide substantial savings for the healthcare system and patients specifically. Future cost-effectiveness studies on VDZ and UST are needed to aid treatment selection for patients with CD.

TGF-ß signaling in health, disease, and therapeutics.

Transforming growth factor (TGF)-ß is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-ß can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-ß can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-ß signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-ß signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-ß and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-ß signaling in physiological conditions as well as in pathological processes. TGF-ß-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-ß signaling and to attract more attention and interest to this research area.

Rhodium and Isothiourea Dual Catalysis: Enantiodivergent Transformation of Terminal Alkynes.

A dual rhodium/isothiourea catalytic system was developed for the enantiodivergent transformation of terminal alkynes. Under synergistic rhodium/isothiourea dual catalysis, terminal alkynes can be creatively utilized as precursors for C1-ammonium enolate species, which subsequently participate in [4 + 2] and [2 + 2] annulation reactions with α,ß-unsaturated ketimines or ketones, respectively. A wide range of chiral lactams and lactones were obtained in excellent yields and stereoselectivities (up to >20:1 dr, 98% ee).

Tumor-derived KLK8 predicts inferior survival and promotes an immune-suppressive tumor microenvironment in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second most common lung cancer worldwide, leading to millions of deaths annually. Although immunotherapy has expanded the therapeutic choices for LUSC and achieved considerable efficacy in a subset of patients, many patients could not benefit, and resistance was pervasive. Therefore, it is significant to investigate the mechanisms leading to patients' poor response to immunotherapies and explore novel therapeutic targets. Using multiple public LUSC datasets, we found that Kallikrein-8 (KLK8) expression was higher in tumor samples and was correlated with inferior survival. Using a LUSC cohort (n = 190) from our center, we validated the bioinformatic findings about KLK8 and identified high KLK8 expression as an independent risk factor for LUSC. Function enrichment showed that several immune signaling pathways were upregulated in the KLK8 low-expression group and downregulated in the KLK8 high-expression group. For patients with low KLK8 expression, they were with a more active TME, which was both observed in the TCGA database and immune marker immunohistochemistry, and they had extensive positive relations with immune cells with tumor-eliminating functions. This study identified KLK8 as a risk factor in LUSC and illustrated the associations between KLK8 and cancer immunity, suggesting the potentiality of KLK8 as a novel immune target in LUSC.

Trajectory Deformation-Based Multi-Modal Adaptive Compliance Control for a Wearable Lower Limb Rehabilitation Robot.

Adaptive compliance control is critical for rehabilitation robots to cope with the varying rehabilitation needs and enhance training safety. This article presents a trajectory deformation-based multi-modal adaptive compliance control strategy (TD-MACCS) for a wearable lower limb rehabilitation robot (WLLRR), which includes a high-level trajectory planner and a low-level position controller. Dynamic motion primitives (DMPs) and a trajectory deformation algorithm (TDA) are integrated into the high-level trajectory planner, generating multi-joint synchronized desired trajectories through physical human-robot interaction (pHRI). In particular, the amplitude modulation factor of DMPs and the deformation factor of TDA are adapted by a multi-modal adaptive regulator, achieving smooth switching of human-dominant mode, robot-dominant mode, and soft-stop mode. Besides, a linear active disturbance rejection controller is designed as the low-level position controller. Four healthy participants and two stroke survivors are recruited to conduct robot-assisted walking experiments using the TD-MACCS. The results show that the TD-MACCS can smoothly switch three control modes while guaranteeing trajectory tracking accuracy. Moreover, we find that appropriately increasing the upper bound of the deformation factor can enhance the average walking speed (AWS) and root mean square of trajectory deviation (RMSTD).

Nanoengineered Red Blood Cells Loaded with TMPRSS2 and Cathepsin L Inhibitors Block SARS-CoV-2 Pseudovirus Entry into Lung ACE2+ Cells.

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed "Nanoengineered RBCs," for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies.

Regulating the Flexibility to Assemble Porous Single-Atom Fe-Coordinated Metallopolymers for Efficient Heterogeneous Catalytic Oxidations.

Metallopolymers as organic-inorganic hybrid materials formulated by metal embedding organic polymers show great potential for novel heterogeneous catalysis, in terms of the facile structural design and tunability. Herein, the disadvantage of nonporous stacking of one-dimensional (1D) structures has been suppressed by chain modulation of the 1D metallopolymers, allowing for the convenient construction of porous assemblies with single-atom dispersion and accessible active sites. By postmodification, the Fe/CM-1 catalyst readily synthesized by coordinating the Fe(II) to the twisted chain of 1D Schiff-base polymer possesses expedient flexibility, showing the highest porosity, remarkable heterogeneous recyclability, and thus prominent catalytic activity for the selective oxidation of benzylamine and alcohols. Moreover, control experiments supported by computational studies demonstrated that the unique pincer structure of Fe/CM-1 effectively maintains the valence state of the anchored single-atom iron, facilitating single-electron transfer and promoting efficient iron redox cycling during the catalytic process. Notably, these 1D metallopolymers have the advantage of cost-effectiveness, easy preparation in gram-scale, and utilization in continuous reaction, providing inspirations for facile synthesis of efficient heterogeneous catalysts from the well-developed 1D metallopolymers.

