Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

Osteoarthritis (OA) is one of the most common chronic diseases in the world. However, current treatment modalities mainly relieve pain and inhibit cartilage degradation, but do not promote cartilage regeneration. In this study, we show that G protein-coupled receptor class C group 5 member B (GPRC5B), an orphan G-protein-couple receptor, not only inhibits cartilage degradation, but also increases cartilage regeneration and thereby is protective against OA. We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression, along with downregulation of anabolic genes in vitro. Furthermore, mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus (DMM) induced OA mouse model, with upregulation of cartilage catabolic factors and downregulation of anabolic factors, consistent with our in vitro findings. Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration. We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-autophagy signaling pathway. Thus, we demonstrate an integral role of GPRC5B in OA pathogenesis, and activation of GPRC5B has the potential in preventing the progression of OA.

BACKGROUND: Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS: Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS: A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
Humans ; Non-alcoholic Fatty Liver Disease/diagnosis* ; Keratin-18 ; Biomarkers ; Biopsy ; Hepatocytes/pathology* ; Apoptosis ; Liver/pathology*

Objective: To clarify the values of autotaxin (ATX) in patients with primary biliary cholangitis (PBC) and PBC-related hepatocellular carcinoma (HCC). Methods: 179 patients with PBC were selected from prospective cohorts of autoimmune liver diseases at the time of first diagnosis of PBC in Department of Hepatology, the Fifth Medical Center of PLA General Hospital, from January 2016 to January 2018, all patients with PBC received UDCA therapy, primary endpoint was event of HCC, the follow-up period was censored at the date of HCC. The relationship between level of ATX and clinical features in patients with PBC and its potential value in predicting disease progression and PBC-related HCC were analyzed. Results: The ATX level in the peripheral blood of patients with PBC was significantly higher than that of alcoholic liver cirrhosis(ALC) (t = 3.278, P = 0.001) and healthy controls(HC) (t = 6.594, P < 0.001), however, when comparing PBC to non-PBC related HCC, no significant difference was found between the groups(t=-0.240, P = 0.811). Consistent with peripheral blood levels, histochemical staining indicated that ATX in the liver of patients with PBC was significantly higher than that of HC (Z=-3.633, P < 0.001) and ALC (Z=-3.283, P < 0.001), and the expression of ATX in PBC with advanced histological stage was significantly higher than PBC with early stage (Z=-2.018, P = 0.034). The baseline ATX level in PBC patients without developing to HCC during follow-up had significant difference to patients with developing to HCC (228.451 ± 124.093 ng/ml vs 301.583 ± 100.512 ng/ml, t = 2.339, P = 0.021). The result in multivariate logistic regression analysis showed that ATX were independent predictors of PBC related HCC(OR 1.245, 95%CI 1.097-1.413). The optimal critical value of peripheral blood ATX level at baseline for predicting HCC was 235.254 ng/ml, with the cut-off value of 0.714 in AUC of the ROC (95% CI was 0.597~ 0.857), sensitivity and specificity were 84.6% and 59.0%, respectively. Conclusion: ATX level was significantly higher in PBC patients over controls, and it's concentration was correlated with UDCA efficacy and fibrosis stage. ATX has potential values in predicting disease progression and PBC-related HCC.

Purpose: Ectopic eruption can be defined as the emergence of a tooth in an abnormal location, where the tooth does not follow its typical eruption pathway. While ectopic eruption within the dentate region is well-documented in the literature, ectopic eruption in non-dentate regions is relatively rare. This study aimed to report 6 cases of ectopic teeth and present a systematic review of the English-language literature on ectopic teeth, emphasizing demographic characteristics, radiographic features, potential complications, and treatment options. Materials and Methods: A literature search was conducted using the PubMed, Medline, Web of Science, and Cochrane databases. The demographic data and radiographic findings of patients presenting with ectopic teeth were recorded. Results: The literature review yielded 61 cases of ectopic teeth, with patients ranging in age from 3 to 74 years. The findings from these previously reported cases demonstrated that the most common location for ectopic teeth was the maxillary sinus, which is consistent with this case series. The Pearson chi-square test was performed to evaluate the correlation between age and location of ectopic teeth, and the results were found to be statistically significant (P<0.05). However, no statistically significant relationship was observed between sex and the location of ectopic teeth. Conclusion The distinct features of these cases warrant reporting. This study presents the first case of supernumerary teeth in the condyle without any associated pathosis. Another notable characteristic is the pre-eruptive resorption of 2 inverted supernumerary teeth ectopically located in the palate, which predisposes to sinus opacification.

