OBJECTIVE To observe the clinical efficacy of Xuefu Zhuyu Decoction(XFZY)in the prevention and treatment of radiation-induced lung fibrosis(RILF)in esophageal cancer patients with blood stasis type underwent concurrent chemoradiotherapy(CRT).METHODS A total of 130 esophageal cancer patients with blood stasis type who treated with concurrent CRT were randomly divided into an experimental group and a control group,with 65 cases in each group.No patients dropped out during the study period.Patients in both groups received CRT and standardized symptomatic treatment was given according to the condition if radiation-induced lung injury occurred during treatment.On the basis of the treatment of the control group,the patients in the experimental group received XFZY from the beginning day until 30 days after the completion of CRT.The TCM syndrome score of the two groups were compared before and after treatment.The incidence of acute radiation pneumonia(RP)and chronic RILF and changes in pulmo-nary function indicators[forced expiratory volume in the first second as a percentage of predicted value(FEV1%pred),forced vital ca-pacity(FVC),FVC as a percentage of predicted value(FVC%pred),FEV1/FVC ratio,and carbon monoxide diffusing capacity as a per-centage of predicted value(DLCO%pred)]and serum cytokine levels[interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),hypoxia-inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF),and transforming growth factor β1(TGF-β1)]were compared at 6 months and 12 months after the completion of CRT.The occurrence of adverse reaction during treatment was recorded.RESULTS The total score of TCM syndrome of the two groups was significantly improved and the experimental group was better than that of the control group(P<0.01)after treatment.The efficacy of TCM syndrome was better in the experimental group than that of the control group(P<0.01).There was no statistically significant difference in the incidence rate of acute RP between the two groups(P>0.05)at 6 months after the completion of CRT.The levels of lung function indicators FEV1%pred,FVC%pred,and DLCO%pred in the experimental group were higher than those in the control group(P<0.05),and the levels of various cytokines in the experimental group were lower than those in the control group(P<0.05).The incidence rate of chronic RILF in the experimental group was significantly lower than that of the control group(P<0.05)at 12 months after the completion of CRT.The DLCO%pred level in the experimental group was higher than that in the control group(P<0.01),and the levels of cytokines HIF-1α,VEGF,and TGF-β1 were lower than those in the control group(P<0.05,P<0.01).There was no serious adverse event observed in either group of patients during the treat-ment.CONCLUSION XFZY can effectively prevent and treat RILF in esophageal cancer patients with blood stasis type underwent CRT,reducing the loss to lung function caused by radiotherapy,and its mechanism may be related to downregulating the levels of cyto-kines of HIF-1α,VEGF,and TGF-β1.

OBJECTIVE To observe the clinical efficacy of Xuefu Zhuyu Decoction(XFZY)in the prevention and treatment of radiation-induced lung fibrosis(RILF)in esophageal cancer patients with blood stasis type underwent concurrent chemoradiotherapy(CRT).METHODS A total of 130 esophageal cancer patients with blood stasis type who treated with concurrent CRT were randomly divided into an experimental group and a control group,with 65 cases in each group.No patients dropped out during the study period.Patients in both groups received CRT and standardized symptomatic treatment was given according to the condition if radiation-induced lung injury occurred during treatment.On the basis of the treatment of the control group,the patients in the experimental group received XFZY from the beginning day until 30 days after the completion of CRT.The TCM syndrome score of the two groups were compared before and after treatment.The incidence of acute radiation pneumonia(RP)and chronic RILF and changes in pulmo-nary function indicators[forced expiratory volume in the first second as a percentage of predicted value(FEV1%pred),forced vital ca-pacity(FVC),FVC as a percentage of predicted value(FVC%pred),FEV1/FVC ratio,and carbon monoxide diffusing capacity as a per-centage of predicted value(DLCO%pred)]and serum cytokine levels[interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),hypoxia-inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF),and transforming growth factor β1(TGF-β1)]were compared at 6 months and 12 months after the completion of CRT.The occurrence of adverse reaction during treatment was recorded.RESULTS The total score of TCM syndrome of the two groups was significantly improved and the experimental group was better than that of the control group(P<0.01)after treatment.The efficacy of TCM syndrome was better in the experimental group than that of the control group(P<0.01).There was no statistically significant difference in the incidence rate of acute RP between the two groups(P>0.05)at 6 months after the completion of CRT.The levels of lung function indicators FEV1%pred,FVC%pred,and DLCO%pred in the experimental group were higher than those in the control group(P<0.05),and the levels of various cytokines in the experimental group were lower than those in the control group(P<0.05).The incidence rate of chronic RILF in the experimental group was significantly lower than that of the control group(P<0.05)at 12 months after the completion of CRT.The DLCO%pred level in the experimental group was higher than that in the control group(P<0.01),and the levels of cytokines HIF-1α,VEGF,and TGF-β1 were lower than those in the control group(P<0.05,P<0.01).There was no serious adverse event observed in either group of patients during the treat-ment.CONCLUSION XFZY can effectively prevent and treat RILF in esophageal cancer patients with blood stasis type underwent CRT,reducing the loss to lung function caused by radiotherapy,and its mechanism may be related to downregulating the levels of cyto-kines of HIF-1α,VEGF,and TGF-β1.

