Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR-RUNX1.

Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic-erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor-Runt-related transcription factor 1 (AhR-RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn-AhR-RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.

Osteoporosis and associated risk factors in patients with severe hemophilia A: a case-control study from China.

INTRODUCTION: People with hemophilia risk osteoporosis more than healthy people, which may be related to specific factors. METHODS: This case-control study included 53 patients with severe hemophilia type A and 49 healthy participants. Dual-energy X-ray absorptiometry (DXA) was used to determine bone mineral density (BMD). Collected information on age, body mass index (BMI), number of joint arthropathies, functional independence score in hemophilia (FISH), bone turnover markers, antibodies, treatment modalities. Identified independent risk factors for osteoporosis. RESULTS: The BMD of the femoral neck (0.80 g/cm2vs.0.97 g/cm2), ward's triangle (0.62 g/cm2vs.0.83 g/cm2), tuberosity (0.63 g/cm2vs.0.80 g/cm2) and hip (0.80 g/cm2vs.0.98 g/ cm2) in the case group were significantly lower than those in the control group, all of which were P < 0.001. However, there was no significant difference in the overall BMD of lumbar spine(L1-L4) (1.07 g / cm2vs. 1.11 g / cm2). The frequency of osteoporosis in the case group was 41.51%. BMI and FISH score were considered as independent risk factors for BMD decrease. CONCLUSION: The BMD of patients with severe hemophilia A is much lower than that of healthy population, and this difference is mainly reflected in the hip. The clear influencing factors were low BMI and functional independence decrease. Osteoclast was active while osteoblast activity was not enhanced synchronously, which may be the pathological mechanism of BMD decrease.

Characteristics of gut microbiota in male periadolescent rats with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder, however, its effect on gut microbiota during the periadolescent period remains unclear. In this study, our objective was to investigate the characteristics of gut microbiota in male periadolescent rats with IBS induced by neonatal maternal separation (NMS). We evaluated visceral sensitivity by electromyography (EMG), analyzed gut microbiota composition using 16S rDNA gene sequencing, and examined intestinal pathological changes between control and IBS-like groups. The IBS-like group had significantly higher discharge amplitude of the external oblique muscle of the abdomen during colorectal distension (CRD) at 40- and 60 mmHg pressures. We observed differences in gut microbiota composition, with an increase in Bacteroidetes abundance and a decrease in Firmicutes in IBS-like rats. Beta-diversity analysis revealed the gut microbiota of the IBS-like group displayed higher consistent, while that of the control group exhibited substantial variation. Linear discriminant analysis effect size (LEfSe) detected 10 bacterial taxonomic clades showing statistically significant differences (7 increased and 3 decreased) in the IBS-like group. Functional analysis revealed that aminoacyl-tRNA biosynthesis and fatty acid biosynthesis were significantly altered, leading to changes in gene expression. Our findings demonstrate a definite correlation between gut microbiota dysbiosis and IBS during the male periadolescent period, with Alloprevotella and Bacteroide positively associated with high risk of IBS. The effects of specific bacterial genera may provide new insights for the development of treatments for IBS.

Rate and risk factors of recurrent immune checkpoint inhibitor-related pneumonitis in patients with lung cancer.

Background: Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer patients. Immune checkpoint inhibitor-related pneumonitis (CIP) was the leading cause of death among ICIs-related adverse events (irAEs). Recurrent episodes of CIP without rechallenge of ICIs were reported in several cases and maybe a unique feature of CIP. Knowledge gaps remain regarding the rate and risk factors associated to CIP's recurrence. Methods: Data from 1,102 lung cancer patients receiving ICIs treatment between January 2016 and January 2021 were retrospectively collected and analyzed. CIP was diagnosed according to typical clinical features and/or new typical imaging changes. Recurrence of CIP (CIP-R) was defined as recurrent CIP after initial CIP improved after proper treatment. Logistic regression was used to assess risk factors associated with CIP recurrence. Results: Eighty out of 1,102 (7.26%) patients were diagnosed with CIP. Twenty of those 78 (25.64%) patients suffered CIP-R, 2 patients died and were therefore excluded from the denominator. The median onset of initial pneumonitis for patients without and with recurrence was 3.49 months [interquartile range (IQR), 0.26-31.93 months] and 2.78 months (IQR, 1.22-20.93 months), respectively (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98-16.70 months). Recurrence of CIP was more common in males (P=0.03), squamous histology (P=0.016), and in patients who received chest radiotherapy (P=0.049). The duration of prednisolone equivalent dose ≥15 mg/day in CIP-R was significantly shorter, at 3.71 weeks (2.86-6.57 weeks) compared with 6.36 weeks in those without recurrence (IQR, 3.12-9.86 weeks) (P=0.001). Non-squamous histology [odds ratio (OR), 0.182; 95% confidence interval (CI): 0.038-0.860; P=0.031] and prolonged administration of prednisolone equivalent dose ≥15 mg/day for more than 4 weeks (OR, 0.082; 95% CI: 0.02-0.342; P=0.001) were independently associated with a decreased odds of CIP-R development. Conclusions: CIP-R in a real-world lung cancer cohort is not uncommon, both in patients with and without rechallenge of ICIs. A duration of prednisolone equivalent dose ≥15 mg/day of at least 4 weeks during the tapering process of corticosteroids were recommend in patients with CIP.

[Progress on surgical treatment for hemophiliac arthropathy].

Surgical treatment is the main treatment for hemophilia arthritis, including synoviectomy, joint replacement and joint fusion. Synoviectomy is suitable for early hemophilia synovitis, and is divided into radiation, chemical, arthroscopy, and open operation. Radionuclides were recommended as the first choice due to its positive efficacy and less side effects, but exsit some problems such as scarcity of nuclides. Chemical synoviectomy is cheap and easy to operate, which is suitable for developing countriesm, while mutiple doses and pain after injection are main fault. Synoviectomy under arthroscope has a significant effect on the advanced lesion, but has a higher surgical risk. Open surgery with severe trauma and postoperative joint stiffness, is rarely performed. Joint replacement could effectively improve range of motion in advanced patients and is suitable for joints with high range of motion. Arthrodesis are effective in improving symptoms but lead to loss of range of motion and are suitable for joints with low range of motion. Operation for hemophilia arthritis has some problems, such as single operation, untimely diagnosis and treatment in early stage, and unsatisfactory curative effect in late stage. In addition, the treatment of hemophilia arthritis should focus on the early treatment, the formation of the whole process, the system of individual treatment concept.