Objective: To investigate the clinicopathological features, molecular genetic features, differential diagnosis and prognosis of ELOC mutated renal cell carcinoma. Methods: From January 2015 to June 2022, 11 cases of renal cell carcinoma with clear-cell morphology, expression of CAⅨ and CK7 and no 3p deletion were collected. Two cases of ELOC mutant renal cell carcinoma were diagnosed using whole exome sequencing (WES). The clinical features, morphology, immunophenotype, FISH and WES results were analyzed. The relevant literature was reviewed. Results: The two patients were both male, aged 29 and 51 years, respectively. They were both found to have a renal mass by physical examination. The maximum diameters of the tumors were 3.5 cm and 2.0 cm, respectively. At the low magnification, the tumors were well-defined. The tumor cells showed a pushing border and were separated by thick fibrous bands, forming nodules. The tumor cells were arranged in a variety of patterns, including tubular, papillary, solid nest or alveolar. At high magnification, the tumor cells were large, with well-defined cell borders and clear cytoplasm or fine eosinophilic granules. CAⅨ was diffusely box-like positive in both cases. Case 1 was partially and moderately positive for CK7, strongly positive for CD10, diffusely and moderately positive for P504S, and weakly positive for 34βE12. In case 2, CK7 and CD10 were both partially, moderately positive and P504s were diffusely positive, but 34βE12 was negative. FISH results showed that both cases had no 3p deletion. ELOC c.235T>A (p.Y79N) mutation was identified using WES in case 1, while ELOC c.236_237inv (p.Y79C) mutation was identified in case 2. Conclusions: As a new clinical entity, ELOC mutated renal cell carcinoma may be underdiagnosed due to its overlap with clear cell renal cell carcinoma in morphology and immunophenotype. The diagnosis of renal cell carcinoma with ELOC mutation should be confirmed by morphology, immunohistochemistry, FISH and gene mutation detection. However, more additional cases are needed to explain its biological behavior and prognosis.
Humans ; Male ; Biomarkers, Tumor/genetics* ; Carcinoma, Renal Cell/pathology* ; Chromosome Aberrations ; Kidney Neoplasms/pathology* ; Molecular Biology ; Mutation ; Prognosis

Purpose: The aim of this study was to characterize the cone-beam computed tomographic (CBCT) imaging features of central giant cell granuloma (CGCG) of the jawbone. Materials and Methods: This study retrospectively reviewed 26 CBCT studies of histologically proven cases of CGCG during a period of 20 years, from 1999 to 2019. Patients’ demographic data were recorded, and radiographic features were assessed (location, border, cortication, appearance of the internal structure, locularity, septation, expansion, cortical perforation, effects on surrounding tissue, whether the lesion crossed the midline, and lesion volume). Results: In this study, CGCGs were seen almost twice as often in the mandible than in the maxilla, and 64.7% of mandibular lesions involved the anterior region. Only 26.9% of lesions crossed the midline, a feature that was considered characteristic of CGCG. Furthermore, 65.4% of lesions were unilocular and 34.6% were multilocular. The correlation between a lesion’s size and its locularity was statistically significant, and larger lesions showed a multilocular appearance. The mean volume of multilocular lesions was greater than that of unilocular lesions. Conclusion CGCGs showed variable radiographic features on CBCT, and this imaging modality is highly effective at demonstrating the radiographic spectrum and lesional extent of CGCGs in the jawbone.

