Hypoprothrombinemia-lupus anticoagulant syndrome(HLAS)is a rare disease in which patients present with varying degrees of bleeding and positive lupus anticoagulant with reduced prothrombin on laboratory tests.This article reports a case of HLAS in a middle-aged woman with recurrent gingival bleeding and epistaxis as the first presentation.After admission,tests revealed prolonged prothrombin time(PT),activated partial thromboplastin time(APTT),and reduced coagulation factor Ⅱ activity,and positive lupus anticoagulant(LA).Meanwhile,the patient had symptoms of dry mouth and dry eyes for a long time,and the examination of autoantibodies,tear secretion test and salivary gland emission computed tomography(ECT)were consistent with the diagnosis of Sjogren's syndrome.The final diagnosis was HLAS secondary to Sjogren's syndrome.After treatment with methylprednisolone and cyclophosphamide,the coagulation disorder gradually improved,and no recurrent bleeding occurred.HLAS is a rare clinical case,which reminds medical staff to be alert to the possibility of HLAS when encountering patients with unexplained prolonged APTT and PT and positive lupus anticoagulant.

Objective:To explore the feasibility of sirolimus as an alternative graft versus host disease (GVHD) prophylaxis in patients with kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Retrospective case series study. Medical records of 11 patients in Peking University People′s Hospital from 1 August 2008 to 31 October 2022, who received sirolimus instead of cyclosporine to prevent GVHD, due to renal insufficiency after allo-HSCT, were analyzed retrospectively. Incidence of GVHD, infection, and transplant-associated thrombotic microangiopathy (TA-TMA), as well as renal function, were evaluated.Results:Among the 11 patients who received sirolimus, 6 were treated with haploidentical donor HSCT, and 5 were treated using matched sibling donor HSCT. The median (range) time of sirolimus administration was 30 (7-167) days after allo-HSCT, and the median (range) sirolimus course duration was 52 (9-120) days. During sirolimus treatment, 1 case did not undergo combined treatment with other prophylactic drugs, 3 cases received combined mycophenolate mofetil (MMF), and 1 case underwent combined CD25 monoclonal antibody treatment, while 6 cases had combined therapy with both MMF and CD25 monoclonal antibody. Of the 11 patients, 2 developed Grade Ⅲ acute GVHD, 1 developed severe pneumonia and died, and 1 developed TA-TMA, while nine patients had normal or improved renal function. Median (range) follow-up time was 130 (54-819) days. Non-relapse mortality was observed in 1 patient. Relapse mortality was also observed in 1 patient.Conclusion:Sirolimus-based alternative GVHD prophylaxis is a potentially viable option for patients undergoing allo-HSCT who cannot tolerate cyclosporine, but its efficacy and safety require further optimization and verification in prospective studies.

