A nomogram for preoperative prediction of vessels encapsulating tumor clusters (VETC) pattern and prognosis of hepatocellular carcinoma.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) pattern of hepatocellular carcinoma (HCC) are associated with unfavorable prognosis. This study aimed to establish a nomogram model to predict VETC patterns based on preoperative CT imaging features. PATIENTS AND METHODS: Patients who underwent surgical resection between January 1, 2016 and August 31, 2022 were retrospectively included. Predictors associated with VETC pattern were determined by using logistic regression analyses, and a nomogram model was constructed. Prognostic factors associated with recurrence-free survival (RFS) after surgical resection were identified by using Cox regression analyses. RESULTS: A total of 84 patients were included for CT analysis. All patients underwent radical surgical resection. AST/ALT >1.07(odds ratio [OR], 4.91; 95 â€‹% CI: 1.11, 21.68; P â€‹< â€‹0.05), intratumoral necrosis (OR, 4.99; 95 â€‹% CI: 1.25, 19.99; P â€‹< â€‹0.05) and enhancing capsule (OR, 3.32; 95 â€‹% CI: 1.27, 8.94; P â€‹< â€‹0.05) were independent predictors of VETC pattern. These features were used for the construction of nomogram model, which showed comparable prediction performance, with AUC value of 0.767 (95%CI [0.662, 0.852]). CK19 status (Hazard ratio [HR], 2.02; 95 â€‹% CI: 1.06, 3.86; P â€‹< â€‹0.05), the number of tumors (HR, 3.31; 95 â€‹% CI: 1.47, 7.45; P â€‹< â€‹0.05) and VETC pattern (HR, 2.52; 95 â€‹% CI: 1.31, 4.86; P â€‹< â€‹0.05) were independent predictors of postoperative RFS. CONCLUSION: A nomogram model based on preoperative CT imaging features could be used for the characterization of VETC pattern, and has prognostic significance for postoperative RFS in patients with HCC.

Prediction of vessels encapsulating tumor clusters pattern and prognosis of hepatocellular carcinoma based on preoperative gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid magnetic resonance imaging.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) is a novel vascular pattern distinct from microvascular invasion that is significantly associated with poor prognosis in patients with hepatocellular carcinoma (HCC). This study aimed to predict the VETC pattern and prognosis of patients with HCC based on preoperative gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI). METHODS: Patients with HCC who underwent surgical resection and preoperative Gd-EOB-DTPA MRI between January 1, 2016 and August 31, 2022 were retrospectively included. The variables associated with VETC were evaluated using logistic regression. A nomogram model was constructed on the basis of independent risk factors. COX regression was used to determine the variables associated with recurrence-free survival (RFS). RESULTS: A total of 98 patients with HCC were retrospectively included. Peritumoral hypointensity on the hepatobiliary phase (HBP) (odd ratio [OR], 2.58; 95% CI, 1.05-6.33; P = .04), tumor-to-liver signal intensity ratio on HBP of ≤0.75 (OR, 27.80; 95% CI, 1.53-502.91; P = .02), and tumor-to-liver apparent diffusion coefficient ratio of ≤1.23 (OR, 4.65; 95% CI, 1.01-21.38; P = .04) were independent predictors of VETC pattern. A nomogram was constructed by combining the aforementioned 3 significant variables. The accuracy, sensitivity, and specificity were 69.79%, 71.74%, and 68.00%, respectively, with an area under the receiver operating characteristic curve of 0.75 (95% CI, 0.65-0.83). The variables significantly associated with RFS of patients with HCC after surgery were Barcelona Clinic Liver Cancer stage (hazard ratio [HR], 2.15; 95% CI, 1.09-4.22; P = .03) and VETC pattern (HR, 2.28; 95% CI, 1.29-4.02; P = .004). CONCLUSION: The preoperative imaging features based on Gd-EOB-DTPA MRI can be used to predict the VETC pattern, which has prognostic significance for postoperative RFS of patients with HCC.

