METTL3-modified lncRNA DSCAM-AS1 promotes breast cancer progression through inhibiting ferroptosis.

Numerous studies have indicated that N6-methyladenosine (m6A) and lncRNAs play pivotal roles in human cancer. However, the underlying functions and mechanisms of m6A-lncRNA in the physiological processes of breast cancer remain unclear. Here, we found that DSCAM-AS1 is an m6A-modified lncRNA that was overexpressed in breast cancer tissues and cells, indicating poor clinical prognosis. Gain/loss functional assays suggested that DSCAM-AS1 inhibited erastin-induced ferroptosis in breast cancer cells. Mechanistically, there were remarkable m6A modification sites on both the 3'-UTR of DSCAM-AS1 and the endogenous antioxidant factor SLC7A11. M6A methyltransferase methyltransferase-like 3 (METTL3) methylated both SLC7A11 and DSCAM-AS1. Moreover, DSCAM-AS1 recognized m6A sites on the SLC7A11 mRNA, thereby enhancing its stability. Taken together, these findings indicated a potential therapeutic strategy for breast cancer ferroptosis in an m6A-dependent manner.

No prognostic impact of staging bone scan in patients with stage IA non-small cell lung cancer.

OBJECTIVE: To investigate the survival benefit of preoperative bone scan in asymptomatic patients with early-stage non-small cell lung cancer (NSCLC). METHODS: This retrospective study included patients with radical resection for stage T1N0M0 NSCLC between March 2013 and December 2018. During postoperative follow-up, we monitored patient survival and the development of bone metastasis. We compared overall survival, bone metastasis-free survival, and recurrence-free survival in patients with or without preoperative bone scan. Propensity score matching and inverse probability of treatment weighting were used to minimize election bias. RESULTS: A total of 868 patients (58.19 ± 9.69 years; 415 men) were included in the study. Of 87.7% (761 of 868) underwent preoperative bone scan. In the multivariable analyses, bone scan did not improve overall survival (hazard ratio [HR] 1.49; 95% confidence intervals [CI] 0.91-2.42; p = 0.113), bone metastasis-free survival (HR 1.18; 95% CI 0.73-1.90; p = 0.551), and recurrence-free survival (HR 0.89; 95% CI 0.58-1.39; p = 0.618). Similar results were obtained after propensity score matching (overall survival [HR 1.28; 95% CI 0.74-2.23; p = 0.379], bone metastasis-free survival [HR 1.00; 95% CI 0.58-1.72; p = 0.997], and recurrence-free survival [HR 0.76; 95% CI 0.46-1.24; p = 0.270]) and inverse probability of treatment weighting. CONCLUSION: There were no significant differences in overall survival, bone metastasis-free survival, and recurrence-free survival between asymptomatic patients with clinical stage IA NSCLC with or without preoperative bone scan.

Frequency and Distribution of Ophthalmic Surgical Procedures among Patients with Inherited Retinal Diseases.