Objective:To investigate the expression profile of IL-36 family members in patients with coronary atherosclerotic heart disease (CAHD) and to assess the regulatory effects of exogenous IL-36 on CD8 + T cell function in CAHD patients. Methods:Twenty controls and 82 CAHD patients including 31 with stable angina pectoris (SAP), 27 with unstable angina pectoris (UAP) and 24 with acute myocardial infarction (AMI) were enrolled in this study. Anti-coagulant peripheral blood samples were collected. Plasma and peripheral blood mononuclear cells were isolated. The levels of IL-36α, IL-36β, IL-36γ and IL-36 receptor antagonist (IL-36RA) in plasma were measured by ELISA. CD8 + T cells were enriched. The expression of IL-36 receptor subunits at mRNA level was semi-quantified by real time PCR. Flow cytometry was used to detect the expression of programmed death-1 (PD-1), cytotoxic T lymphocytes associated protein-4(CTLA-4) and lymphocyte-activation gene-3 (LAG-3) in CD8 + T cells. Levels of periforin, granzyme B, granulysin, IFN-γ and TNF-α in the culture supernatants of CD8 + T cells were measured by ELISA. Purified CD8 + T cells from controls and AMI patients were stimulated with recombinant human IL-36RA. Changes in the expression of immune checkpoint molecules and the secretion of cytotoxic molecules and cytokines after IL-36RA stimulation were analyzed. One-way analysis of variance or paired t-test was used for statistical analysis. Results:There were no significant differences in plasma IL-36α, IL-36β or IL-36γ level between the control, SAP, UAP and AMI groups ( P>0.05). Plasma IL-36RA level was significantly down-regulated in the AMI group as compared with that in the control, SAP and UAP groups[(1 159.57±297.83) pg/ml vs (1 773.47±754.29) pg/ml, (1 600.12±740.48) pg/ml and (1 578.72±720.42) pg/ml; P<0.05]. The expression of IL-1 receptor 6 (IL-1R6) and IL-1 receptor accessory protein (IL-1RAcP) at mRNA level, the expression of PD-1 and CTLA-4, and the secretion of IFN-γ and TNF-α by CD8 + T cells showed no significant differences between the four groups ( P>0.05). Periforin, granzyme B and granulysin levels secreted by CD8 + T cells of the AMI group were significantly higherthan those of the control, SAP and UAP groups ( P<0.05). In the control group, recombinant human IL-36RA stimulation did not affect the expression of immune checkpoint molecule or the secretion of cytotoxic molecules and cytokines by CD8 + T cells ( P>0.05). In the AMI group, the percentage of PD-1 + CD8 + T cells increased after recombinant human IL-36RA stimulation ( P=0.033), but no significant change in the percentage of CTLA-4 + CD8 + T cells was observed ( P=0.288). Moreover, recombinant human IL-36RA stimulation suppressed the CD8 + T cells of AMI patients to secrete periforin, granzyme B and granulysin ( P<0.05), but not affect the secretion of IFN-γ and TNF-α ( P>0.05). Conclusions:The reduced IL-36RA level in AMI patients might induce the enhancement of CD8 + T cell activity by promoting CD8 + T cells to secrete cytotoxic molecules, which was involved in the immunopathogenesis of AMI.

Objective:To analyze the prevalence and risk factors of musculoskeletal diseases among interventional surgeons in top three hospitals, and to provide suggestions for prevention of musculoskeletal diseases.Methods:In June 2022, a self-designed questionnaire was used to collect general information of doctors engaged in interventional surgery (121) and non-interventional surgery (124) in some top three hospitals in Tianjin. The standard version of the Nordic Musculoskeletal Questionnaire was used to investigate information related to musculoskeletal diseases. The prevalence and risk factors of musculoskeletal diseases among interventional and non-interventional surgeons were analyzed.Results:The prevalence of musculoskeletal diseases among interventional surgeons and non-interventional surgeons was 59.50% (72/121) and 62.90% (78/124) . Compared with non-interventional surgeons, interventional surgeons had a higher prevalence of musculoskeletal diseases in the shoulders and upper back, and a lower prevalence of musculoskeletal diseases in the waist. The differences were statistically significant ( P<0.05) . Multivariate logistic regression analysis showed that age, weekly time of physical exercise, time of intervention operation, and wearing protective clothing were independent risk factors for musculoskeletal diseases ( P<0.05) . Conclusion:The prevalence rate of musculoskeletal diseases among doctors engaged in interventional surgery is relatively high in some top three hospitals in Tianjin, and proper enhancement of physical exercise and shortening of interventional time are conducive to reducing musculoskeletal diseases.

