Apoptosis mediated by crosstalk between mitochondria and endoplasmic reticulum: A possible cause of citrinin disruption of the intestinal barrier.

Citrinin (CTN) is a mycotoxin commonly found in contaminated foods and feed, posing health risks to both humans and animals. However, the mechanism by which CTN damages the intestine remains unclear. In this study, a model of intestinal injury was induced by administering 1.25 mg/kg and 5 mg/kg of CTN via gavage for 28 consecutive days in 6-week-old Kunming mice, aiming to explore the potential mechanisms underlying intestinal injury. The results demonstrate that CTN can cause structural damage to the mouse jejunum. Additionally, CTN reduces the protein expression of Claudin-1, Occludin, ZO-1, and MUC2, thereby disrupting the physical and chemical barriers of the intestine. Furthermore, exposure to CTN alters the structure of the intestinal microbiota in mice, thus compromising the intestinal microbial barrier. Meanwhile, the results showed that CTN exposure could induce excessive apoptosis in intestinal cells by altering the expression of proteins such as CHOP and GRP78 in the endoplasmic reticulum and Bax and Cyt c in mitochondria. The mitochondria and endoplasmic reticulum are connected through the mitochondria-associated endoplasmic reticulum membrane (MAM), which regulates the membrane. We found that the expression of bridging proteins Fis1 and BAP31 on the membrane was increased after CTN treatment, which would exacerbate the endoplasmic reticulum dysfunction, and could activate proteins such as Caspase-8 and Bid, thus further inducing apoptosis via the mitochondrial pathway. Taken together, these results suggest that CTN exposure can cause intestinal damage by disrupting the intestinal barrier and inducing excessive apoptosis in intestinal cells.

Endoplasmic reticulum stress promotes oxidative stress, inflammation, and apoptosis: A novel mechanism of citrinin-induced renal injury and dysfunction.

Citrinin (CTN) has been reported to induce renal failure and structural damage, but its nephrotoxic effects and mechanisms are not fully understood. Therefore, we established a model by orally administering CTN (0, 1.25, 5, or 20 mg/kg) to mice for 21 consecutive days. Histological and biochemical analyses revealed that CTN caused structural damage to renal tubules, increased inflammatory cell infiltration, and elevated levels of serum markers of renal function (creatinine, urea, and uric acid). Moreover, mRNA transcript levels of the inflammatory factors TNF-α, IL-1ß, and IL-6 were increased, indicating the occurrence of an inflammatory response. Furthermore, exposure to CTN induced renal oxidative stress by decreasing antioxidant GSH levels, antioxidant enzyme (SOD, CAT) activities, and increasing oxidative products (ROS, MDA). In addition, CTN increased the expression of proteins associated with endoplasmic reticulum (ER)stress and apoptotic pathways. ER stress has been shown to be involved in regulating various models of kidney disease, but its role in CTN-induced renal injury has not been reported. We found that pretreatment with the ER stress inhibitor 4-PBA (240 mg/kg, ip) alleviated CTN-induced oxidative stress, NF-κB pathway mediated inflammatory response, and apoptosis. Interestingly, 4-PBA also partially alleviated renal structural damage and dysfunction. Thus, ER stress may be a novel target for the prevention and treatment of CTN-induced renal injury.

[Clinical Characteristics and Prognosis of Patients with Primary Bone Marrow Lymphoma].

OBJECTIVE: To investigate the clinical characteristics and prognosis of primary bone marrow lymphoma. METHODS: The clinical data of 6 patients with primary bone marrow lymphoma admitted to Gansu Provincial People's Hospital from February 2011 to March 2023 were collected, and their clinical characteristics and prognosis were retrospectively analyzed and summarized. RESULTS: The median age of 6 patients was 61(52-74) years old. There were 2 males and 4 females. All patients had fever and abnormal blood routine examination. Physical examination and imaging examination showed no lymphadenopathy, no extranodal lesions in lung, gastrointestinal, liver and spleen, skin, etc. After strict exclusion of systemic lymphoma involvement in the bone marrow, the diagnosis was confirmed by bone marrow examination, 5 cases were primary myeloid diffuse large B-cell lymphoma and 1 case was primary myeloid peripheral T-cell lymphoma (NOS). 1 case abandoned treatment, 5 cases received CHOP-like or combined R regimen， including 1 case of autologous stem cell transplantation. 4 cases died and 2 case survived. The median OS was 5.5 (1-36) months. CONCLUSION: The prognosis of primary marrow lymphoma is poor, and bone marrow-related examination is an important means of diagnosis. Diffuse large B-cell lymphoma is the most common histomorphologic and immune subtype, and autologous hematopoietic stem cell transplantation may improve the prognosis.

