In recent years, gastrointestinal stromal tumors (GIST) have increased incidence and mortality, and most GIST is caused by the activation mutation of the c-KIT gene. Therefore, c-KIT has become a promising therapeutic target of GIST. At present, the drugs approved for the treatment of GIST including imatinib, sunitinib, regorafenib and ripretinib, are mostly prone to developing resistance and accompanied by various degrees of adverse reactions. Therefore, there is an urgent need to develop new c-KIT inhibitors to solve the problem of resistance. In this study, we investigated the anti-tumor effect of a novel c-KIT inhibitor PN17-1 on gastrointestinal stromal tumor GIST-882 cells in vitro. We found that PN17-1 significantly inhibited the proliferation, colony formation and migration ability of GIST-882 cells, and significantly downregulated the protein expression levels of p-c-KIT and its downstream signals p-AKT, p-STAT5 and p-ERK in GIST-882 cells. In addition, PN17-1 induced apoptosis in GIST-882 cells, and the apoptosis may be mainly related to the mitochondrial-dependent endogenous pathway. In conclusion, the novel c-KIT inhibitor PN17-1 is a promising anti-GIST drug, and this study provides new ideas for further development of c-KIT inhibitors in the future.

Background: From the perspective of Mongolian medicine, hemorrhagic disease is a symptom of bleeding from any part of the body. This disease was compared to the immune thrombocytopenia disease of modern medicine. The treatment of this disease using two medical methods and the prevention of complications and relapses are issues facing the healthcare sector. In this regard, we have chosen this topic to clarify and prove the mechanism of action of the Mongolian drug Gurgem-8, which is widely used to treat bleeding disorders. Aim: To evaluate the therapeutic efficacy of Gurgem-8, in haemostatic treatment. Materials and Methods: The study was conducted using a randomized, controlled (active), open label, single centered clinical trial method. The study was conducted in two phases. First, an acute toxicity study of the Gurgem-8, was conducted in accordance with OECD guideline 423 and evaluated according to GHS classification. A chronic toxicity study was also conducted on Wistar rats (n=20) given the Gurgem-8, at doses of 500 mg/kg, 100 mg/kg, and 150 mg/kg daily for 60 days. Second, a clinical study was conducted on a total of 74 patients, who were randomly divided into 2 groups. The treatment group was given 3 grams of the Gurgem-8, daily, and the comparison group was given 4 capsules of Sheng Xue Xiao Ban Jiao Nang 3 times a day. The results were determined by laboratory methods. The study was conducted with the approval of the Research Ethics Committee of Mongolian National University od Medical Sciences (2024.01.19 №2024/3-01). Results: In the acute toxicity study, Turmeric-8 was found to be of low toxicity according to the GHS classification. No mortality was observed in the chronic toxicity test. As a result of the clinical study, there were significant differences in the blood hemoglobin (χ2=73.923, P<0.001), platelet (χ2=62.465, P<0.001), erythrocyte (χ2=77.113, P<0.001) and leukocyte (χ2=14.771, P<0.001) cell counts between the Gurgem-8, drug group and the comparison group. It was also determined that the platelet (χ2=138.3, P<0.001), erythrocyte (χ2=85.405, P<0.001) and leukocyte (χ2=10.961, P=0.027) cell counts were directly related to the treatment period and the group. When determining the effect on immune cells, there was no significant difference in the lymphocyte cell content before and after treatment (CD4+: t=0.233, P=0.817; CD8+: t=-0.264, P=0.793; CD4/CD8:Z=-0.119, P=0.905). However, the CD4/CD8 ratio was statistically significantly increased in each of the Gurgem-8, drug group and the comparison group (P<0.001, P=0.001). Conclusion In immune thrombocytopenia diseases, the Gurgem-8, has the effect of reducing hemoglobin levels in the blood, increasing platelet counts, reducing CD4+ and CD8+ T cell counts, and increasing the CD4/CD8 ratio.

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules (such as bile acids [BAs], trimethylamine-N-oxide, and short-chain fatty acids), or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Objective: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapyinduced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Methods: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA (NR3C1) and protein were treated with chemotherapy +/− SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. Results: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. Conclusion The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules (such as bile acids [BAs], trimethylamine-N-oxide, and short-chain fatty acids), or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Objective: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapyinduced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Methods: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA (NR3C1) and protein were treated with chemotherapy +/− SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. Results: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. Conclusion The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules (such as bile acids [BAs], trimethylamine-N-oxide, and short-chain fatty acids), or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Objective: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapyinduced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Methods: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA (NR3C1) and protein were treated with chemotherapy +/− SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. Results: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. Conclusion The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

Compared with conventional radiotherapy fields, small field has unique dosimetry characteristics such as high dose gradient, charged particle imbalance, and dose effect caused by source occlusion. These characteristics increase the difficulty of dose measurement and thus the uncertainty of clinical dose measurement, far exceeding the requirement of < 5% measurement error in ICRU 24 report. In recent years, with the development of new radiotherapy technologies, the minimum radiotherapy field can reach the millimeter level, and the single irradiation dose of hypofractionated radiotherapy can exceed 6 Gy. The larger dose gradient at the edge of radiotherapy field requires higher accuracy of dose measurement, and accurate small field dosimetry technologies have gradually become a research hotspot in the field of precision radiotherapy. In order to ensure the high accuracy of measurement, this paper reviews the research on small field dosimetry worldwide, and summarizes the key points of small field dosimetry. In this paper, the characteristics of small field dosimetry are introduced, and the current small field dosimetry technologies and optimization methods are summarized, including the optimization of detector selection and detector sensitive volume. The field output correction factor technologies are analyzed. In view of the difficulty in small field dosimetry, this paper provides suggestions on dosimetry based on clinical needs and the characteristics of medical linear accelerators. Our suggestions provide a scientific reference for small field dosimetry in clinical practice in radiotherapy institutions, and facilitate the development of radiotherapy dose verification.

Pyoderma gangrenosum (PG) is a chronic inflammatory neutrophilic dermatosis often presenting as a solitary enlarging painful ulcer with red to violaceous undermined borders. This report delves into the role of doxycycline in the treatment of PG in a 44-year-old male COVID-19 positive patient who has concomitant active tuberculosis infection and end-stage kidney disease, for which both first-line treatments (systemic corticosteroid and cyclosporine) are contraindicated. After three months on doxycycline and topical corticosteroids, there was resolution of the ulcers and no note of recurrence up to three months from completion of the treatment regimen.