Calcium-sensing receptor (CaSR), a family C G-protein-coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca 2+, Mg 2+, amino acids (e.g., L-Trp and L-Phe), small peptides, anions (e.g., HCO 3- and PO 43-), and pH. CaSR-mediated intracellular Ca 2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca 2+-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.

ObjectiveTo evaluate the validity of four screening questionnaires on chronic obstructive pulmonary disease (COPD) among community residents in Shanghai, and to provide a scientific basis for selecting suitable screening questionnaires and plans for the community use. MethodsA multi-stage random sampling method was used to select community residents aged ≥40 for COPD questionnaire screening and spirometry. The screening questionnaires included the COPD Population Screener Questionnaire (COPD-PS), the COPD Screening Questionnaire (COPD-SQ), the COPD Diagnosis Questionnaire (CDQ), and the Lung Function Questionnaire (LFQ). The diagnostic gold standard for COPD was defined as a ratio of post-bronchodilator forced expiratory volume in one second to forced vital capacity (FEV1/FVC) less than 0.7. The receiver operating characteristic (ROC) curve was used to assess the validity of each questionnaire, and DeLong’s test was used to compare the area under the curve (AUC) of different questionnaires. ResultsAmong the 1 122 residents screened, 99 (8.8%) were diagnosed with COPD based on the gold standard criteria. The AUC values for the four questionnaires ranged from 0.643 to 0.682, with no statistically significant differences in screening accuracy among them (P>0.05). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each questionnaire at recommended cut-off points were as follows: COPD-PS (sensitivity: 33.3%, specificity: 84.9%, PPV: 17.6%, NPV: 92.9%), COPD-SQ (34.3%, 85.8%, 19.0%, 93.1%), CDQ (73.7%, 42.4%, 11.0%, 94.4%), and LFQ (48.5%, 74.8%, 15.7%, 93.8%). Optimal cut-off values for this population differed from the recommended values. When selecting the optimal cut-off value, the sensitivity of COPD-PS (58.6%), COPD-SQ (55.6%), and LFQ (64.7%) increased, while the specificity of CDQ (75.9%) increased. The AUC of sequential lung function testing for all four screening questionnaires increased to 0.7 or above. The optimal cut-off values for the four questionnaires in this population differed from the recommended values. When applying the optimal cut-off values, the sensitivity of three questionnaires increased: COPD-PS (58.6%), COPD-SQ (55.6%), and LFQ (64.7%), while the specificity of CDQ rose to 75.9%. The AUC of each questionnaire increased to above 0.7 when followed by sequential lung function testing. ConclusionThe COPD-PS, COPD-SQ, CDQ, and LFQ have limited value for COPD screening among Shanghai community residents, indicating that further refinement of these tools is needed.