[Risk Prediction and Risk Factors of Thrombotic/Bleeding Events in Patients with Myeloproliferative Neoplasm].

OBJECTIVE: To analyze the clinical characteristics and occurrence of thrombotic/bleeding events of patients with myeloproliferative neoplasm (MPN), and explore the main influencing factors, and create a risk prediction. METHODS: The clinical data of 126 MPN patients with BCR-ABL fusion gene negative in the Department of Hematology of Gansu Provincial Hospital from January 2016 to September 2021 were collected, and their clinical characteristics, occurrence of thrombotic/bleeding events and main influencing factors were analyzed and summarized retrospectively. Then, a risk prediction model for thrombotic/bleeding events in MPN patients was constructed. RESULTS: Among 126 MPN patients, 50 patients (39.7%) had experienced thrombotic/bleeding events, including 44 patients (34.9%) with thrombotic events and 6 patients (4.8%) with bleeding events. Among thrombotic diseases, cerebral thrombosis was the most common (23/44, 52.3%), followed by 9 cases of limb artery thrombosis mainly characterized by finger and toe tip artery ischemia, occlusion and gangrene (9/44, 20.5%). Bleeding events included intracerebral hemorrhage and gastrointestinal hemorrhage. Univariate analysis showed that hypertension, hyperhomocysteinemia, white blood cell (WBC) ≥10×109/L, hematocrit (HCT) ≥49%, platelet (PLT) ≥600×109/L and JAK2V617F gene mutation were risk factors for thrombotic/bleeding events in MPN patients, while CALR gene mutation was a protective factor. Multivariate analysis showed that hypertension and PLT≥600×109/L were independent risk factors for thrombotic/bleeding events in MPN patients. The goodness of fit of the constructed risk prediction model was 0.872, and the area under the ROC curve was 0.838. The model was validated with clinical data, the sensitivity, specificity and accuracy was 78.85%, 87.83% and 84.13%, respectively . CONCLUSION: The risk of thrombotic/bleeding events in MPN patients with high WBC count, hypertension and hyperhomocysteinemia is higher. Controlling hypertension and hyperhomocysteinemia and reducing WBC and PLT counts are helpful to prevent thrombotic/bleeding events and improve the life quality of patients.

Global emergence of double and multi-carbapenemase producing organisms: epidemiology, clinical significance, and evolutionary benefits on antimicrobial resistance and virulence.

Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-ß-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-ß-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

[Clinical Features and Prognostic Analysis of Newly Diagnosed Diffuse Large B-cell Lymphoma Combined with Hemophagocytic Syndrome].

OBJECTIVE: To compare the clinical features and prognosis between newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients with and without hemophagocytic syndrome (HPS). METHODS: The clinical data of 45 DLBCL patients in Gansu Provincial Hospital from January 2012 to December 2021 were retrospectively analyzed. The patients were divided into HPS group (15 cases) and non-HPS group (30 cases). The clinical features and prognosis of the two groups were compared, and survival analysis was performed using Kaplan-Meier method. RESULTS: Patients with HSP were mostly characterized by fever, cytopenia and splenomegaly. The levels of ferritin and soluble CD25 increased in all patients. The level of fibrinogen decreased in 66.67% patients, while triglyceride increased in 53.33% patients, and bone marrow hemophagocytosis occurred in 80.00% patients. Compared with non-HSP group, the proportions of patients with advanced stage (Ann Arbor stage III/IV) and lactate dehydrogenase (LDH) ≥240 U/L were higher in HSP group (both P < 0.05). The median survival time of HSP group was 8.0 months, which was significantly shorter than 45.5 months of non-HSP group (P < 0.001). CONCLUSION: The DLBCL patients with HPS have later Ann Arbor stage, higher LDH and shorter overall survival time compared with patients without HPS.