Objective:To investigate the effect of cyclin A1 on the invasion, metastasis, and prognosis of hepatocellular carcinoma (HCC).Methods:Immunohistochemistry (IHC) was used to detect the expressional condition of cyclin A1 in HCC and paraffin-embedded non-tumor adjacent tissues. Kaplan-Meier method was used for the survival analysis of patients with HCC. Western blot (WB) was used to detect the expression of cyclin A1 in HCCLM3 and QGY-7703 cells. Scratch wound healing assay, transwell migration, and invasion assay were used to detect the effect of cyclin A1 overexpression on cell migration and invasion ability. WB was used to detect changes in the expression of matrix metalloproteinase (MMP) 2, MMP9, and vascular endothelial growth factor (VEGF) after overexpression of cyclin A1. Measurement data were compared using a t-test and analysis of variance. Count data was measured using χ2 test and the Log-rank method was performed for survival analysis. Results:Cyclin A1 expression rates were higher in the tissues of HCC patients with recurrent metastasis than in the tissues of patients without recurrent metastasis (60.42% vs. 46.81%, χ2 = 4.711, P < 0.05). The overall postoperative survival time (OS) and disease-free survival (DFS) were shorter in patients with high cyclin A1 expression than those with low cyclin A1 expression (45.9 months vs. 53.1 months; 42.9 months vs. 51.3 months, and P < 0.01). The postoperative OS and DFS were shorter in patients with high cyclin A1 expression and recurrent metastasis than those with low cyclin A1 expression without recurrent metastasis (31.7 months vs. 43.9 months; 18.0 months vs. 31.5 months, and P < 0.05). HCCLM3 and QGY-7703 cells were higher in the cyclin A1-pEX group than in the empty vector (vector) group (1.56 ± 0.06 vs. 0.18 ± 0.01, t = 18.75, P < 0.001; 1.31 ± 0.05 vs.0.37 ± 0.02, t = 15.17, P < 0.001). The migrated distances of HCCLM3 cells in the cyclin A1-pEX group and the vector group were (536.7 ± 14.5) μm and (327.3 ± 9.3) μm, t = 11.84, P < 0.05, respectively, while the migrated distances of QGY-7703 cells in the two groups were (916.7 ± 35.3) μm and (320.0 ± 20.8) μm, t = 13.54, P < 0.01. The migrated numbers of HCCLM3 cells in the cyclin A1-pEX group and vector group were (37.3 ± 2.4) and (7.0 ± 1.2), t = 12.67, P < 0.001, and the number of invasive cells was (73.7 ± 4.1) and (12.6 ± 1.5), t = 12.36, P < 0.001, respectively. The migrated numbers of QGY-7703 cells in the two groups were (153.3 ± 6.0) and (17.7 ± 3.7), t = 17.59, P < 0.001, and the number of invasive cells was (45.0 ± 2.9) and (9.3 ± 1.5), t = 10.66, P < 0.001, respectively. The expression levels of MMP2, MMP9, and VEGF in HCCLM3 and QGY-7703 cells were significantly higher in the cyclin A1-pEX group than those in the vector group ( P < 0.05). Conclusion:Cyclin A1 plays an important role in HCC invasion and metastasis, but HCC patients with high cyclin A1 expression have a poor prognosis. Hence, cyclin A1 has high guiding significance for evaluating patient prognosis.

Objective:To analyze the prevalence and risk factors of musculoskeletal diseases among interventional surgeons in top three hospitals, and to provide suggestions for prevention of musculoskeletal diseases.Methods:In June 2022, a self-designed questionnaire was used to collect general information of doctors engaged in interventional surgery (121) and non-interventional surgery (124) in some top three hospitals in Tianjin. The standard version of the Nordic Musculoskeletal Questionnaire was used to investigate information related to musculoskeletal diseases. The prevalence and risk factors of musculoskeletal diseases among interventional and non-interventional surgeons were analyzed.Results:The prevalence of musculoskeletal diseases among interventional surgeons and non-interventional surgeons was 59.50% (72/121) and 62.90% (78/124) . Compared with non-interventional surgeons, interventional surgeons had a higher prevalence of musculoskeletal diseases in the shoulders and upper back, and a lower prevalence of musculoskeletal diseases in the waist. The differences were statistically significant ( P<0.05) . Multivariate logistic regression analysis showed that age, weekly time of physical exercise, time of intervention operation, and wearing protective clothing were independent risk factors for musculoskeletal diseases ( P<0.05) . Conclusion:The prevalence rate of musculoskeletal diseases among doctors engaged in interventional surgery is relatively high in some top three hospitals in Tianjin, and proper enhancement of physical exercise and shortening of interventional time are conducive to reducing musculoskeletal diseases.