LncRNA LUESCC promotes esophageal squamous cell carcinoma by targeting the miR-6785-5p/NRSN2 axis.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality worldwide. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in human cancers, including ESCC. However, the detailed mechanisms of lncRNAs in the regulation of ESCC progression remain incompletely understood. LUESCC was upregulated in ESCC tissues compared with adjacent normal tissues, which was associated with gender, deep invasion, lymph node metastasis, and poor prognosis of ESCC patients. LUESCC was mainly localized in the cytoplasm of ESCC cells. Knockdown of LUESCC inhibited cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth in vivo. Mechanistic investigation indicated that LUESCC functions as a ceRNA by sponging miR-6785-5p to enhance NRSN2 expression, which is critical for the malignant behaviors of ESCC. Furthermore, ASO targeting LUESCC substantially suppressed ESCC both in vitro and in vivo. Collectively, these data demonstrate that LUESCC may exerts its oncogenic role by sponging miR-6785-5p to promote NRSN2 expression in ESCC, providing a potential diagnostic marker and therapeutic target for ESCC patients.

CircHIPK3 regulates fatty acid metabolism through miR-637/FASN axis to promote esophageal squamous cell carcinoma.

The oncogenic role of circRNA in cancers including esophageal cancer (EC) has been well studied. However, whether and how circRNAs are involved in cancer cell metabolic processes remains largely unknown. Here, we reported that circRNA, circHIPK3, is highly expressed in ESCC cell lines and tissues. Knockdown of circHIPK3 significantly restrained cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, circHIPK3 was found to act as a ceRNA by sponging miR-637 to regulate FASN expression and fatty acid metabolism in ESCC cells. Anti-sense oligonucleotide (ASO) targeting circHIPK3 substantially inhibited ESCC both in vitro and in vivo. Therefore, these results uncover a modulatory axis constituting of circHIPK3/miR-637/FASN may be a potential biomarker and therapeutic target for ESCC in the clinic.

Complications of microwave ablation in patients with persistent/recurrent hyperparathyroidism after surgical or ablative treatment.

OBJECTIVE: To evaluate the complications associated with microwave ablation (MWA) in treating persistent/recurrent hyperparathyroidism (HPT) post-surgical or ablative treatments. MATERIALS AND METHODS: From January 2015 to December 2022, 87 persistent/recurrent HPT patients (primary HPT [PHPT]: secondary HPT [SHPT] = 13:74) who underwent MWA after surgical or ablative treatment were studied. Grouping was based on ablation order (initial vs. re-MWA), prior treatment (parathyroidectomy [PTX] vs. MWA), and etiology (PHPT vs. SHPT). The study focused on documenting and comparing treatment complications and analyzing major complication risk factors. RESULT: Among the 87 patients, the overall complication rate was 17.6% (15/87), with major complications at 13.8% (12/87) and minor complications at 3.4% (3/87). Major complications included recurrent laryngeal nerve (RLN) palsy (12.6%) and Horner syndrome (1.1%), while minor complications were limited to hematoma (3.4%). Severe hypocalcemia noted in 21.6% of SHPT patients. No significant differences in major complication rates were observed between initial and re-MWA groups (10.7% vs. 13.8%, p = 0.455), PTX and MWA groups (12.5% vs. 15.4%, p = 0.770), or PHPT and SHPT groups (15.4% vs. 13.5%, p > 0.999). Risk factors for RLN palsy included ablation of superior and large parathyroid glands (>1.7 cm). All patients recovered spontaneously except for one with permanent RLN palsy in the PTX group (2.1%). CONCLUSION: Complication rates for MWA post-surgical or ablative treatments were comparable to initial MWA rates. Most complications were transient, indicating MWA as a viable and safe treatment option for persistent/recurrent HPT patients.

HuaChanSu suppresses the growth of hepatocellular carcinoma cells by interfering with pentose phosphate pathway through down-regulation of G6PD enzyme activity and expression.

