Measurement of the distance between tumor micro-foci and gross tumor in rectal cancer pathological specimens: implication on margin distance of clinical target volume treated with high-dose radiotherapy for rectal cancer.

PURPOSE: To measure the micro-foci distance away from gross tumor and to provide reference to create the clinical target volume (CTV) margin for boost radiotherapy in rectal adenocarcinoma. METHODS: Twenty-eight rectal cancer surgical specimens of only total mesorectal excision were collected. The pathological specimens were retrospectively measured, and the nearest distance between the tumor micro-foci and gross tumor was microscopically measured. The "in vivo-in vitro" retraction factor was calculated as the ratio of the deepest thickness laterally and the vertical height superior/inferiorly of the rectal tumor measured in MRI and those measured in immediate pathological specimens. The retraction factor during pathological specimen processing was calculated as the distance ratio before and after dehydration in the lateral, superior, and inferior sides by the "knot marking method." The distances of tumor micro-foci were individually corrected with these two retraction factors. RESULTS: The mean "in vivo-in vitro" tumor retraction factors were 0.913 peripherally and 0.920 superior/inferiorly. The mean tumor specimen processing retraction factors were 0.804 peripherally, 0.815 inferiorly, and 0.789 superiorly. Of 28 patients, 14 cases (50.0%) had 24 lateral micro-foci, 8 cases (28.6%) had 13 inferior micro-foci, and 7 cases (25.0%) had 19 superior micro-foci. The 95th percentiles of the micro-foci distance for 28 patients were 6.44 mm (peripheral), 5.54 mm (inferior), and 5.42 mm (superior) after retraction correction. CONCLUSION: The micro-foci distances of 95% of rectal adenocarcinoma patients examined were within 6.44 mm peripherally, 5.54 mm inferiorly, and 5.42 mm superiorly. These findings provide reference to set the boost radiotherapy CTV margin for rectal cancer.

Gastrodin Ameliorates the Inflammation, Oxidative Stress, and Extracellular Matrix Degradation of IL-1ß-Mediated Fibroblast-Like Synoviocytes via Suppressing the Gremlin-1/NF-κB Pathway.

BACKGROUND: Synovial inflammation plays a crucial role in osteoarthritis (OA). Gastrodin (GAS), an active ingredient derived from the Gastrodia elata Blume rhizome, possesses antioxidant and anti-inflammatory pharmacological effects. This research aimed to evaluate the function and molecular mechanism of GAS on human fibroblast-like synoviocytes of osteoarthritis (HFLS-OA) induced by interleukin (IL)-1ß. METHODS: The impact of GAS on the viability of IL-1ß-treated HFLS-OA cells was assessed using the cell counting kit-8 (CCK-8). Quantitative real-time reverse transcription PCR (qRT-PCR) was employed to detect changes in IL-8, IL-6, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and Gremlin-1 mRNA expression in each group. Corresponding kits were utilized to measure the catalase (CAT) and superoxide dismutase (SOD) activities, as well as the nitric oxide (NO) level. Western blot analysis was conducted to examine the expression of extracellular matrix degradation-associated proteins and nuclear factor kappa-B (NF-κB) pathway-correlated proteins in each group. RESULTS: GAS significantly promoted the proliferation of IL-1ß-induced HFLS-OA cells and concurrently down-regulated Gremlin-1 mRNA expression (p < 0.05). Through the down-regulation of Gremlin-1 expression, GAS exhibited the following effects: decreased IL-8, IL-6, and TNF-α mRNA expression, as well as NO levels (p < 0.05); increased SOD and CAT activities (p < 0.05); down-regulated matrix metallopeptidase 13 (MMP-13) and MMP-1 protein expression levels (p < 0.01); and up-regulated collagen II protein expression level (p < 0.01) in IL-1ß-treated HFLS-OA cells. Additionally, GAS decreased phospho-inhibitory kappa B (p-IκB)/IκB, phospho-inhibitory kappa B kinase (p-IKK)/IKK, and p-p65/p65 ratios in IL-1ß-induced HFLS-OA cells by inhibiting Gremlin-1 expression (p < 0.01). CONCLUSION: GAS demonstrates a positive impact on inflammation, oxidative stress, and extracellular matrix degradation in IL-1ß-mediated HFLS-OA cells. This effect is achieved by suppressing Gremlin-1 expression and reducing NF-κB pathway activity.