OBJECTIVE: In this study, we aimed to characterize the frequency and distribution of ocular surgeries in patients with inherited retinal diseases (IRDs) and evaluate associated patient and disease factors. DESIGN: Retrospective cohort. PARTICIPANTS: Subjects aged ≥ 18 years who were followed at the Johns Hopkins Genetic Eye Disease Center. METHODS: We studied a retrospective cohort of patients with an IRD diagnosis to analyze the occurrence of laser and incisional surgeries. Subjects were categorized into 2 groups: central dysfunction (macular/cone/cone-rod dystrophy, "MCCRD group") and panretinal or peripheral dysfunction (retinitis pigmentosa-like, "RP group"). Genetic testing status was recorded. The association of patient and disease factors on the frequency, distribution, and timing of surgeries was analyzed. MAIN OUTCOME MEASURES: Prevalence, prevalence odds ratio (POR), hazard ratio (HR) of ophthalmic procedures by phenotype. RESULTS: A total of 1472 eyes of 736 subjects were evaluated. Among them, 31.3% (n = 230) had undergone ocular surgery, and 78.3% of those (n = 180/230) had a history of more than 1 surgery. A total of 602 surgical procedures were analyzed. Cataract extraction with intraocular lens implantation (CEIOL) was the most common (51.2%), followed by yttrium aluminum garnet capsulotomy, refractive surgery, retinal surgery, and others. Cataract extraction with intraocular lens implantation occurred more frequently in RP than in MCCRD subjects (POR, 2.59; P = 0.002). Retinitis pigmentosa subjects underwent CEIOL at a younger age than patients with MCCRD (HR, 2.11; P < 0.001). CONCLUSIONS: Approximately one-third of patients with IRD had a history of laser or incisional surgery. Cataract extraction with intraocular lens implantation was the most common surgery; its frequency and timing may be associated with the IRD phenotype. This data may inform the design of prospective research. Such efforts may illuminate routine clinical decision-making and contribute to surgical strategy development for cell and gene therapy delivery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparison of laparoscopic radiofrequency ablation with percutaneous radiofrequency ablation in the treatment of chronic hepatitis B-related hepatocellular carcinoma involving specific sites: A retrospective cohort study.

BACKGROUND: This study compared the effectiveness and safety of laparoscopic radiofrequency ablation (LRFA) and percutaneous radiofrequency ablation (PRFA) in the treatment of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) involving specific sites. METHODS: This retrospective cohort study included patients with HBV-related HCC involving specific sites treated with LRFA or PRFA between January 2012 and December 2020. The overall survival (OS), disease-free survival (DFS), and complications were compared between the LRFA and PRFA groups. The Cox proportional-hazards regression model was used to determine the factors affecting prognosis. RESULTS: This study included 109 patients: 69 in the LRFA group and 40 cases in the PRFA group. No significant differences were found in the 3-year OS rate between the two groups (73.7% vs. 70.0%, P = 0.514), but the LRFA group showed a higher 3-year DFS rate than the PRFA group (58.2% vs. 42.5%, P = 0.018). The RFA method was not associated with OS but was independently associated with DFS (LRPA vs. PRFA, HR = 2.078, P = 0.012). The common complications were ascites, pleural effusion, and fever in the two groups. The occurrence of complications in patients treated with LRFA or PRFA was similar (15.9% vs. 12.5%, P = 0.785). CONCLUSION: LRFA was associated with a better DFS in patients with HBV-related HCC involving specific sites. Thus, LRFA might have more advantages in treating liver cancer involving specific sites.

Nickel-Based Metal-Organic Frameworks Promote Diabetic Wound Healing via Scavenging Reactive Oxygen Species and Enhancing Angiogenesis.

Chronic diabetic wounds remain a worldwide challenge for both the clinic and research. Given the vicious circle of oxidative stress and inflammatory response as well as the impaired angiogenesis of the diabetic wound tissues, the wound healing process is disturbed and poorly responds to the current treatments. In this work, a nickel-based metal-organic framework (MOF, Ni-HHTP) with excellent antioxidant activity and proangiogenic function is developed to accelerate the healing process of chronic diabetic wounds. The Ni-HHTP can mimic the enzymatic catalytic activities of antioxidant enzymes to eliminate multi-types of reactive species through electron transfer reactions, which protects cells from oxidative stress-related damage. Moreover, this Ni-based MOF can promote cell migration and angiogenesis by activating transforming growth factor-ß1 (TGF-ß1) in vitro and reprogram macrophages to the anti-inflammatory phenotype. Importantly, Ni-HHTP effectively promotes the healing process of diabetic wounds by suppressing the inflammatory response and enhancing angiogenesis in vivo. This study reports a versatile and promising MOF-based nanozyme for diabetic wound healing, which may be extended in combination with other wound dressings to enhance the management of diabetic or non-healing wounds.

A modified Blumgart anastomosis with a simple and practicable procedure after laparoscopic pancreaticoduodenectomy: our center's experience.

