Abstract Inhibitor of DNA binding 1(ID1) is a crucial regulator of cell differentiation and plays a significant role in maintaining normal hematopoietic differentiation and development. Due to the lack of DNA-binding motif, ID1 functions as a dominant-negative inhibitor of basic helix-loop-helix factors to antagonize their abilities to bind to DNA and transcriptionally regulate target genes. Abnormal expression of ID1 is strongly associated with various hematologic disorders, including myeloid and lymphoblastic leukemia, multiple myeloma and myeloproliferative neoplasms. ID1 acts as a potential oncogene by participating in multiple signaling pathways that promote the malignant proliferation, invasion and therapy resistance in leukemic cells. Significant strides have yielded promising antileukemic effects of ID1 inhibitors, both alone and in combination with targeted therapies against oncogenic signaling pathways. Here, we review the relationship between ID1 expression and the initiation and progression of blood disorders, and summarize the clinical significance of ID1 as a novel therapeutic target and potential prognostic biomarker for hematologic malignancies.

Case 1,a 69-year-old male patient,was admitted to our hospital due to"dizziness,fatigue,nausea,diarrhea,and oral bleeding for 10 d",with a recent history of field farming work.The patient exhibited leukopenia,thrombocytopenia,and clinical manifestations of multi-organ dysfunction,including coagulation dysfunction,liver function abnormalities,gastrointestinal disorders,myocardial injury,and respiratory failure.Bone marrow aspiration smear revealed hemophagocytosis,and out-of-hospital testing for the severe fever with thrombocytopenia syndrome bunyavirus was positive.The patient was diagnosed with severe fever with thrombocytopenia syndrome(SFTS)complicated by hemophagocytic lymphohistiocytosis(HLH).After diagnosis,glucocorticoid combined with ribavirin treatment was initiated.However,the patient still died,which may be related to factors such as delayed medical consultation,advanced age,and poor control of viral replication.Case 2,a 73-year-old male patient,was admitted to our hospital due to"fatigue for 1 week",with a recent history of field farming work.The patient also presented with leukopenia and thrombocytopenia,combined with liver and coagulation function abnormalities.Bone marrow aspiration smear showed hemophagocytosis,and the patient was highly suspected of SFTS with HLH.We empirically initiated preemptive treatment with favipiravir for antiviral therapy,combined with glucocorticoid for anti-inflammation,to early inhibit novel bunyavirus replication and cytokine storm.Subsequent testing reported the severe fever with thrombocytopenia syndrome bunyavirus nucleic acid quantification as 2.69×103 50%tissue culture infective dose(TCID50)/mL,confirming the diagnosis of SFTS with HLH.The patient's clinical symptoms and various indicators generally improved.Review of these two similar cases suggests that early empirical preemptive use of favipiravir to control viral replication in clinical practice may improve the treatment and prognosis of patients with SFTS complicated by HLH.

Case 1,a 69-year-old male patient,was admitted to our hospital due to"dizziness,fatigue,nausea,diarrhea,and oral bleeding for 10 d",with a recent history of field farming work.The patient exhibited leukopenia,thrombocytopenia,and clinical manifestations of multi-organ dysfunction,including coagulation dysfunction,liver function abnormalities,gastrointestinal disorders,myocardial injury,and respiratory failure.Bone marrow aspiration smear revealed hemophagocytosis,and out-of-hospital testing for the severe fever with thrombocytopenia syndrome bunyavirus was positive.The patient was diagnosed with severe fever with thrombocytopenia syndrome(SFTS)complicated by hemophagocytic lymphohistiocytosis(HLH).After diagnosis,glucocorticoid combined with ribavirin treatment was initiated.However,the patient still died,which may be related to factors such as delayed medical consultation,advanced age,and poor control of viral replication.Case 2,a 73-year-old male patient,was admitted to our hospital due to"fatigue for 1 week",with a recent history of field farming work.The patient also presented with leukopenia and thrombocytopenia,combined with liver and coagulation function abnormalities.Bone marrow aspiration smear showed hemophagocytosis,and the patient was highly suspected of SFTS with HLH.We empirically initiated preemptive treatment with favipiravir for antiviral therapy,combined with glucocorticoid for anti-inflammation,to early inhibit novel bunyavirus replication and cytokine storm.Subsequent testing reported the severe fever with thrombocytopenia syndrome bunyavirus nucleic acid quantification as 2.69×103 50%tissue culture infective dose(TCID50)/mL,confirming the diagnosis of SFTS with HLH.The patient's clinical symptoms and various indicators generally improved.Review of these two similar cases suggests that early empirical preemptive use of favipiravir to control viral replication in clinical practice may improve the treatment and prognosis of patients with SFTS complicated by HLH.