Risk Factors of Lower Extremity Deep Vein Thrombosis After Artificial Femoral Head Replacement for Elderly Femoral Neck Fractures and a Nomogram Model Construction.

Objective: To assess lower extremity deep vein thrombosis (DVT) risk factors after artificial femoral head replacement for elderly femoral neck fractures. A nomogram model was constructed to predict its risk. Methods: In analyzing 144 participants who underwent artificial femoral head replacement for elderly femoral neck fractures, researchers collected clinical data to identify factors associated with lower extremity DVT. The study collected numerous variables ranging from age and sex to history of lower extremity DVT and use of anticoagulant drugs after surgery. The patients were in two groups: those who developed DVT (n = 62) and those who did not (n = 82). Multivariate logistic regression analysis helped to identify factors influencing the occurrence of DVT after artificial femoral head replacement. The software packages used were R 4.1.0 and RMS. Results: Univariate and multivariate regression analysis identified age, ASA level, D-dimer of lower limb DVT, ALB, and PLT as predictive risk factors of lower extremity DVT after artificial femoral head replacement for elderly femoral neck fractures. Those risk factors were used to construct a clinical predictive nomogram. The calibration curves for hypertension in patients with OSAHS risk revealed excellent accuracy of the predictive nomogram model. The unadjusted concordance index (C-index) for the model was 0.877 [95% confidence interval (CI), 0.805-0.942]. The AUC was 0.8375002. Decision curve analysis showed that the predictive model could be applied clinically when the threshold probability was 20 to 80%. Conclusions: The researchers constructed and validated a clinical nomogram to predict the occurrence of lower extremity DVT after artificial femoral head replacement in elderly patients with femoral neck fractures. Age, ASA level, D-dimer, and history of lower limb DVT, ALB, and PLT were demonstrated to be predictive risk factors of lower extremity DVT in this circumstance. This practical prognostic nomogram may help improve clinical decision-making.

Dose Escalation of Biologics in Biologic-Naïve Patients With Ulcerative Colitis: Outcomes From the ODESSA-UC Study.

Background: Dose escalation of biologics may regain treatment response in patients with ulcerative colitis (UC). However, dose escalation rates and associated outcomes and costs are not well characterized in biologic-naïve patients receiving antitumor necrosis factor-alpha (anti-TNF-α) treatments, such as infliximab or adalimumab or vedolizumab. Methods: ODESSA-UC, a retrospective cohort study investigating dose escalation in patients with UC who had received first-line biologics, used data from IBM MarketScan databases. Adults with UC and ≥1 claim for an index drug (adalimumab, infliximab, or vedolizumab) were eligible. A Cox proportional hazards model was used to evaluate the adjusted rate of dose escalation. Logistic regression was used to evaluate the odds of experiencing adverse outcomes (corticosteroid use, infection, sepsis, or inflammatory bowel disease-related hospitalization) and incurring index drug costs. Results: A year after the start of maintenance, a lower proportion of patients experienced dose escalation with vedolizumab (22.3%) than adalimumab (43.0%). The dose escalation risk was significantly higher for infliximab (hazard ratio [HR], 1.894; 95% confidence interval [CI], 1.486-2.413) and adalimumab (HR, 2.120; 95% CI, 1.680-2.675) than for vedolizumab. The odds of experiencing an adverse outcome after dose escalation were higher for anti-TNF-α treatments than for vedolizumab (odds ratio, 2.052; 95% CI, 1.200-3.507). Index drug costs after dose escalation were lowest for vedolizumab. Conclusions: Patients with UC receiving vedolizumab had a lower risk of dose escalation and lower subsequent costs than patients receiving anti-TNF-α treatments. Our study demonstrates the possible clinical and economic implications of dose escalation.

Real-World Persistence of Successive Biologics in Patients With Inflammatory Bowel Disease: Findings From ROTARY.

BACKGROUND: Patients with inflammatory bowel disease (IBD) may receive multiple successive biologic treatments in clinical practice; however, data are limited on the comparative effectiveness of biologics and the impact of treatment sequence on outcomes. METHODS: The ROTARY (Real wOrld ouTcomes Across tReatment sequences in inflammatorY bowel disease patients) study was a retrospective, observational cohort study conducted using data from the Optum Clinical Database between January 1, 2012, and February 29, 2020. Adult patients with Crohn's disease (CD) or ulcerative colitis (UC) who received 2 biologics successively were included. Biologic treatment sequences were analyzed descriptively. Cox proportional hazards models, adjusted for baseline demographics and clinical characteristics, were used to estimate the hazard ratio of switching or discontinuation for each first- and second-line biologic compared with first- and second-line adalimumab, respectively. RESULTS: In total, 4648 patients with IBD (CD, n = 3008; UC, n = 1640) were identified. Most patients received tumor necrosis factor α antagonist (anti-TNFα) treatment followed by another anti-TNFα treatment or vedolizumab. Vedolizumab and infliximab had 39.4% and 34.6% lower rates of switching or discontinuation than adalimumab, respectively, as first-line biologics in patients with CD and 30.8% and 34.3% lower rates as first-line biologics in patients with UC, respectively. Vedolizumab, infliximab, and ustekinumab had 47.2%, 40.0%, and 43.5% lower rates of switching or discontinuation than adalimumab, respectively, as second-line biologics in CD and 56.5%, 43.0%, and 45.6% lower rates as second-line biologics in patients with UC, respectively. CONCLUSIONS: Although anti-TNFα treatments were most commonly prescribed, the adjusted rates of discontinuation for adalimumab as both a first- and second-line biologic were higher than for vedolizumab, infliximab, or ustekinumab.