BACKGROUND: Laparoscopic pancreaticoduodenectomy(LPD) has become the goal of lots of minimally invasive surgical centers in recent years. Postoperative pancreatic fistula(POPF) is still the barrier to attaining the above goal. Thus, improving anastomosis techniques to reduce the rate of POPF has been a hotspot of surgery. Blumgart pancreaticojejunostomy is considered one of the best anastomosis procedures, with low rates of POPF. However, the original Blumgart pancreaticojejunostomy method is not easy for laparoscopic operation. In consequence, we modified a Blumgart pancreaticojejunostomy technique with a simple and practicable procedure and applied to LPD. METHODS: We collected and retrospectively analyzed the perioperative clinical data of patients who underwent modified Blumgart anastomosis from February 2017 to September 2022. The above patients included 53 cases in open pancreaticojejunostomy(OPD) and 58 cases in LPD. After propensity score matching, 44 cases were included for comparison in each group. RESULTS: After propensity score matching, the average time for pancreaticojejunostomy was about 30 min in the LPD group. The Clinically relevant POPF(CR-POPF) rate was 9.1%. The length of postoperative hospitalization was 13.1 days. Compared with the OPD group, The CR-POPF rate in the LPD group are not significant differences. But the postoperative length of hospital stay was significantly shorter in the LPD group. Besides, there were no other severely postoperative complications between two groups. CONCLUSION: The modified Blumgart anastomosis technique applied to LPD in our Center not only has simple and convenient properties but also low rate of CR-POPF. And this method may be a good choice for surgeons to begin to carry out LPD.

Rapid-Hardening and High-Strength Steel-Fiber-Reinforced Concrete: Effects of Curing Ages and Strain Rates on Compressive Performance.

High-strength steel-fiber-reinforced concrete (HSFRC) has become increasingly popular as a cast-in-place jointing material in precast concrete bridges and buildings due to its excellent tensile strength and crack resistance. However, working conditions such as emergency repairs and low-temperature constructions require higher demands on the workability and mechanical properties of HSFRC. To this end, a novel rapid-hardening HSFRC has been proposed, which is produced using sulphoaluminate cement (SC) instead of ordinary Portland cement. In this study, quasi-static and dynamic tests were carried out to compare the compressive behavior of conventional and rapid-hardening HSFRCs. The key test variables included SC replacement ratios, concrete curing ages, and strain rates. Test results showed: (1) Rapid-hardening HSFRC exhibited high early strengths of up to 33.14 and 44.9 MPa at the curing age of 4 h, respectively, but its compressive strength and elastic modulus were generally inferior to those of conventional HSFRC. (2) The strain rate sensitivity of rapid-hardening HSFRC was more significant compared to its conventional counterpart and increased with increasing curing ages and strain rates. This study highlights the great potential of rapid-hardening HSFRC in rapid bridge construction.

RAB6A functions as a critical modulator of the stem-like subsets in cholangiocarcinoma.

RAB6A is a member of RAB GTPase family and plays an important role in the targeted transport of neurotrophic receptors and inflammatory cytokines. RAB6A-mediated secretory pathway is involved in many physiological and pathological processes. Defects in RAB6A-mediated secretory pathway may lead to the development of many diseases, including cancer. However, its role in cholangiocarcinoma (CCA) has not yet been revealed. We explored the regulatory role of RAB6A in the stem-like subsets of CCA. We showed that RAB6A knockdown (KD) impedes cancer stem cells (CSCs) properties and epithelial-mesenchymal transition in vitro and that suppression of RAB6A inhibits tumor growth in vivo. We screened target cargos of RAB6A in CCA cells and identified a extracellular matrix component as the target cargo. RAB6A binds directly to OPN, and RAB6A KD suppressed OPN secretion and inhibited the interaction between OPN and αV integrin receptor. Moreover, RAB6A KD inhibited the AKT signaling pathway, which is a downstream effector of the integrin receptor signaling. In addition, shRNA targeting OPN blocked endogenous expression of OPN and consequently weakened CSCs properties in RAB6A-formed spheres. Similarly, inhibitor of AKT signaling, MK2206 also impedes oncogenic function of RAB6A in the stem-like subsets of CCA cells. In conclusion, our findings showed that RAB6A sustains CSCs phenotype maintenance by modulating the secretion of OPN and consequentially activating the downstream AKT signaling pathway. Targeting the RAB6A/OPN axis may be an effective strategy for CCA therapy.