[Effects of Different Nutritional Scoring Systems on Prognosis of Elderly Patients with Multiple Myeloma].

OBJECTIVE: To analyze the prognostic nutritional index (PNI), controlling nutritional status (CONUT) and fibrinogen/albumin ratio (FAR) levels in elderly patients with multiple myeloma (MM) and their prognostic impact. METHODS: The clinical data of 74 elderly MM patients diagnosed in Gansu Provincial Hospital from January 2020 to July 2022 were retrospectively analyzed. The optimal cut-off values for PNI, CONUT score and FAR were obtained by receiver operating characteristic (ROC) curve, which were used for grouping patients. The correlation of above three indexes with clinical parameters such as sex, serum calcium (Ca), ß2-microglobulin (ß2-MG), serum creatinine (Cr) in elderly MM patients were analyzed. The survival rates of patients with different levels of each index were compared. Univariate and multivariate analysis of the impact of clinical indicators on the prognosis of patients were performed. RESULTS: The optimal cut-off values for PNI, CONUT score and FAR were 39.775, 3.5 and 0.175, respectively, according to which the patients were divided into high and low group. Statistical analysis showed that there were significant differences in albumin level among different groups (all P < 0.05). In addition, there was a significant difference in hemoglobin between high-PNI group and low-PNI group (P < 0.05), while in sex distribution between high-FAR and low-FAR group (P < 0.05). The survival rate of elderly MM patients with increased PNI, decreased CONUT score and FAR was higher (all P < 0.05). Univariate and multivariate analysis showed that ß2-MG, Cr, PNI, CONUT score and FAR were independent prognostic factors for elderly MM patients. CONCLUSION: PNI, CONUT score and FAR are related to some clinical indicators of elderly MM patients, and have an impact on the prognosis.

Identification of concurrent STAT3::RARA and RARA::STAT5b fusions in a variant APL case.

Acute promyelocytic leukemia (APL) with typically PML::RARA fusion gene caused by t (15;17) (q22; q12) was distinguished from other types of acute myeloid leukemia. In a subset of patients with APL, t (15;17) (q22;q21) and PML::RARA fusion cannot be detected. In this report, we identified the coexistence of STAT3::RARA and RARA::STAT5b fusions for the first time in a variant APL patient lacking t (15;17)(q22;q21)/PML::RARA fusion. Then, this patient was resistant to all-trans retinoic acid combined arsenic trioxide chemotherapy. Accurate detection of RARA gene partners is crucial for variant APL, and effective therapeutic regime is urgently needed.

[Clinical Anslysis of TAFRO Syndrome].

OBJECTIVE: To investigate the clinical characteristics, diagnosis, and treatment of one patient with TAFRO syndrome, and to strengthen the understanding of this rare type. METHODS: The clinical manifestations, diagnosis and treatment process, and prognosis of the patient admitted in Gansu Provincial People's Hospital were retrospectively analyzed. RESULTS: Combined with laboratory tests, bone marrow examination, imaging, pathology, etc, the patient was diagnosed with TAFRO syndrome. After three cycles of treatment with pomalidomide (2-3 mg/d, d1-21), cyclophosphamide (300 mg/m2, 0.54 g once a week) and dexamethasone (20 mg/d, two days a week), platelet count, serum creatinine and procalcitonin returned to normal, the systemic edema disappeared, and the patient's condition was alleviated. The therapeutic effect was good. CONCLUSION: TAFRO syndrome is rare, involves multiple systems, progresses rapidly, and has a worse prognosis. The choice of the "Pomalidomide+cyclophosphamide+dexamethasone" regimen is help to improve the survival prognosis of patient with TAFRO syndrome.

Outcome and characteristics of nonsecretory multiple myeloma compared with secretory multiple myeloma: a retrospective multicenter study from China.