The levels of women's awareness, experience, acceptability and preference for Vaginal Human Papillomavirus (HPV) self-sampling in three provinces of China: a cross-sectional study.

BACKGROUND: The primary screening technique for precancerous lesions and cervical cancer is human papillomavirus (HPV) testing, and HPV self-sampling has been shown to be consistent with clinician sampling in terms of the accuracy of the results and may improve cervical cancer screening rates. The aim of this study was to understand the level of awareness, experience, acceptability, and preference for vaginal HPV self-sampling among women in Jiangsu, Zhejiang, and Shanghai, China, and to analyze the possible influencing factors to determine the feasibility of implementing self-sampling. METHODS: Overall, 1793 women were included in the data analysis. A self-administered questionnaire was utilized. In addition to descriptive analysis, univariate and multivariate analyses were used to explore the associations between sociodemographic features, history of cervical cancer screening, and the level of awareness, experience, acceptability, and preference for HPV self-samples. RESULTS: The participants' level of awareness of and experience with HPV self-sampling were moderate. A total of 88.8% of participants rated the acceptability as "high", and self-sampling was preferred by 64.2% of them for cervical cancer screening. People aged 45 to 54 years showed a preference for both clinician sampling(OR = 1.762 (1.116-2.163)) and self-sampling (OR = 1.823 (1.233-2.697)). Those who had graduated from high school or above (OR = 2.305 (1.517-3.503), OR = 2.432 (1.570-3.768), OR = 3.258 (2.024-5.244)) preferred clinician-sampling, and those with a bachelor's degree or above (OR = 1.664 (1.042-2.657)) preferred self-sampling. Middle- and high-income individuals showed no preference for either sampling method (OR < 1). CONCLUSIONS: HPV self-sampling is widely accepted, but awareness, experience and preferences need to be improved. These results may help to adjust public health strategies for the early inclusion of HPV self-sampling as a screening method in national initiatives to prevent cervical cancer.

Gremlin-1 promotes IL-1ß-stimulated chondrocyte inflammation and extracellular matrix degradation via activation of the MAPK signaling pathway.

The role and mechanism of Gremlin-1 in osteoarthritis (OA) were expected to be probed in this study. Firstly, an in vitro OA model was constructed by stimulating human chondrocyte cell line CHON-001 with IL-1ß. Next, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were utilized for assessing the effect of IL-1ß with different concentrations (5, 10, and 20 ng/mL) on the activity and Gremlin-1 messenger RNA of CHON-001 cells, respectively. Besides, the influence of knocking down/over-expressing Gremlin-1 on the inflammatory factors (IL-6, TNF-α, IL-18 and PGE2), oxidative stress-related substances (malondialdehyde [MDA]; superoxide dismutase [SOD]; lactate dehydrogenase [LDH]), extracellular matrix (ECM) degradation-related proteins, and mitogen-activated protein kinase (MAPK) pathway proteins in IL-1ß-stimulated CHON-001 cells were tested by enzyme-linked immunosorbent assay, related kits, qRT-PCR, and western blot, respectively. IL-1ß inhibited CHON-001 cell proliferation and upregulated Gremlin-1 expression in a concentration-dependent manner. Overexpression of Gremlin-1 increased the IL-6, TNF-α, IL-18, PGE2, and MDA levels, enhanced the LDH activity, and decreased the SOD activity in IL-1ß-induced CHON-001 cells; while the effect of Gremlin-1 knockdown on the above factors was in contrast with that of the overexpression. Furthermore, overexpression of Gremlin-1 upregulated protein expression of matrix metalloproteinase (MMP)-3, MMP-13, and ADAMTS4 while downregulated protein expression of collagen III, aggrecan, and SOX-9 in IL-1ß-stimulated CHON-001 cells. Besides, overexpression of Gremlin-1 increased the p-p38/p38 value while decreased the p-JNK/JNK value in L-1ß-stimulated CHON-001 cells; however, knockdown of Gremlin-1 reversed the above results. Gremlin-1 may promote IL-1ß-stimulated CHON-001 cell inflammation and ECM degradation by activating the MAPK signaling pathway.