ObjectiveTo investigate the effects of probiotics combined with bismuth quadruple therapy （BQT） on clinical efficacy、gastrointestinal adverse reactions and intestinal flora in Helicobacter pylori （HP） positive patients. MethodsThe patients who were positive for HP from May 2023 to July 2023 in the department of gastroenterology of Shanghai first people's hospital were randomly divided into2 groups with 40 people in each group. The probiotic group was given 2 weeks of quadruple therapy with probiotics and standard BQT， followed by 4 weeks of oral probiotics after quadruple discontinuation. The placebo group was given 2 weeks of probiotic placebo and standard BQT， followed by 4 weeks of oral probiotic placebo. ¹³C urea breath test was used to evaluate the clinical efficacy， gastrointestinal symptoms rating Scale was used to evaluate the gastrointestinal adverse reactions of patients before and after the intervention， and microbial diversity 16S rDNA sequencing technology was used to detect the level of intestinal flora of patients before and after the intervention. ResultsThere was no significant difference in the eradication rate between the two groups （P>0.05）. Before the intervention， there was no significant difference in the scores of the gastrointestinal symptom rating scale between the probiotic group and the placebo group. After the intervention， patients in the probiotic group had significantly lower pain scores on acid reflux （1.10±0.30 vs 1.35±0.53， P<0.05） and stomach or abdominal hunger than in the placebo group （1.07±0.26 vs 1.30±0.52， P<0.05）. Through the before-and-after comparison of the probiotic group， the scores of abdominal pain （1.24±0.44 vs 1.58±0.71， P<0.05）， stomach or abdominal hunger （1.07±0.26 vs 1.27±0.45， P<0.05） and dry and hard stool （1.24±0.49 vs 1.48±0.75，P<0.05） were significantly lower in the probiotic group than before the intervention in the probiotic group. ConclusionProbiotics combined with BQT can improve the gastrointestinal adverse reactions and intestinal flora disorders in the process of quadruple drug therapy， but it does not improve the eradication rate of HP.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2A^APP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Calcium-sensing receptor (CaSR), a family C G-protein-coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca 2+, Mg 2+, amino acids (e.g., L-Trp and L-Phe), small peptides, anions (e.g., HCO 3- and PO 43-), and pH. CaSR-mediated intracellular Ca 2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca 2+-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.

Objective:This study evaluates the efficacy and safety of dasatinib combined with a multi-agent chemotherapy regimen of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) patients. Methods:This prospective, single-arm, and open clinical study enrolled 30 adult Ph + ALL patients who were newly diagnosed and treated from January 2016 to April 2018 in the center of this study. Standard induction chemotherapy was given for 4 weeks. However, dasatinib (100 mg/d) was continuously administered from day 8 until the end of the whole therapy in the induction therapy. Patients who are available for allogeneic or autologous stem cell transplantation (SCT) received transplantation when the disease was evaluated as complete remission. Results:All 30 patients achieved hematological complete remission (HCR) after the induction chemotherapy, and 70.0% (21/30) of them achieved the accumulated molecular complete remission (MCR) . The patients were followed up with a median follow-up time of 37.8 months (32.0-46.6) . The 3 year overall survival (OS) and 3 year hematological relapse-free survival (HRFS) were 68.1% and 61.6%, respectively. Moreover, 63.3% and 43.3% of the patients achieved molecular major remission and MCR, respectively. Consequently, 60.0% of the patients achieved MCR until 6 months. The patients who achieved MCR within 6 months had superior OS ( P=0.004) , HRFS ( P=0.049) , and event-free survival (EFS; P=0.001) . Fifteen patients (50.0%) received SCT at the first HCR. However, HRFS ( P=0.030) and EFS ( P=0.010) in the SCT group were better than those in the chemotherapy group. Conclusions:The regimen of dasatinib combined with a multi-agent chemotherapy was proven safe and effective in the treatment of newly diagnosed adult Ph + ALL patients. Clinical trial registration:ClinicalTrials.gov, NCT02523976.