BACKGROUND: Nonsecretory multiple myeloma (NSMM) is a rare type of multiple myeloma (MM). Few studies have described the clinical features and outcomes of NSMM in novel agents. Additionally, the prognostic characteristics have remained controversial in recent years. PURPOSE: To investigate the clinical and prognostic features of NSMM and explore the prognostic value of involved free light chain (FLC) levels in NSMM patients in the Chinese population. METHODS: We retrospectively enrolled 176 newly diagnosed NSMM cases between January 2005 and December 2021 from 19 clinical centers in China. The control group was selected using a 1:4 propensity score matching technique of newly diagnosed secretory MM, with age, sex and diagnosis time as the matching variables. RESULTS: The median age of NSMM patients was 60 years, and 22.6% of patients were classified as ISS stage 3. The ORR of the NSMM patients was 87.4%, and the CR was 65.8%. Compared to the matched secretory MM patients, more NSMM patients achieved CR after first-line treatment (65.8% vs. 36%, p = 0.000). The ORR of first-line treatment was not significantly different between NSMM and secretory MM (89.45% vs. 84.7%, p = 0.196). The first-line PFS was 27.5 m and 23 m (p = 0.063), and the median OS was 81 m and 70 months (p = 0.401). However, for CR-achieved NSMM and CR-not-achieved NSMM patients, the median PFS was 37 m vs. 16 m (p = 0.021), while the median OS showed no difference (107 m vs. 87 m, p = 0.290). In multivariate analysis, the significant factors for PFS were age ≥ 65 and ISS-3. ISS-3 was the only independent prognostic factor of OS. The iFLC ≥ 50 mg/L group had a high ORR of 97.3%, and the median PFS and OS were 48 m and NR, respectively. Compared to the matched secretory MM, the iFLC ≥ 50 mg/L group also showed more CR and longer OS (NR vs. 70 m, p = 0.006) and PFS (48 m vs. 23 m, p = 0.003). CONCLUSIONS: Our results revealed that Chinese NSMM patients are younger and have a higher CR but not superior survival. The subgroup of NSMM patients with iFLC ≥ 50 mg/L had better outcomes than secretory MM.

[Efficacy and Safety of Bendamustine in the Conditioning Regiment for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma].

OBJECTIVE: To investigate the clinical efficacy and safety of bendamustine in the conditioning regimen for autologous stem cell transplantation in patients with lymphoma. METHODS: The clinical data of 35 patients with lymphoma, including 5 patients of Hodgkin lymphoma and 30 patients of non-Hodgkin lymphoma, who underwent autologous stem cell transplantation after pretreatment with BeEAM regimen from January 2020 to June 2022 in Gansu Provincial Hospital were retrospectively analyzed. Hematopoietic reconstitution, disease outcome after transplantation and the side effects were analyzed. RESULTS: All 35 patients achieved hematopoietic reconstitution after AHSCT，the median time to neutrophil engraftment was 11 (8-15) days, and the median time to platelet engraftment was 12 (9-17) days. Among the 35 patients, 4 patients died at the end of follow-up, including 3 patients died of lymphoma recurrence or progression and 1 patient died of cerebral hemorrhage. Among 34 patients, 30 had no disease progression at the end of follow-up. The OS rates of patients at 12 and 24 months after transplantation were 90.97% and 90.97%, respectively. The 12 and 24 months PFS rates were 89.64% and 84.92%, respectively. Thiry-five patients underwent grade 3-4 bone marrow suppression. The non-hematological toxicity of BeEAM pretreatment regimen mainly included nausea, vomiting, diarrhea, and oral mucositis, 35 patients experienced nausea and vomiting, but only 4 patients had grade 3-4 nausea and vomiting. Eight patients experienced Grade 1-2 diarrhea. Oral mucositis occurred in 12 patients, including 1 patient of grade 3 oral mucositis. One patient with grade 3 oral mucositis also had grade 3-4 hypokalemia and hypon atremia. 8.6% of patients experienced Grade 1-2 abnormal liver and kidney function. An addition, infectious fever occurred in 18 patients during neutropenia. All patients improved after symptomatic treatment, and there were no transplant-related death. CONCLUSION: Bendamustine as a pretreatment regimen for autologous stem cell transplantation in lymphoma is effective, and the side effects are tolerable.