Objective:To investigate the clinicopathological characteristics and survival of patients with lymphoplasmacytic lymphoma (LPL).Methods:The data of 33 newly diagnosed LPL patients in the First Affiliated Hospital of Dalian Medical University from July 2003 to May 2021 were retrospectively analyzed. The clinical characteristics, bone marrow cell morphology, immunophenotyping, chromosomal karyotype, gene mutation, treatment response and prognosis were analyzed, and Kaplan-Meier method was used to analyze the survival of patients.Results:The median age of onset of 33 patients was 66 years old (55-84 years old). There were 26 males (78.8%) and 7 females (21.2%). The common clinical manifestations were anemia (31 cases, 93.9%), enlarged lymph nodes (16 cases, 48.5%) and B symptoms (8 cases, 24.2%). All patients had bone marrow involvement and M protein, 23 of them (69.7%) were type IgM-κ, 8 cases (24.2%) were type IgM-λ, 1 case (3.0%) was type IgG-κ, and 1 case (3.0%) was type IgA-κ. Lymphocytes, lymphoplasmacytes or plasma cells was increased in bone marrow smear; 22 patients underwent immunophenotyping of bone marrow by flow cytometry, and all patients expressed B cell surface antigens (CD19 and CD20), 16 patients (72.7%) lost the expression of CD5 and CD10, 13 patients (59.1%) expressed or weakly expressed CD138 and 5 patients (22.7%) expressed CD38. Seven out of 23 cases (30.4%) who received chromosome examination had abnormal chromosomal karyotype. Fourteen out of 16 cases (87.5%) who received MYD88 L265P mutation detection harbored the mutation. Among 21 patients with evaluable efficacy, 18 patients (85.7%) responded to treatment, achieving partial remission or stable disease, but the rate of complete remission was low (14.3%, 3/21). The median follow-up time was 34 months (2-102 months), 1 case was lost. The median overall survival time was not reached, and the 3-year and 5-year overall survival rates were 79.2% and 67.9%, respectively.Conclusions:LPL is a rare indolent small B-cell lymphoma with a long course and a variety of manifestations, which is commonly seen in elderly men.Serological examination, bone marrow cell morphology and biopsy, immunophenotyping and MYD88 L265P mutation detection are important for the diagnosis and differential diagnosis.

Objective:Donor cytomegalovirus (CMV) serological negative status may have an adverse effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT), while there is inadequate data for Chinese people. This study is to explore the impact of donor CMV serological status on the outcome of CMV seropositive patients receiving allo-HSCT.Methods:Our study retrospectively analyzed 16 CMV seropositive patients with hematological malignancies receiving allogeneic grafts from CMV seronegative donors (antibody IgG negative) at Peking University People′s Hospital from March 2013 to March 2020, which was defined as D -/R + group. The other 64 CMV seropositive patients receiving grafts from CMV seropositive donors at the same period of time were selected as matched controls through a propensity score with 1∶4 depending on age, disease state and donor-recipient relationship (D +/R + group). Results:Patients in D -/R + group developed CMV DNAemia later than patients in the D +/R + group (+37 days vs. +31 days after allo-HSCT, P=0.011), but the duration of CMV DNAemia in D -/R + group was longer than that of D +/R + group (99 days vs. 34 days, P=0.012). The rate of CMV reactivation 4 times or more in D -/R + group was 4/16, significantly higher than that of D +/R + group (4.7%, 3/64, P=0.01). The incidences of refractory CMV DNAemia (14/16 vs. 56.3%, P=0.021) and CMV disease (4/16 vs. 4.7%, P=0.01) in D -/R + group were both higher than those in D +/R + group. In addition, the application of CMV-CTL as the second-line antiviral treatment in D -/R + group was more than that in D +/R + group. Univariate analysis and multivariate analysis suggested that CMV serological negativity is an independent risk factor for refractory CMV DNAemia and the duration of CMV infection. The cumulative incidence of aGVHDⅡ-Ⅳ, cGVHD, 3-year probability of NRM, overall survival, and the cumulative incidence of relapse were all comparable in two groups. Conclusions:Although there is no significant effect on OS and NRM, the incidence of refractory CMV DNAemia, the frequency of virus reactivation, and the development of CMV disease in D -/R + group are higher than those in controls. Therefore, CMV seropositive donors are preferred for CMV seropositive patients.