Objective:To investigate the effect of genetic polymorphisms of TPMT*2 rs1800462, TPMT*3B rs1800460, TPMT*3C rs1142345, and NUDT15 rs116855232 on the tolerance of 6-mercaptopurine (6-MP) therapy in adult acute lymphoblastic leukemia (ALL) .Methods:A total of 216 adult patients who were diagnosed with ALL and treated with cyclophosphamide, cytarabine, and 6-MP [complementary and alternative medicine (CAM) regimen] from September 2015 to December 2019 were included. Polymorphisms were detected by TaqMan SNP Genotyping Assay. Combined with clinical data, the influence of genetic polymorphism on the tolerance of 6-MP in the treatment of ALL was analyzed.Results:Among the 216 patients, 185 (85.65%) patients had B-ALL and 31 (14.35%) patients had T-ALL. 216 (100%) patients had CC genotype for both TPMT*2 rs1800462 and TPMT*3B rs1800460. The number of TT and TC genotypes for TPMT*3C rs1142345 was 209 (96.76%) and 7 (3.24%) , respectively. The allele frequency was 1.62% for TPMT*3C rs1142345. The number of CC, CT, and TT genotypes for NUDT15 rs116855232 was 166 (76.85%) , 48 (22.22%) , and 2 (0.93%) , respectively. The allele frequency was 12.04% for NUDT15 rs116855232. The TPMT*3C rs1142345 mutant group (TC+CC genotype) had less transfusion volume of packed red blood cell than the wild group (CC genotype) ( P=0.036) , and the mutant group (TC+CC genotype) had a higher risk to develop hepatotoxicity (increased aspartate aminotransferase) than the wild group (CC genotype) ( OR=9.559, 95% CI 1.135-80.475, P=0.038) . The durations of white blood cells (WBC) <1×10 9/L and absolute neutrophil count (ANC) <0.5×10 9/L in the NUDT15 rs116855232 mutation group (CT+TT genotype) were longer than that in the wild group (CC genotype) ( P=0.005, P=0.007) , and the transfusion volume of apheresis-derived platelets in the mutant group (CT+TT type) was greater than that in the wild group (CC genotype) ( P=0.014) . Conclusion:Genetic polymorphism of TMPT and NUDT15 has an effect on the tolerance of 6-MP in the treatment of adult ALL. Detecting genotypes of patients with ALL before treatment helps to optimize the dosage of 6-MP, which may help shorten the bone marrow suppression duration and reduce blood transfusion volume.

Objective: To analyze the clinical , immunological and genetic features of a child with BCL11B mutation induced neurodevelopmental disorder. Methods: The clinical data and genetic test of a child with BCL11B mutation hospitalized in the Department of Rheumatology and Immunology in Children′s Hospital of Chongqing Medical University in December 2018 were extracted and analyzed. The literature was searched with "BCL11B mutation" and "immunodeficiency 49" as key words in Chinese databases and Pubmed until January 2019 was reviewed. Results: A male patient aged 3 years and 11 months with facial dysmorphisms and delayed language and motor development was admitted due to neurodevelopmental retardation over two years. Laboratory tests showed normal human immunoglobulin (IgG 12.90 g/L, IgA 1.02 g/L, IgM 1.15 g/L, IgE 532 000 U/L), Trec (228) and proliferation of T and B cells. The lymphocyte subsets revealeda reduced percentage of B cells (0.108) but normal absolute numbers (0.574×10^-3/L), and an increased percentage (0.828) as well as absolute numbers (4.415×10^-3/L) of T cells. A heterozygous BCL11B mutation was detected by sanger sequencing, showing a de novo frameshift mutation c.1887_c.1893delCGGCGGG in exon 4. Two papers were found which were all in English, with total of 14 patients(13 patients with complete information). Thirteen mutations were reposed, including 7 frameshift, 2 nonsense, 2 missense, and 2 chromosomal rearrangements; Thirteen patients had heterozygous mutations. All patients had delayed language and motor development and facial dysplasia which were mainly hypertelorism, thin eyebrows and small palpebral fissures. Some patients had dental anomalies, ametropia and allergy, and a few were combined with immune impairment, but without overt signs of immunodeficiency. Only one patient had multisystem anomalies and profound immune deficiency. Conclusions BCL11B is essential for development of the nervous and the immune system. In this study, the de novo mutation of BCL11B gene resulted in neurodevelopmental and immunological disorders.