HuaChanSu is active water extracts from the skin of Bufo bufo gargarizans Cantor. It has been already used to treat clinical cancers including HCC (Hepatocellular carcinoma, HCC), however, the molecular mechanisms under HuaChanSu's anti-cancer effects remain unclear. PPP (Pentose phosphate pathway, PPP), the major source of ribose and NADPH (Nicotinamide adenine dinucleotide phosphate, NADPH), is always over-activated and particularly critical for tumor cells growth. In this study, firstly, we illustrate that HuaChanSu restrains the growth of human hepatoma cells. More importantly, we demonstrate that the expression of G6PD (Glucose-6-phosphate dehydrogenase, G6PD), the first rate-limiting enzyme of the PPP, is restrained in human hepatoma cells after treatment with HuaChanSu. Additionally, our results show that G6PD enzyme activity and dimer formation are inhibited by HuaChanSu. Furthermore, we find that HuaChanSu could inhibit NADPH production and nucleotide level. In addition, we identify that expression of PLK1 (Polo-like kinase 1, PLK1) is also reduced in response to HuaChanSu, and knockdown of PLK1 restrains enzyme activity and dimer formation of G6PD, but has no effect on G6PD protein level. Subsequently, we demonstrate that inhibition of G6PD could restrain the proliferation of tumor cells and enhance the inhibitory effect of HuaChanSu on cell proliferation of human hepatoma cells. In conclusion, for the first time, our study reveals that HuaChanSu interferes with PPP via suppression of G6PD expression and enzyme activity to restrain growth of tumor cells, and these results provide a novel insight for the anti-hepatoma mechanisms of HuaChanSu and promote the innovation of the research model of TCM. Moreover, the development of drugs targeting abnormal tumor metabolism is currently a hot topic, our works provide theoretical support for further drug development from HuaChanSu, meanwhile, the revelation of the new molecular mechanism also provides a new perspective for the study of the pathogenesis of liver cancer. Short abstract: HuaChanSu suppresses expression of G6PD, the first rate-limiting enzyme of the PPP, restrains G6PD enzyme activity and dimer formation via inhibition of PLK1, knockdown of G6PD could impair the growth of human hepatoma cells and increase the blocking effect of HuaChanSu on cell proliferation of cancer cells. In addition, HuaChanSu restrains NADPH production and nucleotide level, implying the suppression of PPP flux. Our study suggests that HuaChanSu interferes with PPP via G6PD inhibition to exert anti-hepatoma effects.

Safety enhancement of improved hydrodissection for microwave ablation in secondary hyperparathyroidism.

OBJECTIVE: To study the safety of improved hydrodissection based on the periparathyroidal fascial space during microwave ablation (MWA) for secondary hyperparathyroidism (SHPT). MATERIALS AND METHODS: Data from 337 patients (162 males and 175 females; mean age, 50.8 ± 12.8 [range, 16-84] years) who underwent MWA for SHPT were retrospectively reviewed. Among them, 177 patients underwent traditional hydrodissection (traditional group) and 160 patients underwent improved hydrodissection based on periparathyroidal fascial spaces (improved group). Safety enhancement was analyzed by comparing the complications between the two groups. The characteristics of the hydrodissected fascial spaces, complications, and the follow-up results were recorded. The baseline data, clinical parameters, laboratory indices and characteristics of SHPT lesions were analyzed to assess the risk factors associated with hoarseness. RESULTS: Hydrodissection was successfully performed in all the enrolled patients according to the protocol. Six periparathyroid fascial spaces were hydrodissected, depending on the location of the SHPT lesions. The incidence of hoarseness due to recurrent laryngeal nerve injury, the most common complication of thermal ablation for SHPT lesions, was lower in the improved group than in the traditional group (6.9% vs. 13.0%, p = 0.044). The median hoarseness recovery time in the improved group was shorter than that in the traditional group (2 vs. 6 months, p < 0.001). There was no difference in technical efficiency between the two groups (improved group vs. traditional group: 75.0% vs. 70.6%; p > 0.05). CONCLUSIONS: Compared with traditional hydrodissection, improved hydrodissection based on periparathyroidal fascial spaces could enhance safety during MWA for SHPT.

Functional reconstruction of the impaired cortex and motor function by hMGEOs transplantation in stroke.

Stroke is the leading cause of death and long-term disability worldwide. But treatments are not available to promote functional recovery, and efficient therapies need to be investigated. Stem cell-based therapies hold great promise as potential technologies to restore function in brain disorders. Loss of GABAergic interneurons after stroke may result in sensorimotor defects. Here, by transplanting human brain organoids resembling the MGE domain (human MGE organoids, hMGEOs) derived from human induced pluripotent stem cells (hiPSCs) into the infarcted cortex of stroke mice, we found that grafted hMGEOs survived well and primarily differentiated into GABAergic interneurons and significantly restored the sensorimotor deficits of stroke mice for a long time. Our study offers the feasibility of stem cell replacement therapeutics strategy for stroke.

Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke.

Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.

Mid-term low back pain improvement after total hip arthroplasty in 306 patients with developmental dysplasia of the hip.