Application of systemic treatment in conversion therapy options for liver cancer.

Radical hepatectomy is the main treatment method to improve the prognosis of patients with intermediate and early-stage liver cancer. Most liver cancer patients in China are in the advanced stage at the initial diagnosis, losing the opportunity for surgical treatment. Therefore, it is essential to down-stage unresectable liver cancer to resectable liver cancer clinically, which is an important way to improve patients' survival and a hotspot of current clinical research. In recent years, with the increase in effective treatment methods for liver cancer, the resection rate of conversion surgery for unresectable advanced liver cancer has been significantly improved, and a growing number of patients benefit from conversion therapy. This article mainly reviews the connotation of conversion therapy for liver cancer, the patient selection, the selection of conversion strategy, the timing of sequential operations, the scheme and safety, etc.

FBXO31 sensitizes cancer stem cells-like cells to cisplatin by promoting ferroptosis and facilitating proteasomal degradation of GPX4 in cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a malignant tumour originating from the biliary epithelium that easily infiltrates, metastasizes and recurs. The deficiency of FBXO31 facilitates the initiation and progression of several types of cancer. However, the involvement of FBXO31 in CCA progression has remained unclear. METHODS: qRT-PCR was used to detect the expression of FBXO31 in CCA. The biological functions of FBXO31 were confirmed in vivo and in vitro. Sphere formation and flow cytometry were used to identify the stem cell properties of CCA. RESULTS: FBXO31 is downregulated in CCA and that deficiency of FBXO31 is associated with the TNM stage of CCA. Functional studies showed FBXO31 inhibits cell growth, migration, invasion, cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) in vitro and impedes tumour growth in vivo. In addition, overexpression of FBXO31 increases the cisplatin (CDDP) sensitivity of CCA cells. RNA-sequencing analysis revealed that FBXO31 is involved in redox biology and metal ion metabolism in CCA cells during CDDP treatment. Further studies revealed that FBXO31 enhances ferroptosis induced by CDDP in CCA and CSC-like cells. FBXO31 enhances ubiquitination of glutathione peroxidase 4 (GPX4), which leads to proteasomal degradation of GPX4. Moreover, overexpression of GPX4 compromises the promoting effects of FBXO31 on CDDP-induced ferroptosis in CCA and CSC-like cells. CONCLUSIONS: Our studies indicate that FBXO31 functions as a tumour suppressor in CCA and sensitizes CSC-like cells to CDDP by promoting ferroptosis and facilitating the proteasomal degradation of GPX4.

Damage prevention effect of milk-derived peptides on UVB irradiated human foreskin fibroblasts and regulation of photoaging related indicators.

Long-term exposure to UVB can trigger acute inflammation of the skin and lead to skin photoaging. To scrutinize the anti-photoaging functions of peptides obtained from milk, the physicochemical including molecular weight and amino acid compositions were first analyzed. Totally 267 peptides were screened out and identified by PEAKS X software, and then evaluated through Peptide Ranker and BIOPEP-UMW. Six peptides with the highest antioxidant ability and relative abundance were selected. This study was then conducted in UVB-damaged human foreskin fibroblasts with proadministration of peptides. The results indicated that at concentrations of 0.08-0.10 mg/mL, milk-derived peptides could realize a damage prevention effect through inhibiting the generation of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA). Also, these peptides were found to promote the photoaging related enzyme activities of superoxide dismutase (SOD) and catalase (CAT), while to block the production of matrix metalloproteinases-1. Through this study, we found that milk-derived peptide mixture is effective in preventing photoaging damage. Milk-derived peptides found in this study could serve as raw materials for future development of antioxidant functional foods.

