Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study.

Background: Currently, there has been observed a significant alteration in the composition of the gut microbiome (GM) and serum metabolites in patients with psoriatic arthritis (PsA) compared to healthy individuals. However, previous observational studies have shown inconsistent results regarding the alteration of gut microbiota/metabolites. In order to shed light on this matter, we utilized Mendelian randomization to determine the causal effect of GM/metabolites on PsA. Methods: We retrieved summary-level data of GM taxa/metabolites and PsA from publicly available GWAS statistics. Causal relationships between GM/metabolites and PsA were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the robustness of our findings, we conducted sensitivity analyses, multivariable MR analysis (MVMR), and additional analysis including replication verification analysis, LDSC regression, and Steiger test analysis. Furthermore, we investigated reverse causality through a reverse MR analysis. Finally, we conducted an analysis of expression quantitative trait loci (eQTLs) involved in the metabolic pathway to explore potential molecular mechanisms of metabolism. Results: Our findings reveal that eight GM taxa and twenty-three serum metabolites are causally related to PsA (P < 0.05). Notably, a higher relative abundance of Family Rikenellaceae (ORIVW: 0.622, 95% CI: 0.438-0.883, FDR = 0.045) and elevated serum levels of X-11538 (ORIVW: 0.442, 95% CI: 0.250-0.781, FDR = 0.046) maintain significant causal associations with a reduced risk of PsA, even after adjusting for multiple testing correction and conducting MVMR analysis. These findings suggest that Family Rikenellaceae and X-11538 may have protective effects against PsA. Our sensitivity analysis and additional analysis revealed no significant horizontal pleiotropy, reverse causality, or heterogeneity. The functional enrichment analysis revealed that the eQTLs examined were primarily associated with glycerolipid metabolism and the expression of key metabolic factors influenced by bacterial infections (Vibrio cholerae and Helicobacter pylori) as well as the mTOR signaling pathway. Conclusion: In conclusion, our study demonstrates that Family Rikenellaceae and X-11538 exhibit a strong and negative causal relationship with PsA. These particular GM taxa and metabolites have the potential to serve as innovative biomarkers, offering valuable insights into the treatment and prevention of PsA. Moreover, bacterial infections and mTOR-mediated activation of metabolic factors may play an important role in this process.

Somatic mutations of activating signalling, transcription factor, and tumour suppressor are a precondition for leukaemia transformation in myelodysplastic syndromes.

The transformation biology of secondary acute myeloid leukaemia (AML) from myelodysplastic syndromes (MDSs) is still not fully understood. We performed paired self-controlled sequencing, including targeted, whole exome, and single-cell RNA sequencing, in a cohort of MDS patients to search for AML transformation-related mutations (TRMs). Thirty-nine target genes from paired samples from 72 patients with MDS who had undergone AML transformation were analysed. The targeted sequencing results showed that 64 of 72 (88.9%) patients presented TRMs involving signalling pathway activation, transcription factors, or tumour suppressors. Of the 64 patients, most of the TRMs (62.5%, 40 cases) emerged at the leukaemia transformation point. Paired whole exome sequencing showed some presumptive TRMs, which were not included in the reference targets in three patients. No patient developed AML only by acquiring mutations involved in epigenetic modulation or ribonucleic acid splicing. Single-cell sequencing indicated that the activating cell signalling route was related to TRMs in one paired sample. Targeted sequencing defined TRMs were limited to a small set of seven genes (in the order: NRAS/KRAS, CEBPA, TP53, FLT3, CBL, PTPN11, and RUNX1, accounting for nearly 90.0% of the TRMs). In conclusion, somatic mutations involved in signalling, transcription factors, or tumour suppressors appeared to be a precondition for AML transformation from MDS.

[Yield of CD34(+) cells in graft can be increased significantly by G-CSF used at appropriate time after chemotherapy for AutoPBSCT].

This study was aimed to investigate the influence of timing using G-CSF after chemotherapy on graft yield of mobilized peripheral blood stem cells for autoPBSCT. 39 patients with lymphoma or multiple myeloma (MM) received the same chemotherapy mobilization regimen, including CTX 400 mg/m² d1; VLB 2 mg/m(2) d1; Ara-C 60 mg/m ²× d1-5; VP-16 60 mg/m² × d1-5; and prednisone 40 mg/m² × d1-5. The historical control group (12 cases) received G-CSF subcutaneously (filgrastim) at the first restoration after the initial nadir of the peripheral WBC count. The experimental group (27 cases) received G-CSF during the steady rise of the WBC count (end of fluctuating after initial nadir). G-CSF was given in a single daily subcutaneous dose of 5 µg/kg until the final PBSC apheresis. When the peripheral WBC and mononuclear cell (MNC) counts reached 10 × 109/L and 1.0 × 109/L respectively, leukapheresis was carried out using the COBE Spectra blood cell separator. The results indicated that despite there was comparable treatment with alkylating agents between 2 groups, a significantly increased yield of CD34 positive cells was observed in the experimental group (26.4 × 106/kg), as compared to the historical control group (3.1 × 106/kg) (p = 0.0031). It is concluded that the appropriate timing for the use G-CSF mobilization after chemotherapy is important to increase the CD34(+) cell yield in auto-graft.