Cu2+-regulated one-pot wet-chemical synthesis of uniform PdCu nanostars for electrocatalytic oxidation of ethylene glycol and glycerol.

The fabrication of effective and stable electrocatalysts is crucial for practical applications of direct alcohol fuel cells (DAFCs). In this study, bimetallic PdCu nanostars (PdCu NSs) were fabricated by a Cu2+-modulated one-pot wet-chemical method, where cetyltrimethyl ammonium bromide (CTAB) worked as a structure-regulating reagent. The morphology, compositions, crystal structures and formation mechanism of the as-prepared PdCu NSs were investigated by a series of techniques. The unique architectures created abundant active sites, which resulted in a large electrochemical active surface area (9.5 m2 g-1). The PdCu NSs showed negative shifts in the onset potentials and large forward peak current densities by contrast with those of commercial Pd black for the catalytic ethylene glycol oxidation reaction (EGOR) and glycerol oxidation reaction (GOR). It revealed that the PdCu NSs outperformed Pd black in the similar surroundings. This work provides a constructive strategy for fabrication of high-efficiency electrocatalysts for alcohol fuel cells.

Experience and acceptability for HPV self-sampling among women in Jiangsu province, China: a cross-sectional survey.

This aim of this study was to investigate women's knowledge about HPV along with their experience and acceptability of self-sampling in Jiangsu province, China. A total of 862 women aged 25-63 years old from Jiangsu province who purchased an HPV self-sampling test kit were invited to complete a questionnaire designed by the authors. Participants had high acceptability for HPV self-sampling with a mean score of 4.2 (95% [CI], 4.1-4.22) out of 5 points. 27% of participants preferred clinician-sampling, 33% preferred self-sampling, other 40% expressed no preference. Women with good knowledge about HPV and with a good experience with HPV self-sampling were more acceptable for self-sampling (P < 0.05). The biggest concern about HPV self-sampling of the participants includes 'specimens' spoilage', 'incorrect sampling', 'can't get results in time', and so on. HPV self-sampling can be used to improve cervical cancer screening coverage and participation rates in China.

Cancer screening and can be an alternative primary screening for cervical cancer.•What the results of this study add? This study adds new findings about Chinese women's experience and acceptability of HPV self-sampling. We found that most women had high acceptability for HPV self-sampling in Jiangsu province, China, and high knowledge about HPV as well as good•What is already known on this subject? HPV self-sampling testing was proven to be useful for improving the uptake rate of cervical experience of self-sampling can improve the acceptability for self-sampling in women.•What the implications are of these findings for clinical practice and/or further research? Further research should assess the acceptability of women with less education or who never screened.

CEBPD is a master transcriptional factor for hypoxia regulated proteins in glioblastoma and augments hypoxia induced invasion through extracellular matrix-integrin mediated EGFR/PI3K pathway.

Hypoxia contributes to the initiation and progression of glioblastoma by regulating a cohort of genes called hypoxia-regulated genes (HRGs) which form a complex molecular interacting network (HRG-MINW). Transcription factors (TFs) often play central roles for MINW. The key TFs for hypoxia induced reactions were explored using proteomic analysis to identify a set of hypoxia-regulated proteins (HRPs) in GBM cells. Next, systematic TF analysis identified CEBPD as a top TF that regulates the greatest number of HRPs and HRGs. Clinical sample and public database analysis revealed that CEBPD is significantly up-regulated in GBM, high levels of CEBPD predict poor prognosis. In addition, CEBPD is highly expressed in hypoxic condition both in GBM tissue and cell lines. For molecular mechanisms, HIF1α and HIF2α can activate the CEBPD promotor. In vitro and in vivo experiments demonstrated that CEBPD knockdown impaired the invasion and growth capacity of GBM cells, especially in hypoxia condition. Next, proteomic analysis identified that CEBPD target proteins are mainly involved in the EGFR/PI3K pathway and extracellular matrix (ECM) functions. WB assays revealed that CEBPD significantly positively regulated EGFR/PI3K pathway. Chromatin immunoprecipitation (ChIP) qPCR/Seq analysis and Luciferase reporter assay demonstrated that CEBPD binds and activates the promotor of a key ECM protein FN1 (fibronectin). In addition, the interactions of FN1 and its integrin receptors are necessary for CEBPD-induced EGFR/PI3K activation by promoting EGFR phosphorylation. Furthermore, GBM sample analysis in the database corroborated that CEBPD is positively correlated with the pathway activities of EGFR/PI3K and HIF1α, especially in highly hypoxic samples. At last, HRPs are also enriched in ECM proteins, indicating that ECM activities are important components of hypoxia induced responses in GBM. In conclusion, CEPBD plays important regulatory roles in the GBM HRG-MINW as a key TF, which activates the EGFR/PI3K pathway through ECM, especially FN1, mediated EGFR phosphorylation.

