Study on the Relationship between Integrin 2A and Drug Resistance in Chronic Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the expression pattern and clinical significance of Integral membrane protein 2A（ITM2A） in drug resistant patients with chronic myeloid leukemia (CML).@*METHODS@#The expression of ITM2A in CML was evaluated by qRT-PCR, Western blot and immunocytochemistry. In order to understand the possible biological effects of ITM2A, apoptosis, cell cycle and myeloid differentiation antigen expression of CML cells were detected by flow cytometry after over-expression of ITM2A. The nuderlying molecular mechanism of its biological effect was explored.@*RESULTS@#The expression of ITM2A in bone marrow of CML resistant patients was significantly lower than that of sensitive patients and healthy donors（P<0.05）. The CML resistant strain cell K562R was successfully constructed in vitro. The expression of ITM2A in the resistant strain was significantly lower than that in the sensitive strain(P<0.05). Overexpression of ITM2A in K562R cells increased the sensitivity of K562R cells to imatinib and blocked the cell cycle in G2 phase(P<0.05), but did not affect myeloid differentiation. Mechanistically, up-regulation of ITM2A reduced phosphorylation in ERK signaling (P<0.05).@*CONCLUSION@#The expression of ITM2A was low in patients with drug resistance of CML, and the low expression of ITM2A may be the key factor of imatinib resistance in CML.

Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

An infant with premature closure of cranial sutures due to variant of ERF gene and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical and genetic characteristics of an infant with craniosynostosis.@*METHODS@#An infant who was admitted to Wuhan Children's Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in April 2021 due to widening of the lateral ventricles for over a month was selected as the study subject. Clinical data of the patient was collected. Peripheral blood samples were collected from the infant and her parents for chromosomal karyotyping and whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Relevant literature was retrieved from the PubMed, Wanfang and CNKI databases (up to December 2021) by using key words including ERF gene, craniosynostosis, ERF mutation, craniosynostosis and ERF-related craniosynostosis.@*RESULTS@#The infant, a 1-month-and-16-day-old female, was found to have sagittal synostosis by cranial X-ray radiography. Genetic testing revealed that she has harbored a heterozygous c.787C>T (p.Q263*) variant of the ERF gene, which was not found in either parent. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PS2+PM2_Supporting). In total 63 relevant cases were retrieved from the database, and a total of 64 individuals were analyzed by genetic testing. Most of the cases were sporadic and males. Multiple cranial sutures (including at least two of the sagittal suture, coronal suture, lambdoid suture, and frontal suture) were involved in 45.45% of the cases, and those with sagittal suture closure only have accounted for 20.00%. The main clinical manifestations have included hypertelorism, exophthalmos, development delay, malar dysplasia, etc. Chiari type 1 malformation may present in some patients. Variants of the ERF gene have mainly included splicing and deletional variants, and there was a strong genetic heterogeneity among the infants and their pedigrees.@*CONCLUSION@#The c.787C>T (p.Q263*) variant of the ERF gene probably underlay the craniosynostosis of this infant. Above finding has enriched the phenotype ~ genotype spectrum of the ERF gene.

Correlation of probiotic consumption with serum inflammatory cytokines, endotoxin and post-stroke depression severity in patients with ischemic stroke / 国际脑血管病杂志

Objective:To investigate the correlation of probiotic consumption level with serum inflammatory cytokines, endotoxin and post-stroke depression (PSD) severity in patients with ischemic stroke.Methods:Patients with ischemic stroke visited the Department of Neurology, the Third Affiliated Hospital of Naval Medical University from May 2021 to June 2022 were prospectively included. At 6 months after discharge, the outpatient follow-up was conducted to investigate the consumption of probiotic products in the past six months, and depression was evaluated using the Self-rating Depression Scale (SDS). Multiple linear regression analysis was used to determine the correlation of consumption levels of probiotic products and serum inflammatory cytokines, endotoxin, and PSD severity.Results:A total of 168 patients with ischemic stroke were included, including 74 patients (44.0%) in the probiotic product high consumption group and 94 (56.0%) in the low consumption group. The incidence of PSD in the high consumption group was significantly lower than that in the low consumption group (22.97% vs. 38.30%; χ2=6.551, P=0.036). The serum pro-inflammatory cytokine interleukin-6 (IL-6) and endotoxin levels at the follow-up in the high consumption group were significantly lower than those in the low consumption group, while the anti-inflammatory cytokine IL-10 was significantly higher than that in the low consumption group (all P<0.05). Multiple linear regression analysis shows that the probiotic consumption level was significantly negatively correlated with the serum IL-6 ( β=-0.178, P=0.001) and endotoxin ( β=-0.107, P=0.035) at follow-up. PSD severity (SDS score) was negatively correlated with probiotic consumption level ( β=-0.309, P=0.001), and was positively correlated with IL-6 ( β=0.306, P=0.027) and endotoxin ( β=0.360, P=0.017) at follow-up. Conclusion:Probiotic products can reduce the severity of serum pro-inflammatory cytokines, endotoxin and PSD, and may be a non-drug treatment direction for PSD.