Objective:To explore the relationship between anti-human leukocyte antigen (HLA) antibodies and transplant outcomes in patients with hematological diseases who underwent matched sibling donor transplantation (MSDT).Methods:A retrospective analysis was conducted in 168 patients with hematological diseases who received MSDT in Peking University People's Hospital from March 2015 to November 2017. All patients received detection of anti-HLA antibodies before transplantation, and the correlation between anti-HLA antibodies and transplant outcomes such as hematopoietic cells implantation, blood product transfusion and prognosis after transplantation were analyzed.Results:Among the 168 patients, 28 (16.7%) were positive for anti-HLA class Ⅰ or class Ⅱ antibodies, and 14 (8.3%) were positive for both anti-HLA class Ⅰ and class Ⅱ antibodies. All patients received neutrophil engraftment, 164 patients (97.9%) received platelet engraftment. Univariate analysis showed that there were no effects of anti-HLA antibodies on neutrophil engraftment and engraftment time, platelet engraftment and engraftment time, the volume of red cell transfusion, the volume of platelet transfusion, overall survival (OS) rate, disease free survival (DFS) rate and transplant-related mortality (TRM) in patients with hematological diseases underwent MSDT (all P > 0.05). Multivariate analysis showed that platelet engraftment was associated with better OS ( HR=0.065, 95% CI 0.017-0.252, P < 0.01), better DFS ( HR=0.083, 95% CI 0.024-0.289, P < 0.01) and lower TRM ( HR=0.094, 95% CI 0.014-0.626, P=0.015). Conclusion:Anti-HLA antibodies have no effect on transplant outcomes of patients with hematological diseases who have received MSDT.

Objective:To evaluate the role of hypoxia-inducible factor-1α (HIF-1α) in hydrogen-induced inhibition of lipopolysaccharide (LPS)-induced inflammatory responses in mouse macrophages.Methods:The mouse RAW264.7 macrophages cultured in vitro were divided into 4 groups ( n=24 each) according to the random number table method: control group (C group), LPS group (L group), hydrogen-rich solution plus LPS group (H+ L group), and hydrogen-rich solution plus LPS plus HIF-1α inhibitor 2-methoxyestradiol (2ME2) group (H+ L+ M group). LPS 1 μg/ml was added, and the cells were incubated for 6 h in group L. In group L+ H, LPS was added first, the medium was changed to 0.6 mmol/L hydrogen-rich solution, and cells were incubated for 6 h. In group H+ L+ M, 2ME2 10 μmol/L was given first, cells were then incubated for 30 min, LPS and hydrogen-rich solution were added, and cells were incubated for 6 h. Western blot was used to determine the expression of HIF-1α, Beclin-1, Bcl-2/E1B-19 kDa interacting protein 3 (BNIP3) and LC3.Enzyme-linked immunosorbent assay was used to detect the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the supernatant.The number of autophagosomes was observed using a transmission electron microscope. Results:Compared with group C, the concentrations of TNF-α, IL-6 and IL-1β in the supernatant were significantly increased, the expression of HIF-1α, Beclinl and BNIP3 in macrophages was up-regulated, the ratio of LC3Ⅱ/LC3Ⅰ was increased, and the number of autophagosomes was increased in group L ( P<0.05). Compared with group L, the concentrations of TNF-α, IL-6 and IL-1β were significantly decreased, the expression of HIF-1α, Beclin-1 and BNIP3 in macrophages was up-regulated, LC3Ⅱ/LC3Ⅰ ratio was increased, and the number of autophagosomes was increased in group H+ L ( P<0.05). Compared with group H+ L, the concentrations of TNF-α, IL-6 and IL-1β in the supernatant were significantly decreased, the expression of HIF-1α, Beclin-1, and BNIP3 in macrophages was down-regulated, and the ratio of LC3Ⅱ/LC3Ⅰ was decreased, and the number of autophagosomes was decreased in group H+ L+ M ( P<0.05). Conclusion:HIF-1α-mediated activation of autophagy is involved in the process of hydrogen-induced inhibition of LPS-induced inflammatory responses in mouse macrophages.