Patients with inflammatory bowel disease are commonly treated with different sequences of biologics. This study shows that patients who receive adalimumab as their first or second biologic treatment either stop or switch to another biologic at a greater rate than those who are treated with vedolizumab, infliximab, and ustekinumab.

Dorsal root entry zone fenestration for intramedullary ependymal cyst: illustrative case.

BACKGROUND: Intramedullary ependymal cysts are rare and difficult to distinguish from syringomyelia and neuroenteric cysts. Almost all cases in the literature have been case reports and have been performed with the traditional posterior median sulcus incision, which is difficult to identify accurately during spinal rotation. Approximately 40% of cases have transient neurological deterioration. The dorsal root entry zone has been proven to be an effective incision area in the treatment of intramedullary lesions, but so far, its utilization in intramedullary ependymal cysts has been rarely reported. OBSERVATIONS: This study is the first to report on six cases of intramedullary ependymal cysts treated with an 8-mm incision in the dorsal root entry zone to fully establish the communication between the cyst and the subarachnoid space. Imaging changes and neurological improvement were analyzed in all cases before and after surgery and were followed up for 49.7 months. LESSONS: The utilization of dorsal root entry zone fenestration in intramedullary ependymal cyst has demonstrated feasibility and effectiveness, ensuring the functional integrity of the posterior column.

CXXC finger protein 1 (CFP1) bridges the reshaping of genomic H3K4me3 signature to the advancement of lung adenocarcinoma.

Histone H3 lysine 4 trimethylation (H3K4me3) is a canonical chromatin modification associated with active gene transcription, playing a pivotal role in regulating various cellular functions. Components of the H3K4me3 methyltransferase complex, known as the proteins associated with SET1 (COMPASS), have been implicated in exerting cancer-protective or cancer-inhibitory effects through inducive H3K4me3 modification. However, the role of the indispensable non-catalytic component of COMPASS CXXC-type zinc finger protein 1 (CFP1) in malignant progression remains unclear. We have unveiled that CFP1 promote lung adenocarcinoma (LUAD) cell proliferation, migration, and invasion while impairing cell apoptosis through in vitro and in vivo models. In addition, high CFP1 expression was identified as emerged as an adverse prognostic indicator across multiple public and in-house LUAD datasets. Notably, CFP1 deficiency led to dual effects on cancer cell transcriptome including extensive inactivation of cancer-promoting as well as activation of cancer repressors. Combining this with the chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we showed that CFP1 ablation reshaped the genomic H3K4me3 distribution signature, with prominent effects on TGF-ß and WNT signaling pathways. Collectively, our study proposes that CFP1 mediates tumorigenesis by genomic histone methylation reprogramming, offering insights for future investigations into epigenetic modifications in cancer progression and potential therapeutic advancements.

KLF12 overcomes anti-PD-1 resistance by reducing galectin-1 in cancer cells.

BACKGROUNDS: Immune checkpoint blockade has revolutionized cancer treatment and has improved the survival of a subset of patients with cancer. However, numerous patients do not benefit from immunotherapy, and treatment resistance is a major challenge. Krüppel-like factor 12 (KLF12) is a transcriptional inhibitor whose role in tumor immunity is unclear. METHODS: We demonstrated a relationship between KLF12 and CD8+ T cells in vivo and in vitro by flow cytometry. The role and underlying mechanism that KLF12 regulates CD8+ T cells were investigated using reverse transcription and quantitative PCR, western blot FACS, chromatin immunoprecipitation-PCR and Dual-Luciferase reporter assays, etc, and employing small interfering RNA (siRNA) and inhibitors. In vivo efficacy studies were conducted with multiple mouse tumor models, employing anti-programmed cell death protein 1 combined with KLF12 or galectin-1 (Gal-1) inhibitor. RESULTS: Here, we found that the expression of tumor KLF12 correlates with immunotherapy resistance. KLF12 suppresses CD8+ T cells infiltration and function in vitro and in vivo. Mechanistically, KLF12 inhibits the expression of Gal-1 by binding with its promoter, thereby improving the infiltration and function of CD8+ T cells, which plays a vital role in cancer immunotherapy. CONCLUSIONS: This work identifies a novel pathway regulating CD8+ T-cell intratumoral infiltration, and targeting the KLF12/Gal-1 axis may serve as a novel therapeutic target for patients with immunotherapy resistance.