BACKGROUND: Low back pain (LBP) from hip and spinal disorders has been one of the main reasons for visiting physicians in patients with developmental dysplasia of the hip (DDH). It is essential to identify the LBP improvement among all grades of DDH patients treated with total hip arthroplasty (THA) at 5-year follow-up. METHODS: The study included 407 hips of 306 patients (38 males, 268 females) who underwent THA between July 2007 and December 2016. There were 65 hips in Crowe I, 61 hips in Crowe II, 69 hips in Crowe III, and 212 hips in Crowe IV. One hundred and fourteen hips received subtrochanteric shortening. Patients included 101 bilateral THA (BTHA) and 205 unilateral THA (UTHA). The evaluation was performed through Back Pain Function Scale (BPFS), Harris hip score, Visual Analogue Scale (VAS), operative data and radiographic examinations. RESULTS: The BPFS in patients of unilateral Crowe III and IV relieved significantly more (p < 0.05). However, the BPFS in patients with bilateral symmetry DDH hips relieved significantly less than other groups of DDH hips (p < 0.05). Harris in hips of Crowe II improved significantly more (p < 0.05). The VAS in hips of Crowe II and III improved significantly more (p < 0.05). The unilateral THA surgical time, blood loss, blood transfusion, and osteotomy number and length in Crowe IV were significantly more (p < 0.05). CONCLUSION: THA is reliable to relieve LBP in DDH patients of unilateral Crowe III and IV; however, in patients with unilateral Crowe I, Crowe II, and bilateral DDH hips, the LBP improvements were limited. This should assist shared decision-making between orthopedic surgeons and patients. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Association between hospital surgical case volume and postoperative mortality in patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Postoperative mortality is an important indicator for evaluating surgical safety. Postoperative mortality is influenced by hospital volume; however, this association is not fully understood. This study aimed to investigate the volume-outcome association between the hospital surgical case volume for gastrectomies per year (hospital volume) and the risk of postoperative mortality in patients undergoing a gastrectomy for gastric cancer. METHODS: Studies assessing the association between hospital volume and the postoperative mortality in patients who underwent gastrectomy for gastric cancer were searched for eligibility. Odds ratios were pooled for the highest versus lowest categories of hospital volume using a random-effects model. The volume-outcome association between hospital volume and the risk of postoperative mortality was analyzed. The study protocol was registered with Prospective Register of Systematic Reviews (PROSPERO). RESULTS: Thirty studies including 586 993 participants were included. The risk of postgastrectomy mortality in patients with gastric cancer was 35% lower in hospitals with higher surgical case volumes than in their lower-volume counterparts (odds ratio: 0.65; 95% CI: 0.56-0.76; P <0.001). This relationship was consistent and robust in most subgroup analyses. Volume-outcome analysis found that the postgastrectomy mortality rate remained stable or was reduced after the hospital volume reached a plateau of 100 gastrectomy cases per year. CONCLUSIONS: The current findings suggest that a higher-volume hospital can reduce the risk of postgastrectomy mortality in patients with gastric cancer, and that greater than or equal to 100 gastrectomies for gastric cancer per year may be defined as a high hospital surgical case volume.

MiR-29a-3p: a potential biomarker and therapeutic target in colorectal cancer.

Cancer is frequently caused by microRNAs, which control post-transcriptional levels of gene expression by binding to target mRNAs. MiR-29a-3p has recently been shown to play a twofold function in the majority of malignancies, including colorectal cancer (CRC), according to mounting evidence. Here, we not only briefly summarize such connection between miR-29a-3p and cancers, but aslo primarily evaluate the miR-29a-3p expression pattern, clinical applicability, and molecular mechanisms in CRC to provide a guide for future studies. This review established the diagnostic and prognostic value of miR-29a-3p abnormalty in a variety of clinical samples for CRC. Furthermore, current molecular mechanisms of miR-29a-3p for regulating cancerous biological processes such growth, invasion, metastasis, the epithelial-mesenchymal transformation process, and immunomodulation through its upstream regulatory factors and downstream targeted genes were briefly explored. More specifically, miR-29a-3p has been linked to a few medications that have been shown to have anticancer benefits. To sum up, miR-29a-3p is a promising biomarker and prospective therapeutic target for the diagnosis and prognosis of CRC, but further research is still needed to establish a theoretical basis for more practical applications.

Mid-term outcomes after total hip arthroplasty in 106 Crowe II/III hips: different hip center positions.