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are relapsed or refractory to ruxolitinib: A single-arm, open-label, phase 2, multicenter study.

Ruxolitinib has demonstrated efficacy in patients with myelofibrosis (MF). However, substantial number of patients may not respond after 3-6 months of treatment or develop resistance over time. In this phase 2 trial, patients with a current diagnosis of intermediate or high-risk MF who either had an inadequate splenic response or spleen regrowth after ruxolitinib treatment were enrolled. All patients received jaktinib 100 mg Bid. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR 35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profile. From July 6, 2021, to January 24, 2022, 34 ruxolitinib-refractory or relapsed patients were enrolled, 52.9% (18 of 34) were DIPSS intermediate 2 or high risk. SVR 35 at week 24 was 32.4% (11 of 34, 95% CI 19.1%-49.2%) in all patients and 33.3% (6 of 18, 95% CI 16.3%-56.3%) in the intermediate 2 or high-risk group. A total of 50% (8 of 16) transfusion-independent patients with hemoglobin (HGB) <100 g/L at baseline had HGB elevation ≥20 g/L within 24 weeks. Furthermore, 46.4% (13 of 28) of patients had a ≥ 50% decrease in the total symptom score (TSS 50) at week 24. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (32.4%), anemia (32.4%), and leukocytosis (20.6%). In total, 13 (38.2%) of 34 patients had serious adverse events (SAE), of which drug-related SAEs were found in 5 patients (14.7%). These results indicate that jaktinib can be a promising treatment option for patients with MF who have either become refractory to or relapsed after ruxolitinib treatment.

[Risk Factors and Prognosis of Cardiovascular Damage in Hypereosinophilia].

OBJECTIVE: To investigate the risk factors and prognosis of cardiovascular damage in hypereosinophilia (HE). METHODS: The clinical data of 62 patients with HE in Gansu Provincial Hospital from January 2015 to December 2020 were retrospectively analyzed, including clinical characteristics and laboratory indicators, and the influencing factors of survival and prognosis were also analyzed. RESULTS: In this study, there were 34 males and 28 females, with a median age of 53.5 (20-79) years, 35 patients without cardiovascular damage, 27 patients with cardiovascular damage, including 22 patients with abnormal electrocardiogram (ECG) (81.5%), 18 patients with abnormal echocardiography (ECHO) (66.7%), 9 patients with single ECG abnormality, 5 patients with single ECHO abnormality, and other 13 patients with multiple abnormalities. In cardiovascular damage group, peripheral white blood cell count, absolute value of eosinophils, troponin T (TNT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin (IL)-4 and IL-5 levels at initial diagnosis were significantly higher than those in the non-cardiovascular damage group (P <0.01), while hemoglobin, IL-2 and interferon-γ levels were significantly lower (P <0.01). There were no significant differences in age, sex, course of disease, etiological classification, platelet count, serum creatine kinase, serum creatine kinase isoenzyme and lactate dehydrogenase between the two groups (P >0.05). The 5-year overal survival rate of patients with cardiovascular damage was 88.9%, and that of patients without cardiovascular damage was 100%, the difference was statistically significant (P =0.012). The 5-year event-free survival (EFS) rate of patients with cardiovascular damage was 59.3%, and the median time was 37 (21-52) months, while that of patients without cardiovascular damage was 80%, and the median time was 63 (51-74) months (P =0.002). Age (>60 years old), course of disease (>24 months), NT-proBNP (>3 000 pg/ml), TNT (>100 ng/L), elevated IL-4 and IL-5 were associated with EFS shortening in patients with cardiovascular damage, which were independent risk factors for EFS. CONCLUSION: The EFS rate in HE patients without cardiovascular damage is significantly higher than patients with cardiovascular damage. Age, course of disease, NT-proBNP, TNT, IL-4 and IL-5 are independent risk factors affecting EFS of patients with cardiovascular damage.

miR-100-5p is upregulated in multiple myeloma and involves in the pathogenesis of multiple myeloma through targeting MTMR3.