INTRODUCTION: Haze is a recurrent problem in Southeast Asia. Exposure to haze is linked to ophthalmic, respiratory and cardiovascular diseases, and mortality. In this study, we investigated the role of demographic factors, knowledge and perceived risk in influencing protective behaviours during the 2013 haze in Singapore. METHODS: We evaluated 696 adults in a cross-sectional study. Participants were sampled via a 2-stage simple random sampling without replacement from a large residential district in Singapore in 2015. The questionnaire measured the participant's knowledge, perceived risk and behaviours during the Southeast Asian haze crisis in 2013. Reliability and validity of the questionnaire were assessed using comparative fit index (≥0.96) and root mean square error of approximation (≤0.05). We performed structural equation modelling to examine the relationship between the hypothesised factors and protective behaviours. RESULTS: More than 95% of the individuals engaged in at least 1 form of protective behaviour. Knowledge was strongly associated with protective behaviours via direct effect (β=0.45, 95% CI 0.19-0.69, CONCLUSION Knowledge was associated with protective behaviours, suggesting the importance of public education. Efforts should target those of lower education level and smokers. The wearing of N95 masks correlates with uptake of other protective behaviours.
Adult ; Asia, Southeastern ; Cross-Sectional Studies ; Ethnic Groups ; Humans ; Minority Groups ; Reproducibility of Results ; Singapore/epidemiology*

Adult ; Candy ; Dust ; Health Surveys ; Hearing Loss, Noise-Induced/etiology* ; Humans ; Male ; Middle Aged ; Noise, Occupational/adverse effects* ; Occupational Diseases ; Occupational Exposure

OBJECTIVE：To compare the methods for the con tent determination of polysaccharide and reducing sugar in Polygonatum cyrtonema， and to optimize the wine-steaming technology of P. cyrtonema . METHODS ： The contents of polysaccharide in P. cyrtonema were determined by anthrone-sulfuric acid method and phenol-sulfuric acid method. The contents of reducing sugar in P. cyrtonema were determined by anthrone-sulfuric acid method ， phenol-sulfuric acid method and 3， 5-dinitrosalicylic acid （DNS）method，respectively. Taking appearance and property scores of processed products ，the contents of polysaccharide，reducing sugar and total sugar as indicators ，the amount of alcohol added ，steaming time and moistening time as factors，the wine-steaming technology of P. cyrtonema was optimized by Latin square design. The contents of polysaccharide ， reducing sugar and total sugar were compared before and after steaming. RESULTS ：The linear ranges of polysaccharide and reducing sugar obtained by anthrone-sulfuric acid method were both 0.006 6-0.033 mg/mL（R2＝0.999 9）. RSDs of precision ， stability（90 min）and reproducibility tests were all lower than 3％ and 2％，respectively. Average recoveries were 99.75％（RSD＝ 0.48％，n＝6）and 103.40％（RSD＝1.25％，n＝6），respectively. The linear ranges of polysaccharide and reducing sugar obtained by phenol-sulfuric acid method were both 0.002 5-0.025 mg/mL（R2＝0.999 2）. RSDs of precision ，stability （90 min） and reproducibility tests were all lower than 5％ and 6％，respectively. Average recoveries were 112.80％（RSD＝2.36％，n＝6）and 99.20％（RSD＝3.47％，n＝6）. The linear range of reducing sugar obtained by DNS method was 0.01-0.18 mg/mL（R2＝0.999 9）. RSDs of precision ，stability（90 min）and reproducibility tests were all lower than 2％. Average recoveries was 96.95％（RSD＝ 1.19％，n＝6）. The optimal wine-steaming technology of P. cyrtonema included the amount of alcohol added of 20％，moistening time of 2 h and steaming time of 7 h. RSDs of average contents of polysaccharide ，reducing sugar and total sugar in wine-steamed products were all lower than 3％ in 3 times of validation tests （n＝3）. The average contents of polysaccharide ，reducing sugar and total sugar in 4 batches of P. cyrtonema were 16.3％，11.2％ and 27.4％；those of 4 batches of wine-steamed products were 3.4％， 61.0％ and 64.4％，respectively. CONCLUSIONS ：The anthrone- ） sulfuric acid method is the best for the determination of poly- saccharide in P. cyrtonema ；DNS method is the best for the pandongmei1228@126.com determination of reducing sugar in P. cyrtonema. The content ofpolysaccharide in wine-steamed products is decreased signifi- cantly，while the contents of reducing sugar and total sugar are increased significantly.