Effects of active inter-hospital transfer on the clinical outcomes of neonatal acute respiratory distress syndrome / 中国新生儿科杂志

Objective:To study the effects of active inter-hospital transfer on the clinical outcomes of neonatal acute respiratory distress syndrome (nARDS).Methods:From September 2018 to December 2020, neonates with nARDS transferred by ground ambulance to NICU of our hospital were retrospectively analyzed. The neonates were assigned into active transfer group and passive transfer group. Their general status, severity of nARDS, incidences of complications, duration of oxygen therapy, mechanical ventilation and hospital stay were analyzed.Results:A total of 78 neonates were enrolled in the study, including 45 cases in active transfer group and 33 cases in passive transfer group. No significant differences existed in gestational age, body weight, severity of nARDS, transfer distance and transfer duration between the two groups ( P>0.05). Active transfer group had significantly lower incidence of pneumothorax (3/45, 6.7%) than passive transfer group (6/33, 18.2%) ( P<0.05). No significant differences existed in the incidences of pulmonary hemorrhage, persistent pulmonary hypertension of newborn, intraventricular hemorrhage, hypoxic ischemic encephalopathy and length of hospital stay between the two groups ( P>0.05). Active transfer group had significantly shorter duration of oxygen therapy [(9.7±2.9) d vs. (11.3±4.0) d], non-invasive[(2.7±1.0) d vs. (3.7±1.4) d] and invasive ventilation [(5.0±1.9) d vs. (6.2±2.3) d] than passive transfer group ( P<0.05). Conclusions:Active inter-hospital transfer may reduce the incidence of pneumothorax in neonates with nARDS, shorten the duration of oxygen therapy, non-invasive and invasive ventilation during hospitalization without affecting the length of hospital stay.

Prognostic Significance of Tumor Mutation Burden among Patients with Non-small Cell Lung Cancer Who Received Platinum-based Adjuvant Chemotherapy:An Exploratory Study

This study aimed to investigate the prognostic significance of tumor mutation burden (TMB) among patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Tumor tissue specimens after surgical resection were collected for DNA extraction. Somatic mutation detection and TMB analysis were conducted using next-generation sequencing (NGS). Recurrence status of the patients was assessed in the hospital during the adjuvant chemotherapy period, and long-term survival data of patients were obtained by telephone follow-up. Univariate analysis between TMB status and prognosis was carried out by survival analysis. A retrospective review of 78 patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy showed a median disease-free survival of 3.6 years and median overall survival (OS) of 5.3 years. NGS analysis exhibited that the most common mutated somatic genes among the 78 patients were tumor suppressor protein p53 (TP53), epidermal growth factor receptor, low-density lipoprotein receptor related protein 1B, DNA methyltransferase 3 alpha and FAT atypical cadherin 3, and their prevalence was 56.4%, 48.7%, 37.2%, 30.7%, and 25.6%, respectively. TMB status was divided into TMB-L (≤ 4.5/Mb) and TMB-H (> 4.5/Mb) based on the median TMB threshold. Relevance of TMB to prognosis suggested that the median OS of patients with TMB-L was significantly longer than that of patients with TMB-H (NR vs. 4.6, P = 0.014). Higher TMB status conferred a worse implication on OS among patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy.