Retrospective analysis of risk factors for distant metastasis of early-onset gastric cancer during the perioperative period.

Background: Although the overall global incidence of gastric cancer has been declining, the number of new cases in people under the age of 50 is increasing, which is related to metastasis, late pathological stages, and poor prognosis. There is a scarcity of large-scale studies to evaluate and predict distant metastasis in patients with early-onset gastric cancer. Methods: From January 2010 to December 2019, data on early-onset GC patients undergoing surgery were gathered from the Surveillance, Epidemiology, and End Results (SEER) database. We investigated the independent risk factors for distant metastasis in patients with early-onset gastric cancer. Based on these risk factors, we developed a nomogram to predict distant metastasis. The model underwent internal validation on the test set and external validation on 205 patients from the First Affiliated Hospital of Sun Yat-sen University and the seventh Affiliated Hospital of Sun Yat-sen University. The novel nomogram model was then evaluated using the receiver operating characteristic (ROC) curve, calibration, the area under the curve (AUC), and decision curve analysis (DCA). The training set nomogram score was used to classify the different risk clusters of distant metastasis. Results: Our study enrolled 2217 patients after establishing the inclusion and exclusion criteria, with 1873 having no distant metastasis and 344 having distant metastasis. The tumor size, total lymph nodes, whether or not receiving radiotherapy and chemotherapy, T stage, and N stage were significant predictors of advanced distant metastasis (p < 0.05). The AUC of the ROC analysis demonstrated our model's high accuracy. Simultaneously, the prediction model shows high stability and clinical practicability in the calibration curve and DCA analysis. Conclusions: We developed an innovative nomogram containing clinical and pathological characteristics to predict distant metastasis in patients younger than 50 years old with gastric cancer. The tool can alert clinicians about distant metastasis and help them develop more effective clinical treatment plans.

[Hypoglycemic effect of electroacupuncture at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus based on AMPK].

OBJECTIVE: To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas. METHODS: Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence. RESULTS: ①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05). CONCLUSION: Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.

The association between victimization and inflammation: A meta-analysis.

BACKGROUND: To meta-analyze the existing studies examining the association of childhood and adulthood victimization with inflammation and to explore the moderating variables that affect these relationships. METHODS: Relevant work published before 28th February 2021 was identified by searching five major databases. We analyzed the cross-sectional data extracted from cross-sectional and longitudinal studies using the random-effects model to estimate the correlation (r) as the pooled effect size and further conducted subgroup analyses and sensitivity analyses. RESULTS: A total of 37 articles finally met the inclusion criteria, including studies for C-reactive protein (CRP) (k = 23; NCRP = 11,780), interleukin-6 (IL-6) (k = 31; NIL-6 = 8943), and tumor necrosis factor-alpha (TNF-α) (k = 14; NTNF-α = 4125). Overall, victimization has a significantly positive association with inflammation, with a small effect size (r = 0.122). Specifically, effect sizes were the largest for TNF-a (r = 0.152), followed by IL-6 (r = 0.119), and CRP (r = 0.084). Additionally, the effect sizes for victimization against children were r = 0.145 (k = 6) for childhood victimization - childhood inflammation, and r = 0.139 (k = 27) for childhood victimization - adulthood inflammation, which appear to be larger than that of victimization against adults (r = 0.039; k = 2). LIMITATIONS: Only a small number of studies on adult victimization were included. In addition, we only analyzed the cross-sectional relationship and did not have sufficient data to compare different types of victimization and single vs. multiple victimizations. CONCLUSIONS: Victimization is associated with a heightened inflammatory response. As victimization against children may have a stronger effect than victimization against adults, prevention of victimization targeting the childhood period may be necessary. Studies with more robust methodologies (i.e., representative, longitudinal, and multi-country designs) are needed to confirm these findings and to unpack the underlying mechanisms.