OBJECTIVES: MicroRNA (miRNA) is a kind of highly conserved single-stranded small endogenous non-coding RNA associated with multiple diseases, particularly cancer. The miRNAs expression profile in multiple myeloma (MM) has been barely elucidated. METHODS: The miRNAs expression profiles in bone marrow plasma cells of 5 MM individuals and 5 iron-deficiency anemia volunteers were analyzed using RNA-sequencing. Quantitative polymerase chain reaction (QPCR) was performed to validate the expression of selected miR-100-5p. The biological function of selected miRNA was predicated by bioinformatics analysis. Finally, the function of miR-100-5p and its target on MM cells were evaluated. RESULTS: MiRNA-sequencing showed that miR-100-5p was obviously upregulated in MM patients, which was further validated in an expanded cohort. Receiver operating characteristic curve analysis characterized miR-100-5p as a valuable biomarker of MM. Bioinformatics analysis predicted that miR-100-5p is targeted to CLDN11, ICMT, MTMR3, RASGRP3, and SMARCA5, and their low expression are associated with poor prognosis of MM patients. Kyoto encyclopedia of genes and genomes analysis suggested that the major interacting proteins of these five targets are mainly enriched in inositol phosphate metabolism and phosphatidylinositol signaling system pathway. In vitro study showed that miR-100-5p inhibition promoted the expression of these targets, especially MTMR3. In addition, miR-100-5p inhibition declined living number and metastasis, whereas promoted apoptosis of RPMI 8226 and U266 MM cells. The function of miR-100-5p inhibition was weakened by MTMR3 inhibition. CONCLUSION: These results indicates that miR-100-5p is a promising biomarker for MM, and that it may involve in the pathogenesis of MM by targeting MTMR3.

LncRNA RP11-1100L3.8 Involves in the Pathogenesis of Multiple Myeloma by Regulating NR4A1.

PURPOSE: Although numerous studies have revealed that various long-non coding RNA (lncRNA) are implicated in multiple myeloma (MM) regulation, MM lncRNA profile and novel functional lncRNAs in MM need to be elucidated. METHODS: Herein, lncRNAs and mRNAs (messenger ribonucleic acids) patterns in MM were evaluated using RNA-sequencing (RNAseq). Differentially expressed (DE) genes were defined and a complex regulatory network based on validation and predication was shaped. RESULTS: LncRNA-seq data analysis identified 539 DE lncRNAs and RP11-1100L3.8 was the most up-regulated known lncRNA. Subsequently, the upregulation and clinical RP11-1100L3.8 utilization value was verified in an expanded cohort. Based on the results of Cis nearby-targets and co-expression analysis, 1 correlation pair RP11-1100L3.8-nuclear receptor subfamily 4 group A member 1 (NR4A1) was defined. It is worth noting that NR4A1 is one of the top 5 significantly up-regulated DE mRNAs in MM patients. Moreover, it was found that NR4A1 overexpression is associated with poor prognosis in MM patients, making it suitable as biomarker. Additionally, spearman correlation analysis revealed the positive association between RP11-1100L3.8 and NR4A1 in MM patients. Furthermore, the dominant NR4A1 interacted genes were predicated and it was found that the genes containing NR4A1 were remarkably enriched in phosphatidylinositol 3-kinase (PI3K)-AKT (protein kinase B) signaling pathway. In addition, in vitro experiment suggested that RP11-1100L3.8 downregulation decreased NR4A1 expression in U266 and RPMI 8226 MM cells. RP11-1100L3.8 inhibition declined proliferation and promoted apoptosis in MM cells, which were rescued by NR4A1 overexpression. Moreover, it was found that RP11-1100L3.8 inhibition impeded PI3K and AKT phosphorylation and rapamycin mammalian target in MM cells, which was rescued by NR4A1 overexpression. CONCLUSIONS: This study identifies RP11-1100L3.8 as a potential MM biomarker, and it may be involved in MM pathophysiology by regulating NR4A1-mediated PI3K-AKT signaling pathway. This study provides a novel biomarker candidate for MM therapy.