The effects of sacubitril-valsartan tablets on the expressions of NT-proBNP,cTnⅠ and cardiac function in patients with chronic cardiac insufficiency / 中国药师

Objective To observe the effects of sacubitril-valsartan tablets on the expressions of N terminal pro B type natriuretic peptide(NT-proBNP),troponin Ⅰ(cTnⅠ)and cardiac function in patients with chronic cardiac insufficiency.Methods Patients with chronic cardiac insufficiency who were diagnosed and treated in Beijing Friendship Hospital of Capital Medical University from November 2021 to December 2022 were selected as the study subjects,and were divided into the study group(sacubitril-valsartan tablets)and the control group(valsartan capsules)according to the random number table method.The total effective rate,cardiac function indexes[left ventricular ejection fraction(LVEF),left ventricular end systolic diameter(LVESD),left ventricular end-diastolic diameter(LEVDD)],plasma NT-proBNP,cTnⅠ,soluble growth stimulation expression gene 2 protein(sST2),angiotensin(AngⅡ)and the incidence of adverse reactions were observed in the two groups.Results A total of 100 patients with cardiac insufficiency were included in the study,with 50 in the study group and 50 in the control group.After treatment,the total effective rate of the study group was higher than that of the control group(P＜0.05).The LVEF in the study group was significantly higher than that in the control group,while the LVESD,LEVDD were significantly lower than those in the control group(P＜0.05).After treatment,the plasma of NT-proBNP,cTnⅠ,AngⅡ,and sST2 in two groups had statistical difference(P＜0.05)and the difference in the above indicators before and after treatment in two groups were statistically siginficant(P＜0.05).The differences in adverse reactions between two groups were not statistically significant(P＞0.05).Conclusion The treatment of chronic heart failure patients with sacubitril-valsartan tablets can improve heart function,prognosis,and safety.

Dosimetric effects of field of view on intensity-modulated radiotherapy for breast cancer / 中华放射医学与防护杂志

Objective:To investigate the effects of CT images reconstructed using different field of view (FOV) sizes on the automatic segmentation of organs at risk and dose calculation accuracy in radiotherapy after radical mastectomy.Methods:Under the same scanning conditions, CT values-electron density conversion curves were established by reconstructing the original CT images of a phantom placed at the isocenter and extended FOV (eFOV) positions using FOV sizes of 50, 60, 70 and 80 cm. Then, these curves were compared. A standard phantom with a known volume was scanned, and the automatic segmentation result of the phantom on CT images reconstructed using different FOV sizes was compared. A total of 30 patients in Guangdong Second Provincial General Hospital from January 2020 to June 2022 with breast cancer were randomly selected. Through simulated positioning, their CT images were reconstructed using different FOV sizes for the purpose of automatic segmentation of organs at risk, followed by comparison between the outcomes of automatic segmentation and physicians′segmentation. The treatment plan established based on CT images reconstructed using a FOV size of 50 cm (FOV 50 images for short) was applied to CT images reconstructed using FOV sizes of 60, 70 and 80 cm (FOV 60, FOV 70 and FOV 80 images for short) for dose calculation, and the dose calculation result were compared. Results:The CT values - electron density conversion curves derived from CT images reconstructed using different FOV sizes were roughly consistent. At the isocenter, the difference between the segmented volume and actual volume of the standard phantom increased up to a maximum of 6 cm 3 (4.8%) with an increase in the FOV size. As indicated by the automatic segmentation result, the segmentation accuracy of the spinal cord, trachea, esophagus, thyroid, healthy mammary gland, and skin decreased with an increase in the FOV size ( t = -28.43-8.23, P < 0.05). The comparison of dose calculated based on CT images reconstructed using different FOV sizes showed that there was no statistically significant differences( P>0.05) in the dose to target volume ( V95) and the maximum and average doses in the supraclavicular lymph node region, as well as the dose to organs at risk. The coverage for planned target volume decreased with an increase in the FOV size, with a maximum difference of 4.06%. Conclusions:It is recommended that, for radiotherapy after radical mastectomy, FOV 50 images should be selected for the automatic segmentation of organs at risk, CT-values-electron density conversion curves should be established based on the electron density phantom images of the eFOV region, and the eFOV 80 images should be preferred for dose calculation.