Case report: Treatment of intraductal papillary mucinous neoplasms located in middle-segment pancreas with end-to-end anastomosis reconstruction after laparoscopic central pancreatectomy surgery through a pigtail-tube-stent placement of the pancreatic duct.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is one type of pancreatic cystic neoplasm. IPMNs can be classified into three types: main duct-IPMN (MD-IPMN), branch duct-IPMN (BD-IPMN), and mixed type-IPMN (MT-IPMN). It is universally accepted by most surgeons that patients who suffered from MD-IPMN with a high risk of malignant transformation should undergo surgical resection. However, a consensus on the best surgical strategy for MD-IPMN located in the pancreatic neck has still eluded the surgical community worldwide. Recently, one patient suffering from this condition in our Minimally Invasive Pancreas Center underwent a successful surgical procedure. In this case report, we performed a laparoscopic central pancreatectomy for this patient. During this surgical procedure, we used a method of end-to-end anastomosis reconstruction through a pigtail-tube-stent placement of the pancreatic duct. Before the construction of the remnant pancreas, the surgical margins of the frozen section should be negative. After surgery, the outcome of this case was satisfactory. No complications such as postoperative hemorrhage, abdominal infection, pancreatitis, delayed gastric emptying, and clinically relevant postoperative pancreatic fistula occurred, which demonstrated that this surgical strategy could achieve a good clinical therapeutic effect for the pancreatic neck MD-IPMN. The result of postoperative routine pathology confirmed the diagnosis of MD-IPMN. The pathological features also showed that there was a high degree of hyperplasia in the local epithelium, which indicated the necessity of surgical treatment.

Optimizing the IPSA Conditions to Improve the Treatment Plan Quality in Brachytherapy for Cervical Cancer.

Recent prevalent use of three-dimensional image-guided brachytherapy (3D brachytherapy) has dramatically improved the treatment outcomes of cervical cancer. Inverse planning simulated annealing (IPSA) is one of the commonly used algorithms in 3D brachytherapy, but different conditions may affect the treatment plan quality. In this study, we compared HRCTV (high-risk clinical target volume) D90 (dose prescription) and HRCTV D95 D2cc (dose received by 2.0cc) of the rectum, bladder, and sigmoid in 30 patients with cervical cancer under four IPSA conditions. The HRCTV D90 (mean ± SD cGy) was 607.32 ± 37.86, 599.01 ± 23.62, 598.67 ± 13.07, and 596.45 ± 10.94 in four groups, respectively. The HRCTV D95 was 558.19 ± 38.51, 558.17 ± 25.72, 557.03 ± 16.12, and 555.26 ± 12.78, respectively. The sigmoid D2cc was 282.96 ± 44.84, 273.14 ± 60.69, 268.94 ± 62.32, and 292.69 ± 52.44. HRCTV D90, HRCTV D95, and sigmoid D2cc were not statistically different among the four groups (p > 0.05). However, the target fitness in group one, especially at the cervix, was poor. The rectum D2cc was 351.49 ± 32.90, 361.49 ± 28.09, 370.82 ± 24.44, and 375.33 ± 30.90. The rectum D2cc in group one was the lower than that in group three and group four (p < 0.05). The bladder D2cc was 423.59 ± 31.39, 380.75 ± 37.25, 383.27 ± 32.55, and 385.22 ± 25.79. The bladder D2cc in group one was higher than the other groups (p < 0.05). The maximum rectum limit dose (400cGy) is lower than the bladder (500cGy), and HRCTV is a whole in the IPSA algorithm; these result in the insufficiency or even absence of cervix dose that first need to meet in clinics. In conclusion, IPSA condition optimization can improve the quality of treatment plan in 3D brachytherapy and make it closer to clinical practice.

Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis.

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu+). Both of them cooperatively function to amplify the production of intracellular radical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heightening cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity to multiple drug-resistant cancer cells. Importantly, CuHPT effectively inhibits in vivo drug-resistant tumor growth and doubles the survival time of tumor-bearing mice. Thus, along with CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers through precisely deconstructing their redox homeostasis.