[Objective] To report a Chinese family with maturity-onset diabetes of the young, type 2 (MODY2) caused by a novel glucokinase (GCK) gene mutation and to analyze its genetic and clinical characteristics. [Methods] Gene sequencing, clinical data collection and analysis were performed on a MODY2 family. [Results] A total of 18 members of this family were investigated, of whom 11 were diabetic, including the proband and her younger brother, father, uncle, cousin and other paternal members. The proband and her brother, father and uncle all had heterosense mutations of GCK gene (exon1: c.45G>A: p.K15K). Bioinformatics function prediction suggested that the mutation might affect mRNA splicing and lead to impaired GCK function. The mutation has not been reported in research on domestic population. The glycosylated hemoglobin levels of the proband and her younger brother were 6.49% and 6.72%; their fasting blood glucose levels were 6.80 mmol/L and 7.01 mmol/L, respectively. The diabetes autoantibody profiles were negative. Blood glucose levels remained stable during 6-18 months of follow-up. [Conclusion] The heterosense mutation of GCK gene in the MODY-2 family (exon1: c.45G>A: p.K15K) is a newly discovered mutation site in the Chinese population, and its clinical manifestations are mild, persistent and stable fasting hyperglycemia, and elevated glycosylated hemoglobin. The pathogenicity of GCK gene synonymous mutations should not be underestimated.

Objective:To explore the expression patterns of inhibitor of differentiation(ID)family in patients with chronic myeloid leukemia(CML)and analyze their clinical implications.Methods:Quantitative PCR and quantitative methylation-specific PCR were conducted to de-tect the transcript levels of ID2/ID3/ID4 and the methylation levels of ID4 in the bone marrow mononuclear cells of non-hematological ma-lignancies(acting as controls)and patients with CML treated at The Affiliated People's Hospital of Jiangsu University from January 2010 to December 2017.The clinical implications of ID family alterations were further analyzed.Results:ID2 and ID3 expression was significantly up regulated(P<0.001 and P<0.05,respectively),whereas ID4 expression was markedly down regulated in patients with CML(P<0.01).The re-ceiver operating characteristic curve demonstrated that the ID2 transcript level is a potential biomarker for distinguishing CML from controls(AUC=0.895,P<0.001).The frequency of ID4 promoter methylation in patients with CML was drastically higher than that in the controls(P=0.001).Moreover,ID4 methylation was negatively correlated with ID4 expression in patients with CML(r=-0.424,P=0.002).Clinically,CML with high ID2 expression occurred more frequently in males(P=0.040).Patients with low ID4 expression or high ID4 methylation showed a markedly higher frequency of an accelerated phase/blast crisis(P=0.003 and P<0.001,respectively).In addition,patients with CML in an accelerated phase/blast crisis exhibited markedly lower ID4 expression and higher ID4 methylation levels than those in the chronic phase(both P<0.001).Furthermore,univariate and multiple Logistic regression analyses revealed that the ID4 methylation level was an inde-pendent risk factor for CML progression(P=0.007).Conclusions:The ID family was differentially expressed in patients with CML;specifically,ID2 and ID3 expression was significantly increased,whereas ID4 expression was markedly decreased and correlated with ID4 promoter hy-permethylation.Hence,ID4 expression and methylation are confirmed to be associated with CML progression,and ID4 methylation could be an independent risk factor for CML progression.