The Relationship between MicroRNA Expression Profiling in Imatinib-Resistant Cell Line K562/G and Potential Mechanism through FOXO3/Bcl-6 Signaling Pathway / 中国实验血液学杂志

OBJECTIVE@#To investigate the drug resistant related FOXO3/Bcl-6 signaling pathway in K562/G cell line and its related microRNA(miRNA) mechanisms.@*METHODS@#The drug resistance potency of imatinib on K562/G was detected by MTT assay. The expression of FOXO3 and Bcl-6 proteins in K562 and K562/G cells was detected by Western blot. Real-time PCR (RT-PCR) was used to detect the expression of FOXO3 and Bcl-6 mRNA. The miRNA expression profiling in K562 and K562/G cells was analyzed by microarray technique, and the miRNA targeted to FOXO/Bcl-6 signaling pathway was identified.@*RESULTS@#The expression of FOXO3 and Bcl-6 protein was significantly increased in K562/G cells as compared with that in K562 cells (P<0.01), the expression level of Bcl-6 mRNA showed no increase in K562/G cells. However, FOXO3 mRNA was up-regulated in K562/G cells (P<0.05). MiRNA microarray results showed that 109 miRNAs were expressed differentially in K562 and K562/G cells. The expression of 81 miRNAs were up-regulated while 28 miRNAs were down-regulated. Through reverse prediction by bioinformatics, miR-6718-5p, miR-5195-5p, miR-4711-3p, miR-4763-5p, miR-4664-5p and miR-3176 were related to FOXO/Bcl-6 signaling pathway.@*CONCLUSION@#The FOXO3/Bcl-6 signaling pathway contributes to imatinib resistance in K562/G cell line, and the miRNA expression profiles showed significant differences between K562/G and K562 cells.

Characteristic and prognosis of patients with non-EBV infection-associated hemophagocytic lymphohistiocytosis / 中华血液学杂志

Objective: To explore the clinical characteristics and outcomes of patients with non-Epstein-Barr virus (EBV) infection-associated hemophagocytic lymphohistiocytosis (IAHLH) . Methods: Clinical data of 48 patients diagnosed with non-EBV IAHLH in Beijing Friendship Hospital from January 2015 to March 2021 were collected, and the clinical characteristics, treatment, curative effect and prognosis of the patients were analyzed retrospectively. Results: This study included 48 patients, 28 males and 20 females, with a median (range) age of 34.5 (2-74) years. Pathogens that cause IAHLH were as follows: virus (16 cases, 33.3%) , bacteria (17 cases, 35.4%) , parasitic agents (13 cases, 27.1%) , and fungi (2 cases, 4.2%) . The median time from onset to diagnosis of hemophagocytic syndrome (HLH) was 40 (10-160) days. The median (range) time duration from prodrome to the definite diagnosis of IAHLH was 67 (23-270) days. The clinical characteristics were fever (48 cases, 100%) , splenomegaly (34 cases, 70.8%) , cytopenia (38 cases, 79.1%) , elevated ferritin (45 cases, 93.8%) , elevated fasting triglyceride levels (7 cases, 14.6%) , hypofibrinogenemia (17 cases, 35.4%) , decrease natural killer cell activity (26 in 44 cases, 59.1%) , and elevated sCD25 (35 cases, 74.5%) . Twenty-five patients (52.1%) had adenopathy. Once a certain pathogen was identified as the causative factor of hemophagocytic lymphohistiocytosis (HLH) , cytotoxic agents and glucocorticoids were withdrawn, and specific pathogen-directed treatment was initiated. After treatment, 36 cases (75.0%) achieved complete response, and 14 of 15 patients (93.3%) with parasitic and fungal HLH got a response; however, the response rate of patient with bacterial and viral HLH was only 66.7% (22 of 33 patients) . The estimated 5-year overall survival rate was 72.3% (95%CI 50.3%-69.8%) . The adverse prognostic factors were total bilirubin over the upper limit of normal (OR=20.0, 95%CI 1.1-378.3, P=0.046) and pathogenic infection not fully controlled (OR=19.9, 95%CI 2.9-134.5, P=0.002) . Conclusion: Non-EBV IAHLH has a good prognosis. When diagnosed, cytotoxic agents and glucocorticoids should be tapered off, and pathogen-targeted therapy should be critically administered to clear the triggering infection.