[Clinical Features and Prognosis of Patients with Castleman's Disease].

OBJECTIVE: To analyze the clinical features and prognosis of patients with Castleman's disease (CD) and improve the diagnosis and treatment of CD. METHODS: Clinical data of patients diagnosed with CD by pathological biopsy in Gansu Provincial Hospital from January 2009 to November 2020 were retrospectively analyzed. According to clinical classification, the patients were divided into two groups: UCD (unicentric CD) group (n=20) and MCD (multicentric CD) group (n=9). The clinical manifestations, laboratory examination, treatment regimens, pathological examination and follow-up data were statistically analyzed. RESULTS: There were no significant differences in average age and gender ratio between UCD group and MCD group. In UCD patients, 80.0% were hyaline vascular type, and 20.0% were plasma cell type. In MCD patients, 33.3% were hyaline vascular type, 55.6% were plasma cell type, and 11.1% were mixed type. There was significant difference in pathological classification between the two groups (P=0.039). The UCD patients usually presented asymptomatic single lymph node enlargement with mild clinical symptoms, while the MCD patients were characterized by multiple superficial and deep lymph node enlargement throughout the body. The incidences of asthenia, splenomegaly, serous effusion in MCD group were higher than those in UCD group (P<0.05). Meanwhile, the incidences of anemia, hypoproteinemia, increased ESR, elevated serum globulin and elevated ß2-microglobulin were significantly higher than those in UCD group too (P<0.05). There was no significant difference in the incidences of abnormal WBC, PLT and elevated LDH between the two groups (P>0.05). Among 20 patients with UCD, 13 cases reached complete remission (CR), 1 case achieved partial remission (PR). Among 9 patients with MCD, 3 cases received CR and 4 cases received PR. CONCLUSION: Patients with CD requires pathological examination for diagnosis. Patients with UCD show mild clinical symptoms, good surgical treatment effect and good prognosis. Patients with MCD have diversified clinical manifestations and relatively poor prognosis, and these patients require comprehensive treatment.

Bortezomib-containing regiment in treating glomerulopathy with fibronectin deposits combined with monoclonal gammopathy of undetermined significance: a case report and literature review.

Background: Glomerulopathy with fibronectin deposits (GFND) is a newly recognized rare glomerular disease. As its onset can be stably inherited in affected families without sex differences and fibronectin 1 (FN1) mutations can be detected in 40% of patients' families, GFND is considered to be an autosomal dominant genetic disease. The main clinical manifestations are proteinuria, progressive renal failure, edema, hypertension, hematuria, and type 4 renal tubular acidosis. The diagnosis was confirmed by renal biopsy, and there was no specific treatment. Monoclonal gammopathy refers to the existence of monoclonal immunoglobulin (MIg) produced by monoclonal plasma cells in serum. When MIg damages the kidney by direct deposition or indirect mechanisms, it is defined as monoclonal gammopathy of renal significance (MGRS). The principle of treatment is to inhibit plasma cells from producing MIg. Case Description: We report the efficacy of a case of GFND combined with monoclonal gammopathy of undetermined significance (MGUS) treated with a bortezomib-containing regimen. A 44-year-old female patient was admitted to the hospital for "edema of both lower extremities for 1 month and aggravation for 5 days". In May 2018, after exertion, the patient developed edema of both lower extremities, accompanied by foamy urine with no obvious deepening of urine color or decreased output, no gross hematuria, and gradual aggravation with fatigue. Conclusions: After treatment, the edema of patient subsided, urinary protein decreased significantly, and serum albumin increased near to normal. It is achieving a very good therapeutic effect and long-term event-free survival. The treatment is safety and there are no obvious toxic side effects. It provides a new idea for the treatment of GFND.

[Clinical Characteristics and Prognosis of Patients with Primary Bone Diffuse Large B-Cell Lymphoma].