Objective:To compare the efficacy and safety of endoscopic digestive resection and laparoscopic surgery in the treatment of gastric stromal tumor with diameter<3.5 cm.Methods:Stratified sampling was used to select 100 patients with diameter<3.5cm gastric stromal tumor from January 2018 to January 2020 in Yuncheng Central Hospital, and they were divided into two groups by touching the ball method.The control group (50 cases) was treated with laparoscopic surgery, and the observation group (50 cases) was treated with digestive endoscopic resection.The therapeutic effects of the two groups were compared.Results:The operative time of the observation group was (63.51±13.52)min, which was shorter than that of the control group [(71.24±15.04)min] ( t=2.703, P=0.004). The intraoperative blood loss in the observation group was (38.15±2.55)mL, which was less than that in the control group [(40.12±3.56)mL] ( t=3.181, P=0.001). The postoperative fasting time of the observation group was (20.02±3.85)h, which was shorter than that of the control group [(22.12±2.96)h] ( t=3.058, P=0.001). The postoperative recover defecation time of the observation group was (18.61±1.89)h, which was shorter than that of the control group [(20.05±3.13)h] ( t=2.785, P=0.003). The length of hospital stay in the observation group was (6.25±1.96)d, which was shorter than that in the control group [(7.06±1.16)d] ( t=2.515, P=0.007). The incidence of complications was 4.00% in the observation group, and 8.00% in the control group, the difference between the two groups was statistically significant(χ 2=0.177, P=0.673). There was no statistically significant difference in tumor risk classification between the two groups ( Z=0.386, P=0.534). Conclusion:Endoscopic digestive resection in the treatment of gastric stromal tumor with diameter<3.5cm has advantages of short operation time, less bleeding and fast postoperative recovery, etc., and has certain efficacy and safety.

Objective: To investigate the impact of homocysteine inducible endoplasmic reticulum(ER) protein with ubiquitin like domain 1 protein (Herpud1) in the homocysteine (Hcy) -induced phenotypic switching of vascular smooth muscle cells (VSMCs). Methods: VSMCs were derived from thoracic aortic artery of male Sprague Dawley rats and cultured VSMCs (4-7 passage) were treated with various concentrations of Hcy (0, 100, 500 and 1 000 μmol/L) and applied to immunofluorescence to observe the morphological changes of VSMCs via SM-actin staining. Western blot was used to detect the expression of VSMCs phenotypic markers, including Osteopontin, Calponin and smooth muscle myosin heavy chain (SM-MHC) and the expression of endoplasmic reticulum stress (ERS) related proteins, including C/EBP-homologous protein (CHOP), inositol-requiring kinase 1 (IRE-1) and glucose regulating protein 78 (GRP78) in the absence and presence of non-selective inhibitor of ERS, 4-phenylbutyric acid (4-PBA, 2 mg/ml). The Herpud1 mRNA and protein levels were determined in Hcy-stimulated VSMCs treated with 4-PBA or transfected with specific siRNA targeting Herpud1. Results: Compared with the control group, SM-actin staining results showed that the shape of VSMCs treated with different concentrations of Hcy for 24 hours changed from long fusiform into round form, arrangement of myofilament became irregular and the most significant alteration was found in the 500 μmol/L Hcy group. After intervention of 24 hours, various concentration of Hcy increased protein expression of Osteopontin, and reduced Calponin and SM-MHC protein expressions in VSMCs (all P<0.05). In addition, the results showed that Hcy increased the expression of CHOP, IRE-1 and GRP78 in a dose-dependent manner, which could be reversed by 4-PBA treatment (all P<0.05). However, 4-PBA inhibited Hcy induced upregulation of Osteopontin and downregulation of Calponin and SM-MHC, suggesting that ERS was involved in Hcy-induced phenotypic switching of VSMCs. Herpud1 protein was mostly expressed in the cytoplasm and was also expressed in the nucli, both in the control, Hcy and Hcy+4-PBA groups. Moreover, Hcy increased mRNA and protein levels of Herpud1 (P<0.05), whereas treatment with 4-PBA could significantly reduce Hcy-induced upregulation of Herpud1 (P<0.05). Furthermore, knockdown of Herpud1 abrogated the effects of Hcy on VSMCs phenotype markers. Conclusion Herpud1 plays an important role in Hcy-induced phenotypic switching of VSMCs.