Design, synthesis and evaluation of novel curcumin analog as potential anti-lung cancer agent.

Curcumin is a polyphenolic compound derived from the plant turmeric and the structural instability of which limits its further clinical applications. In this study, 11 curcumin analogs with more stable scaffold were prepared and evaluated. The results indicated that the optimal compound Y-11 exhibited the strongest antiproliferative activities against lung cancer cells including H460 and H1650. Further studies showed that Y-11 potentially inhibited hDHODH, induced cell cycle arrest and apoptosis as well as down-regulated crucial signal pathway protein expression in H1650 cells. In the conclusion, the newly designed curcumin analog Y-11 may be suitable for further development in lung cancer treatment.

[Pollution Characteristics and Emission Factors of PCDD/Fs from Iron and Steel Industry].

The pollution level, emission characteristics, and emission factors of PCDD/Fs from a number of steel plants were investigated in a particular province of China. The results showed that the concentration of PCDD/Fs was at a low level and decreased by 1-2 orders of magnitude compared with that in 2005-2019. In detail, the concentrations of PCDD/Fs ranged from 0.003-0.557 ng·m-3(I-TEQ), and the mean value was 0.165 ng·m-3 for the sintering process. Moreover, the concentrations of PCDD/Fs ranged from 0.006 to 0.057 ng·m-3, and the mean value was 0.025 ng·m-3 for the electric furnace process. In addition, the concentration of PCDD/Fs in the iron and steel industry from 2005 to 2020 increased first and then decreased, especially after the implementation of the new emission standard and the ultra-low emission control of conventional pollutants such as smoke, showing a significant decline. The results of fingerprint analysis showed that 2,3,7,8-TCDF was the largest congener contributing to the mass concentration, and lower chlorinated PCDFs were increased. This result differed from those of previous studies in which highly chlorinated PCDFs and PCDDs dominated, indicating that the generation source of PCDD/Fs had changed. The congener and isomer profiles of PCDD/Fs in flue gas from the sintering process were similar to those in the flue gas from the electric furnace process. Additionally, showing the characteristics of the typical high-temperature thermal process, the de novo synthesis may be the dominant mechanism of formation of PCDD/Fs in the sintering process and electric furnace process. The emission factor was 0.003-0.5 µg·t-1 (I-TEQ), and the average emission factor was (0.18±0.22) µg·t-1 for the sintering process. The emission factor was 0.04-0.5 µg·t-1, and the average emission factor was (0.27±0.23) µg·t-1 for the electric furnace process. These values were far lower than those of the standard toolkit for identification and quantification of dioxin and furan emissions released by UNEP in 2013 and the emission factors in the dioxin emission inventory of China in 2004. It is suggested that the emission factors of PCDD/Fs in the iron and steel industry of China should be studied and updated.

Mutation of KIT in cellular extraskeletal myxoid chondrosarcoma: a case report and literature review.

BACKGROUND: Extraskeletal myxoid chondrosarcomas (EMCs) are solid tumors that have been genetically and biologically characterized. Only a few studies have discussed the role of the KIT gene or CD117 expression in EMCs, identified by immunohistochemical (IHC) staining. Herein, we present a novel case of cellular EMC exhibiting an EWSR1-NR4A3 fusion, KIT exon 13 mutations and strong diffuse expression of CD117. CASE PRESENTATION: A 69-year-old man presented with a fist-sized tumor on his left shoulder. CT revealed a tumor in the left thoracic and dorsal muscle space. The tumor was completely resected. Histologically, the tumor cells had a nodular structure and infiltrated the peripheral fat and muscle tissues. The tumor cells were uniform in size with round nuclei, well-defined nucleoli and eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CD117, vimentin, CD56 and NSE and focally expressed desmin; the cells were negative for myogenin, S-100, SYN, INSM1, CD34, STAT6, INI-1, Brachyury, ERG, TLE1, AE1/AE3, WT-1, CD99 and SMA. NGS revealed an EWSR1-NR4A3 fusion and KIT exon 13 mutations. The patient had no further treatment after surgery, and no recurrence or metastasis occurred during the ~ 10 month follow-up period. CONCLUSIONS: Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations noted in this case report may offer fresh insights into EMCs treatment options.