AbstractObjective: To investigate the clinical characteristics and prognosis of patients with primary bone diffuse large B-cell lymphoma. METHODS: The clinical data of 15 patients with primary diffuse large B-cell lymphoma treated in our hospital from January 2013 to December 2020 were collected, the clinical data and prognosis of the patients were analyzed retrospectively. RESULTS: The median age of the 15 patients was 59 (19-89) years old; among the patients, 7 were males and 8 were females, ostealgia was the initial symptom. The pathological types of the 15 patients were diffuse large B-cell lymphoma (DLBCL), 5 cases of Has type GCB subtype (5/15), and 10 cases of Non-GCB subtype (10/15). After 15 patients were diagnosed, 11 patients (11/15) received chemotherapy, 3 patients (3/15) received surgery, and 1 patient was untreated (1/15), median chemotherapy courses was 5 (1-9). 8 patients have achieved complete remission (8/15), 3 patients achieved partial remission (3/15), and 1 patient achieved stable disease (1/15), 1 patient was lost to follow-up (1/15), 1 patient was untreated (1/15), and 1 patient was progression of disease (1/15). Age, pathological subtype, sex, stage, ß2-MG level, LDH level, and the using of rituximab were not correlated with the complete remission rate of the patients(P>0.05), while the IPI score was correlated with the recent complete remission rate (P<0.05). The median follow-up time was 19 (1-38) months, 10 patients survived, in which 6 cases were still in complete remission, and the median time to progression-free survival was 15 (1-38) months. CONCLUSION: The first symptom of primary bone diffuse large B-cell lymphoma is bone pain, the main pathological subtype is Non-GCB, the optimal treatment is combined chemotherapy, and the IPI score is related to the prognosis of the treatment.

Treatment and outcome patterns of patients with Waldenström's macroglobulinemia: a large, multicenter retrospective review in China.

In this study, we aimed to investigate treatment options and the prognosis of patients with WM in China. This retrospective study included 1141 patients diagnosed with symptomatic WM between January 2003 and December 2019 at 35 tertiary hospitals in 22 provinces of China. Fifty-four patients (7.3%) received monotherapy, 264 (36.0%) received chemoimmunotherapy, 395 (53.8%) received other combination regimens without rituximab, and 21 (2.9%) received ibrutinib. Using a multivariable Cox regression model, age > 65 years old, platelets <100 × 109/L, serum albumin <3.5 g/dl, ß2 microglobulin concentration ≥4 mg/L and LDH ≥250 IU/L predicted poor OS. In summary, our study showed that frontline treatment choices for WM are widely heterogeneous. We validated most of the established prognostic factors in the rIPSS (age >65 years, LDH ≥250 IU/L, ALB <3.5 g/dl and ß2 microglobulin ≥4 mg/L) together with PLT ≤ 100 × 109/L indicate a poor prognosis for patients with WM.

[Coagulation Indexes and Their Prognostic Significance in Patients with Multiple Myeloma].

OBJECTIVE: To analyze the relationship between coagulation indexes and prognosis of patients with multiple myeloma (MM). METHODS: A total of 99 newly diagnosed MM patients treated in Gansu Provincial Hospital from October 2017 to October 2019 were enrolled. Plasma thromboplastin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer (D-D), platelet (PLT), and other laboratory indexes were detected. The relationship between coagulation indexes and clinical characteristics of MM patients was analyzed. The differences in survival rates among MM patients with different levels of coagulation indexes were compared, and the effect of each clinical index on the prognosis of MM patients was analyzed by univariate and multivariate. RESULTS: Each coagulation index was correlated to sex, disease classification and stage, and ß2-MG level of MM patients. Disease stage and ß2-MG level were positively correlated with coagulation indexes, which means that patients with late-stage disease or high ß2-MG, IgA and IgG levels were more likely to develop into coagulation disorders (P<0.05). The survival rate of patients with MM exhibiting elevated PT, FIB, and D-D levels was significantly lower (P<0.05). Univariate and multivariate analysis showed that each coagulation index was the influencing factor on the follow-up outcomes of MM patients, in which FIB was an independent prognostic factor. CONCLUSION: Coagulation function is correlated with multiple clinical indicators of patients with MM and plays an important role in their prognosis.