Aim To investigate the effects of midazolam on porcine isolated coronary artery rings pre-contracted by potassium chloride(KCl)and the possible mechanism.Methods The vessel tension recorder system was used.Isotonic tension of porcine isolated coronary artery rings precontracted by KCl(30 mmol·L-1)was recorded.The vasorelaxing action of midazolam and effects of various drugs were observed in the rings.Results Midazolam(3×10-6～1×10-4 mol·L-1)respectively concentration-dependently reduced the contraction induced by KCl,and there was significant difference between the rings with intact and denude endothelium(P<0.05).On KCl-induced precontraction,midazolam′s relaxation was depressed by L-NAME and the blend of L-NAME and L-Arg(P<0.05),but was not affected by Indo,L-Arg and 1400W.The contraction was not prevented by pretreatment with the inhibitor of Na+/Ca2+ exchanger(KB-R7943).The inhibitor of KATP(Gli)restrained the diastolic function of midazolam(P<0.05),while the inhibitor of BKCa(TEA),Kir(BaCl2),KV(4-AP)had no obvious effect.Conclusions Midazolam produces remarkable vasodilatation on KCl pre-contracted porcine isolated coronary artery rings.Its relaxtion effect is via concentration-dependent and endothelium-dependent mechanisms and relevant to the production of NO.Na+/Ca2+ exchanger is not involved midazolam′s vasodilatation on KCl pre-contracted porcine coronary artery rings.The relaxant mechanism of midazolam may be concerned with KATP.The Kir,BKCa and KV may be not involved.

Objective To explore the relations of clinical phenotypes of type Ⅰ-ⅣV spinal muscular atrophy (SMA) with neural electrophysiological features and survival motor neuron (SMN)gene.Methods A total of 85 patients with SMA,including 46 with infantile form in which 19 of type Ⅰ and 27 of type Ⅱ,24 with juvenile form (type Ⅲ),and 15 with adult form (type ⅣV),were involved in this clinical study.Their clinical data were analyzed.The neural conduction,needle electromyography (EMG)and SMN1 gene deletion were analyzed.Results There existed different clinical features among patients who suffered from type Ⅰ to type ⅣV SMA.However,the major clinical features of SMA were displayed by progressively aggravating of flaccid paralysis in muscles of the four limbs,and the younger of the patients,the more serious of the clinical manifestations.EMG exhibited neurogenic lesion in all 43 SMA patients,33 patients presented generalized neurogenic lesions,and the abnormal degree of muscles in lower limbs was more severe than that of upper limbs,and the proximal muscles was more severe than that of the distal ones.The abnormal rate of spontaneous potential,weak contraction with raise potential and amplitude of compound motor active potential in adult and juvenile SMA were significantly lower than those in infantile SMA.SMN1 gene exon 7 and 8 were detected in all 85 patients with SMA.A total of 61 patients were found with deletion of exon 7 and/or 8 in SMN1 gene.Infantile SMA patients enjoyed 95.7％ (44/46) detection rate,juvenile SMA patients enjoyed 70.8％ (17/24) detection rate;no adult SMA patients were found with deletion ofexon 7 and/or 8 in SMN1 gene.Conclusions The more serious of clinical manifestations in SMA patients,the higher abnormality rote in electrophysiological tests.The exons deletion in SMN1 gene could result in alterations of SMA phenotypes,but it has nothing to do with the severity of SMA.Gene deletion analysis of SMN1 gene can be considered as the preferred fimal diagnosis method for infantile SMA patients.But as for juvenile form,its diagnosis depending on gene deletion analysis of SMN1 gene will be analyzed with precaution.While as for adult form of SMA,the incidence of SMA may be independent with SMN1 gene deletion.Therefore,generally,SMN1 gene assay is not taken as the routine diagnose method for adult form SMA.

Objective To explore mechnism and effect of fentanyl on proliferation of gastric cancer SGC-7901 cell.Methods Gastric cancer SGC-7901 cell was cultured with fentanyl of 0 (negative control), 0.5, 5 and 50 nmol/L, MTT method was used to detect the effect of fentanyl on SGC-7901 viability.The effect of fentanyl on SGC-7901 cell cycle was measured by flow cytometry.The level of cell related protein,cell cycle protein cyclin D1, Bcl-2.Results Compared with control group, fentanyl (0.5, 5, 50 nmol/L) could inhibit SGC-7901 cell viability, and the inhibitory rate was highest at 48 h.0.5, 5, 50 nmol/L fentanyl made cell cycle arrested in G1 phase.Compared with control group, fentanyl can significantly inhibit cyclinD1 and Bcl-2 expression with drug concentration increasing(P<0.05).Conclusion These results suggeste fentanyl inhibit proliferation of gastric cancer SGC-7901 cell.