BACKGROUND: Under the obvious acetabular superolateral bone defect of Crowe II/III hips, this study aimed to investigate the difference in surgical technique of different hip center positions from the surgical data and clinical outcomes. METHODS: From July 2007 to December 2016, 87 patients (106 Crowe II/III hips) consecutively received total hip arthroplasty (THA). The minimum follow-up time was 5 years. The mean limb length discrepancy was 1.97 ± 1.81 cm. Twenty-four hips had surgical histories. The patients were divided into three groups according to the acetabular prosthesis positions, depending on the Crowe classification, respectively, group 1 (Crowe I), group 2 (Crowe II) and group 3 (Crowe III). The surgical data and clinical results were used to evaluate the outcome of different surgical techniques of different hip center positions, including surgical time, blood loss, blood transfusion, number of osteotomy hips, osteotomy length, the distribution of prothesis, postoperative inpatient days, Harris hip scores, Visual Analogue Scale (VAS), Back Pain Function Scale (BPFS) and complications. RESULTS: The mean follow-up time was 8.93 ± 2.55 years. Nineteen hips performed intraoperative osteotomy. From group 1 to group 3, the mean osteotomy length were 0.53 ± 1.11 cm, 0.05 ± 0.22 cm, and 0.00 ± 0.00 cm, respectively (p = 0.083); the surgical time were 142.57 ± 57.94 min, 118.4 ± 41.22 min, and 120.00 ± 84.85 min, respectively (p = 0.324); the blood loss were 498.21 ± 368.53 mL, 333.33 ± 167.62 mL, and 350.00 ± 212.13 mL, respectively (p = 0.255); the blood transfusion were 288.48 ± 381.68 mL, 128.00 ± 235.17 mL, and 385.00 ± 219.20 mL, respectively (p = 0.199); the postoperative inpatient days were 7.95 ± 4.42 d, 7.47 ± 4.29 d, and 6.50 ± 0.71 d, respectively (p = 0.831). Among the groups, the distribution of acetabular prosthesis, acetabular liner, acetabular prosthesis sizes, femoral head sizes and femoral prothesis distal sizes were not significantly different (p > 0.05). Only the distribution of femoral prosthesis was significantly different (p = 0.046); the Harris, VAS, BPFS, and the distribution of complications were not significantly different (p > 0.05). CONCLUSIONS: We provided a framework to guide decision-making in Crowe II/III hips for surgeons: the surgical technique of different hip center positions was stable and had good outcomes, but the acetabular prothesis position and femoral prothesis should be determined according to the intraoperative situation. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

The burden and trend of gastric cancer and possible risk factors in five Asian countries from 1990 to 2019.

The burdens and trends of gastric cancer are poorly understood, especially in high-prevalence countries. Based on the Global Burden of Disease Study 2019, we analyzed the incidence, death, and possible risk factors of gastric cancer in five Asian countries, in relation to year, age, sex, and sociodemographic index. The annual percentage change was calculated to estimate the trends in age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR). The highest ASIR per 100,000 person-years in 2019 was in Mongolia [44 (95% uncertainty interval (UI), 34 to 55)], while the lowest was in the Democratic People's Republic of Korea (DPRK) [23 (95% UI, 19 to 29)]. The highest ASDR per 100,000 person-years was in Mongolia [46 (95% UI, 37 to 57)], while the lowest was in Japan [14 (95% UI, 12 to 15)]. Despite the increase in the absolute number of cases and deaths from 1990 to 2019, the ASIRs and ASDRs in all five countries decreased with time and improved sociodemographic index but increased with age. Smoking and a high-sodium diet were two possible risk factors for gastric cancer. In 2019, the proportion of age-standardized disability-adjusted life-years attributable to smoking was highest in Japan [23% (95% UI, 19 to 28%)], and the proportions attributable to a high-sodium diet were highest in China [8.8% (95% UI, 0.21 to 33%)], DPRK, and the Republic of Korea. There are substantial variations in the incidence and death of gastric cancer in the five studied Asian countries. This study may be crucial in helping policymakers to make better decisions and allocate appropriate resources.

EMP80 mediates the C-to-U editing of nad7 and atp4 and interacts with ZmDYW2 in maize mitochondria.