Anti-inflammatory action of geniposide promotes wound healing in diabetic rats.

CONTEXT: As a major active iridoid glycoside from Gardenia jasminoides J. Ellis (Rubiaceae), geniposide possesses various pharmacological activities, including anti-platelet aggregation and anti-inflammatory action. OBJECTIVES: This study explores the effect of geniposide in diabetic wound model by anti-inflammatory action. MATERIALS AND METHODS: Diabetic rodent model in Wistar rats was induced by streptozotocin combined with high-fat feed. The selected rats were divided into control group, the diabetic model group and geniposide subgroups (200, 400 and 500 mg/kg), and orally administrated once daily with saline or geniposide. Wound area and histochemical indicators were measured on day 7 after continuous administration, to assess lesion retraction, inflammatory cells and fibroblasts. RESULTS: Geniposide notably enhanced lesion retraction by 1.06-1.84 times on day 7 after surgical onset in diabetic rats (p < 0.05). In the pathological experiment by HE staining, geniposide significantly reduced inflammatory cell infiltration and proliferation of fibroblasts in the central lesion regions. In diabetic rats treated with geniposide, the levels of pro-inflammatory factors (tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß)) and IL-6 were significantly reduced (p < 0.05), followed with the increment of IL-10 in a dose-dependent manner. The IC50 of geniposide on TNF-α, IL-1ß and IL-6 could be calculated as 1.36, 1.02 and 1.23 g/kg, respectively. It assumed that geniposide-induced IL-10 expression contributed to inhibiting the expression of pro-inflammatory factors. DISCUSSION AND CONCLUSIONS: Geniposide promoted diabetic wound healing by anti-inflammation and adjusting blood glucose. Further topical studies are required to evaluate effects on antibacterial activity and skin regeneration.

Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma.

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease.

BACKGROUND: Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians. AIM: To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations. METHODS: From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis. RESULTS: The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro, IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D. CONCLUSION: WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.

A single amino acid mutant in the EAR motif of IbMYB44.2 reduced the inhibition of anthocyanin accumulation in the purple-fleshed sweetpotato.

Purple-fleshed sweetpotato (Ipomoea batatas（L.）Lam.) is rich in anthocyanins. R2R3-type MYB transcription factors（TFs）with EAR motifs inhibiting anthocyanin biosynthesis have been reported, and there is still a lack of information on how mutations in the EAR motifs of MYBs affect anthocyanin accumulation. In this study, we obtained three IbMYB44 TFs by bioinformatics. Among these TFs, IbMYB44.1, IbMYB44.3 with a complete EAR motif and IbMYB44.2 with a single amino acid mutant in the EAR motif caused an amino acid substitution from leucine to valine. RT-qPCR analysis showed that IbMYB44s was expressed at lower levels in the purple-fleshed sweetpotato than in nonpurple-fleshed sweetpotato (P < 0.01). Transient expression assays showed that the inhibitory effect of IbMYB44.1/3 was stronger than IbMYB44.2 in tobacco leaves and red-skinned pears. RT-qPCR analysis further proved that IbMYB44.1/3 significantly inhibited the expression of anthocyanin biosynthesis-related genes compared with IbMYB44.2 in tobacco leaves and red-skinned pears. A dual luciferase reporter assay showed that IbMYB44s cannot directly activate the IbANS promoter, and the result was also verified by yeast one-hybrid (Y1H) experiments. Moreover, we identified the interaction of IbMYB340 with IbMYB44.1, IbMYB44.2 and IbMYB44.3 via yeast two-hybrid (Y2H) assays. Thus, IbMYB44.1/3 could interact with IbMYB340 to negatively regulate anthocyanin biosynthesis. This study enriched the regulatory network of anthocyanins and also provided a theoretical basis for a single amino acid mutant from leucine to valine in the EAR motif of IbMYB44.2 affecting anthocyanin biosynthesis in the purple-fleshed sweetpotato.

The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis.

Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)-target genes, and meanwhile suppresses type I interferons (IFNs) and IFN-stimulated genes (ISGs) to promote ERα-positive breast cancer cell growth and tumorigenesis. KDM5C-interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P-TEFb complex to activate ERα-target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.