CircRNA_0001795 sponges miRNA-339-5p to regulate yes-associated protein 1 expression and attenuate osteoporosis progression.

Osteoporosis (OP) is one of the most common bone diseases, especially in women after menopause. Increasing evidence shows that non-coding RNAs are implicated in the pathogenesis of OP. In this study, based on the published circular RNA profiling data between OP patients and healthy controls, we found that circRNA_0001795 (circ_0001795) is downregulated in OP samples, which was further validated in the OP samples collected in this study. We therefore investigated the functional role and molecular mechanism of circ_0001795 in the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) hBMSCs by alkaline phosphatase (ALP) activity assay, ALP and Alizarin Red S (ALS) Staining, luciferase reporter assay. Our data revealed that the overexpression of circ_0001795 could significantly promote the osteogenic differentiation of hBMSCs. MiRNA-339-5p (miR-339-5p) was identified as a target of circ_0001795, and miR-339-5p mimic attenuated the effect of circ_0001795 overexpression. MiR-339-5p downregulated yes-associated protein 1 (YAP1), which mediates the effect of circ_0001795 overexpression. Overall, this study uncovered the role of circ_0001795/miR-339-5p/YAP1 axis in regulating osteogenic differentiation, indicating that targeting Circ_0001795 could serve as a novel therapeutic target for OP.

Troglitazone inhibits hepatic oval cell proliferation by inducing cell cycle arrest through Hippo/YAP pathway regulation.

Hepatic oval cells have strong proliferation and differentiation capabilities and are activated when chronic liver injury occurs or when liver function is severely impaired. Peroxisome proliferation-activated receptors (PPARs) are ligand-dependent, sequence-specific nuclear transcription factors. PPARγ is closely related to liver diseases (such as liver cancer, liver fibrosis and non-alcoholic fatty liver disease). As the main effector downstream of the Hippo signaling pathway, YAP can activate the hepatic progenitor cell program, and different expression or activity levels of YAP can determine different liver cell fates. We found that troglitazone (TRO), a classic PPARγ activator, can inhibit the growth of hepatic oval cells, and flow cytometry results showed that TRO inhibited the growth of WB-F344 cells by arresting the cells in the G0/1 phase. Western blot results also confirmed changes in G0/1 phase-related protein expression. Further experiments showed that PPARγ agonists induced hepatic oval cell proliferation inhibition and cell cycle G0/1 phase arrest through the Hippo/YAP pathway. Our experiment demonstrated, for the first time, the relationship between PPARγ and the Hippo/YAP pathway in liver oval cells and revealed that PPARγ acts as a negative regulator of liver regeneration by inhibiting the proliferation of oval cells.

Improving regorafenib's organ target precision via nano-assembly to change its delivery mode abolishes chemoresistance and liver metastasis of colorectal cancer.

Distant metastases and chemotherapy repellency are the key causes of colorectal cancer (CRC)-related mortality. Regorafenib, an oral multi-kinase inhibitor approved for treating advanced CRC with distant metastases and/or chemo-resistance, however only improves median overall survival by 1.4 months. Such limited therapeutic effect is likely due to the low bioavailability of orally administered hydrophobic regorafenib. A regorafenib nanodrug is fabricated by one-step self-assembly with a clinically often-used fluorescent agent (indocyanine green) for overcoming regorafenib's limitations, towards improving regorafenib's therapeutic efficacy in advanced CRC. This nanodrug (nanoRF) was characterized, and its antitumor effects were assessed in three preclinical CRC models. NanoRF converts regorafenib's delivery approach from oral to intravenous with a significantly high encapsulation efficacy of regorafenib (96%) and a long-time colloidal stability. Nanodrug (nanoRF) markedly prolongs regorafenib's blood circulation by halving clearance rate, and enhances regorafenib's tumor accumulation. Across three preclinical CRC models (xenografted tumor, chemodrug-resistant xenografted tumor, and liver metastasis), nanoRF drastically enhances regorafenib's tumor inhibiting efficacy by 0.5-4 folds and effectively extends survival by 0.5-5 folds. This regorafenib nanodrug is a simple, safe, and efficient therapeutic nanodrug for treating advanced CRC with a ready-to-be-clinically-translated potential.