Primary lymphoma of bone: a case report and review of the literature.

The purpose of this study was to investigate the clinical signs and therapy of primary lymphoma of bone (PLB). One primary lymphoma of bone is described, and review of the pertinent literature is introduced. The patient achieved complete remission with no evidence of local recurrence. PLB are uncommon malignancies. Patients with PLB commonly present with local bone pain, soft tissue swelling and a mass or a pathological fracture. Most cases of PLB are classified as diffuse large B-cell lymphomas in the WHO classification of hematological malignancies. Comprehensive immunohistochemical studies are required to establish an accurate histological diagnosis of PLB. Early diagnosis and active treatment can improve the prognosis.

[Efficacy of induction chemotherapy for patients with high-risk myelodysplastic syndrome (MDS) or MDS-transformed acute myeloid leukemia with CHG regimen and its comparison with regimen GAG and HA].

This study was aimed to investigate the efficacy of moderate intensity regimen, CHG (homoharringtonine, cytarabine and granulocyte colony-stimulating factor (G-CSF)) on the patients with high-risk MDS or MDS-transformed acute myeloid leukemia. 30 newly diagnosed adult patients with high-risk MDS or MDS-transformed AML were enrolled in this clinical trial to evaluate the efficacy of sequential low-dose homoharringtonine/cytarabine chemotherapy combined with G-CSF priming. Homoharringtonine and Ara-C were injected intravenously at doses of 1 mg and 25 mg daily for 14 consecutive days respectively, G-CSF was injected subcutaneously once daily at a dose of 300 microg on 12 hours prior to chemotherapy and continued given until the end of chemotherapy or when the peripheral WBC count reached > 20 x 10(9)/L. This regimen was given only for one course, and followed by conventional chemotherapy as maintenance or consolidation therapy when CR achieved. 33 patients with high- risk MDS and MDS-transformed AML were injected aclarubicin/Ara-C intravenously at doses of 10 mg and 25 mg for 8 and 14 consecutive days respectively, G-CSF was used at the same dose and the same way as the CHG regimen. 33 patients with high-risk MDS and MDS-transformed AML were treated with HHT/Ara-C intravenously at doses of 2 - 3 mg and 100 - 150 mg daily for 7 consecutive days respectively, G-CSF was injected when WBC count was below 4 x 10(9)/L, and it was stopped to be used when WBC count was > 4 x 10(9)/L. The results showed that (1) 14 patients achieved complete remission (CR) (46.67 %) and 7 patients achieved partial remission (PR) (23.33 %) with one course of CHG regimen, total effective rate was 70%; 14 patient achieved CR (42.4%) and 9 patients achieved PR (27.3%) with one course of CAG regimen, total effective rate was 69.7%; 7 patient achieved CR (33.3%) and 3 patients achieved PR (9.1%) with one course of HA regimen, total effective rate was 42.4%. There was no statistical difference between the effective rate of CHG and CAG, but difference was significant between CHG and HA. (2) Agranulocytosis (neutrophil < 0.5 x 10(9)/L) occurred in 12 cases (40%) of CHG-treated patients with a mean 8 days of agranulocytic period, so the infectious complications were less serious and tolerable without treatment-related death. (3) Among 14 out of 30 patients with CR, 9 relapsed, the mean duration from CR to replace was 8.2 months. All relapsed patients reusing CHG regimen did not achieved CR again. (4) Among 13 cases with CR, 6 patients just received HA or DA regimens as consolidatory and intensive chemotherapy after CR have relapsed, the mean CR time was only 6.1 months. Otherwise, the mean CR time of 7 CR patients received alternative succeeded chemotherapy containing mitoxantrone/idarubicin/THP/homoharringtonine/daunorubicin/aclarubicin after CR was 10.6 months; and among them 4 are still in continuous CR. It is concluded that the CHG chemotherapy regimen has a similar effect with CAG but better than HA, and in a saft chemotherapy regimen with slight myelosuppression in clinical application, strong and alternative succeeded chemotherapy is necessary for CR patients to keep longer CR and survival.

Downregulation and CpG island hypermethylation of NES1/hK10 gene in the pathogenesis of human gastric cancer.

The normal epithelial cell-specific-1 (NES1)/Kallikrein 10 gene is proposed to be a novel putative tumor suppressor gene in several malignant diseases. The role of NES1 gene in gastric cancer has not been fully understood. Our study revealed that CpG island hypermethylation plays an important role in the downregulation of NES1 mRNA expression in gastric cancer. In situ hybridization showed that loss or reduction of NES1 mRNA expression is associated with differentiation level during tumor progression suggesting that NES1 inactivation might contribute to the malignant progression of human gastric cancers.