RNA C-to-U editing is important to the expression and function of organellar genes in plants. Although several families of proteins have been identified to participate in this process, the underlying mechanism is not fully understood. Here we report the function of EMP80 in the C-to-U editing at the nad7-769 and atp4-118 sites, and the potential recruitment of ZmDYW2 as a trans deaminase in maize (Zea mays) mitochondria. Loss of EMP80 function arrests embryogenesis and endosperm development in maize. EMP80 is a PPR-E+ protein localised to mitochondria. An absence of EMP80 abolishes the C-to-U RNA editing at nad7-769 and atp4-118 sites, resulting in a cysteine-to-arginine (Cys→Arg) change in Nad7 and Atp4 in the emp80 mutant. The amino acid change consequently reduces the assembly of complexes I and V, leading to an accumulation of the F1 subcomplex of complex V. EMP80 was found to interact with atypical DYW-type PPR protein ZmDYW2, which interacts with ZmNUWA. Co-expression of ZmNUWA enhances the interaction between EMP80 and ZmDYW2, suggesting that EMP80 potentially recruits ZmDYW2 as a trans deaminase through protein-protein interaction, and ZmNUWA may function as an enhancer of this interaction.

Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common invasive malignancy worldwide with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been reported to be involved in cancer development. However, lncRNAs that are functional in ESCC and the underlying molecular mechanisms remain largely unknown. METHODS: Transcriptomic analysis was performed to identify dysregulated lncRNAs in ESCC tissue samples. The high expression of LINC00680 in ESCC was validated by RT-qPCR, and the oncogenic functions of LINC00680 was investigated by cell proliferation, colony formation, migration and invasion assays in ESCC cells in vitro and xenografts derived from ESCC cells in mice. RNA-seq, competitive endogenous RNA (ceRNA) network analysis, and luciferase reporter assays were carried out to identify LINC00680 target genes and the microRNAs (miRNAs) bound to LINC00680. Antisense oligonucleotides (ASOs) were used for in vivo treatment. RESULTS: Transcriptome profiling revealed that a large number of lncRNAs was dysregulated in ESCC tissues. Notably, LINC00680 was highly expressed, and upregulation of LINC00680 was associated with large tumor size, advanced tumor stage, and poor prognosis. Functionally, knockdown of LINC00680 restrained ESCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, LINC00680 was found to act as a ceRNA by sponging miR-423-5p to regulate PAK6 (p21-activated kinase 6) expression in ESCC cells. The cell viability and motility inhibition induced by LINC00680 knockdown was significantly reversed upon PAK6 restoration and miR-423-5p inhibition. Furthermore, ASO targeting LINC00680 substantially suppressed ESCC both in vitro and in vivo. CONCLUSIONS: An oncogenic lncRNA, LINC00680, was identified in ESCC, which functions as a ceRNA by sponging miR-423-5p to promote PAK6 expression and ESCC. LINC00680/miR-423-5p/PAK6 axis may serve as promising diagnostic and prognostic biomarkers and therapeutic targets for ESCC.

Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction.

Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.

Bmal1 inhibits phenotypic transformation of hepatic stellate cells in liver fibrosis via IDH1/α-KG-mediated glycolysis.

Hepatic stellate cells (HSCs) play an important role in the initiation and development of liver fibrogenesis, and abnormal glucose metabolism is increasingly being considered a crucial factor controlling phenotypic transformation in HSCs. However, the role of the factors affecting glycolysis in HSCs in the experimental models of liver fibrosis has not been completely elucidated. In this study, we showed that glycolysis was significantly enhanced, while the expression of brain and muscle arnt-like protein-1 (Bmal1) was downregulated in fibrotic liver tissues of mice, primary HSCs, and transforming growth factor-ß1 (TGF-ß1)-induced LX2 cells. Overexpression of Bmal1 in TGF-ß1-induced LX2 cells blocked glycolysis and inhibited the proliferation and phenotypic transformation of activated HSCs. We further confirmed the protective effect of Bmal1 in liver fibrosis by overexpressing Bmal1 from hepatic adeno-associated virus 8 in mice. In addition, we also showed that the regulation of glycolysis by Bmal1 is mediated by the isocitrate dehydrogenase 1/α-ketoglutarate (IDH1/α-KG) pathway. Collectively, our results indicated that a novel Bmal1-IDH1/α-KG axis may be involved in regulating glycolysis of activated HSCs and might hence be used as a therapeutic target for alleviating liver fibrosis.