CMTM6 as a candidate risk gene for cervical cancer: Comprehensive bioinformatics study.

Background: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) is an important programmed cell death 1 ligand 1 regulator (PD-L1). CMTM6 was reported as an important regulator of PD-L1 by promoting PD-L1 expression in tumor cells against T cells. However, the function of CMTM6 in cervical cancer is not well characterized. In addition, the role of CMTM6 in the induction of epithelial-mesenchymal transition (EMT) in the context of cervical cancer is unknown. Methods: In this study, we evaluated the role of CMTM6, including gene expression analysis, miRNA target regulation, and methylation characteristic, using multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database. The expression of CMTM6 in cervical cancer tissues and non-cancerous adjacent tissues was assessed using immunohistochemistry. In vitro and in vivo function experiments were performed to explore the effects of CMTM6 on growth and metastasis of cervical cancer. Results: Human cervical cancer tissues showed higher expression of CMTM6 than the adjacent non-cancerous tissues. In vitro assays showed that CMTM6 promoted cervical cancer cell invasion, migration, proliferation, and epithelial-mesenchymal transition via activation of mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK)/p38 signaling pathway. We identified transcription factors (TFs), miRNAs, and immune cells that may interact with CMTM6. Conclusion: These results indicate that CMTM6 is a potential therapeutic target in the context of cervical cancer.

Tumor-targeting pH/redox dual-responsive nanosystem epigenetically reverses cancer drug resistance by co-delivering doxorubicin and GCN5 siRNA.

Multidrug resistance (MDR) is a major cause accounting for chemotherapy failure and recurrence of malignant tumors. A prominent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp, a drug efflux pump). Promoting drug delivery efficacy by targeting tumor and concurrently suppressing drug efflux through down-regulating P-gp emerges as an effective strategy to enhance intracellular drug accumulation for combating MDR tumor. General Control Non-repressed 5 (GCN5), a histone acetyltransferase acting as an epigenetic regulator of multidrug resistance protein 1 (MDR1), positively regulates P-gp levels in drug-resistant cancer cells. Herein, a hyaluronic acid-coated, pH/redox dual-responsive nanosystem (HPMSNs) is fabricated for co-delivering doxorubicin (DOX) and GCN5 siRNA (siGCN5). This nanosystem can effectively encapsulate DOX and siRNA preventing premature leakage and releasing these therapeutics intracellularly via its pH/redox dual responsiveness. Through CD44-mediated targeting, DOX/siGCN5@HPMSNs increases drug internalization in CD44-overexpressing cancer cells, and markedly promotes DOX retention by down-regulating P-gp expression in drug-resistant cancers through silencing GCN5. Of note, in an MDR breast tumor model, DOX and siGCN5 co-delivered HPMSNs inhibits MDR tumor growth by 77%, abolishes P-gp-mediated drug resistance, and eliminates DOX's systemic toxicity. Thus, the tumor-targeting, stimuli-responsive nanosystem is an effective carrier for co-delivering anticancer drug and siRNA for combating cancer drug resistance. STATEMENT OF SIGNIFICANCE: We designed a tumor-targeting, pH/redox dual-responsive nanosystem (HPMSNs) for chemo-drug and siRNA co-delivery. This nanosystem efficiently co-delivered DOX and siGCN5 into drug-resistant cancer cells and significantly inhibited the tumor growth through: (1) HA shell enhanced the cellular internalization of loaded DOX and siGCN5 via CD44-mediated targeting; (2) the pH/redox dual-responsive nanosystem released the cargos in response to the intracellular environment; (3) the released siGCN5 downregulated P-gp epigenetically. In an MDR breast tumor model (MCF7/ADR), DOX and siGCN5 loaded HPMSNs markedly inhibited tumor growth, almost completely abolished P-gp expression, and minimized systemic toxicity of DOX.