Cucurbitacin B inhibits cell proliferation and induces cell apoptosis in colorectal cancer by modulating methylation status of BTG3.

A previous report has revealed that cucurbitacin B (CuB) inhibits cancer cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC) through epigenetic modifications of several genes. However, whether CuB regulates cell proliferation and apoptosis by altering methylation status of BTG3 in colorectal cancer (CRC) remains unknown. In the present study, the results showed that BTG3 was downregulated in CRC tissues compared with adjacent normal tissues. CuB significantly increased BTG3 levels, induced promoter demethylation, and decreased the levels of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) in both CRC cell lines (SW480 and Caco-2), and the effects of CuB were comparable with those of 5-Aza-dC. We also found that CuB inhibited cell proliferation, accompanied with decreased expression of Ki67. Furthermore, CuB treatment induced cell cycle arrest at G1 phase in SW480 and Caco-2 cells, as well as decreased levels of Cyclin D1 and Cyclin E1. Incubation with CuB promoted cell apoptosis in both CRC cell lines in vitro, accompanied with elevation of cleaved caspase-3 and cleaved PARP. BTG3 knockdown abolished the effects of CuB in CRC cells. In summary, CuB-induced proliferation inhibition and cell apoptosis may be due to the reactivation of BTG3 by promoter demethylation. CuB may be a promising agent for CRC therapy.

[Efficacy analysis of LVIS and Enterprise stent assisted coil in the treatment of vertebral artery dissection aneurysm].

Objective: To observe and evaluate the therapeutic efficacy of LVIS stent and Enterprise stent assisted coil in embolization of vertebral artery dissection aneurysm (VDA). Methods: Clinical data of 96 patients with VDAs treated by LVIS stent and Enterprise stent assisted coil were analyzed retrospectively between January, 2013 and June, 2017.Of all, the LVIS stent assisted coil was performed in 28 patients (LVIS-stent group) and Enterprise in 68 patients (Enterprise-stent group). The clinical and imaging follow-up were performed. The instant embolization rate, complications, and recurrence rate were analyzed and compared between the two groups. Results: Instant angiographic results:in the LVIS stent group, complete occlusion was achieved in 17 VDAs (60.7%), near-complete occlusion in 10VDAs (35.7%), and partial occlusion in 1 VDA (3.6%). In the Enterprise stent group, complete occlusion was achieved in 27 VDAs (39.7%), near-complete occlusion in 34VDAs(50.0%), partial occlusion in 7VDAs (10.3%). Procedure-related complications occurred in 3 patients (10.7%) in LVIS stent group and 3 patients (4.4%) in Enterprise stent group. DSA follow-up was performed during 6 to 12 months after surgery, and 10 patients with vertebral artery dissection aneurysm recurred, 2 in the LVIS group and 8 in the Enterprise stent group. The latest modified Rankin Scale score was 0 in 55 patients,1 in 13, 2 in 1, 3 in 1, and 6 in 1. Among them, all follow-up patients in the LVIS stent group had good prognosis, while in the Enterprise stent group, 50 patients (94.4%) had a good prognosis. Conclusions: The stent-assisted coils have a higher degree of embolization in the vertebral artery dissection aneurysms, a higher rate of near-total embolization, a lower incidence of neurological complications, and a good prognosis. The complete andnear-complete occlusion rates and the incidence of neurological complicationsin the LVIS group was higher than that in the Enterprise groupand the recurrence ratesin the LVIS group was lower than that in the Enterprise group,both with no statistically significant difference.

[Endovascular thrombectomy in patients with intracranial large artery occlusion and atrial fibrillation].

Objective: To investigate the safety and efficacy of mechanical thrombectomy in patients with atrial fibrillation complicated with acute intracranial arterial occlusion. Methods: Fifty-eight patients with atrial fibrillation complicated with acute intracranial arterial occlusion in the intervention group of East (Endovascular Therapy for Acute ischemic Stroke Trial) were analyzed. According to the TOAST (Trial of Org 10 172 in Acute Stroke Treatment) classification, patients were divided into ICAS (Intracranial Atherosclerotic Stenosis) group and cardiogenic embolism group. Clinical characteristics, treatment methods and clinical prognosis were compared between ICAS group and cardiogenic embolism group. Results: A total of 58 patients with atrial fibrillation complicated with acute intracranial arterial occlusion were included in this study, including 46 patients in the cardiogenic embolism group (79%) and 12 patients in the ICAS group (21%). The pre-hospital transport time in ICAS group was longer than that in cardiogenic embolism group (P<0.05).Patency rate in patients with atrial fibrillation complicated with acute intracranial arterial occlusion was 98.3% (57/58), The rate of patients with the 90-day function independent (mRS 0-2) was 51.7% (30/58). There were no statistically significant differences in functional independence, mortality rate, ICH and sICH at 90 days between the cardiogenic embolism group and the ICAS group. Conclusions: Mechanical thrombectomy is an effective method to treat patients with atrial fibrillation complicated with acute intracranial arterial occlusion.

[Clinical analysis of five cases of autism spectrum disorder complicated with epilepsy with chromosome copy number variation].

Objective: To explore the clinical features and genetic causes of autism spectrum disorder (ASD) patients with epilepsy. Methods: The clinical data of five patients with ASD and epilepsy admitted to Xuanwu Hospital between September 2017 and September 2018 were collected, including medical history, intelligence level, developmental level, physical examination, neuroimaging and electroencephalogram. High-throughput whole-genome sequencing was applied to five patients and their parents. Results: Of five patients, four were male and one was female. All five patients had mild mental retardation, and one patient had significant growth retardation and craniofacial deformity. The average epilepsy onset age was 6.3 years old (7 months to 16 years). The main epileptic type was tonic-clonic seizure with abnormal EEG results. All patients have a favorable response to anti-epileptic drugs. Whole-exome sequencing (WES) revealed copy number variation in all 5 patients. Among them, 3 cases were reported to be pathogenic, and 2 cases were not reported (chromosome 16p13.3 duplication and chromosome 21q22.3 deletion). Conclusions: The results of current study support that autism spectrum disorders with seizures is often associated with copy number variations, such as Williams-Beuren region duplication syndrome, chromosome 15q11.2 duplication syndrome and chromosome 15q11.2 deletion syndrome. We reported two novel copy number variations (chromosome 16p13.3 duplication and chromosome 21q22.3 deletion) in two autism spectrum disorder patients with epileptic seizures.

[Proteomic analysis of aqueous humor in acute primary angle-closure glaucoma].

Objective: To analyze the difference among expression of aqueous humor proteins in acute primary angle-closure glaucoma (APACG). Methods: Case-control study. The patients with APACG combined cataract (APACG with cataract group) and patients with cataract (cataract group), who had undertaken surgical treatment at the Tianjin Medical University Eye Hospital from October 2016 to June2017 were collected. Upon receipt of patient's consent, 50 µl of aqueous humor were collected with 1 ml syringe and No.1 needle through the surgical access during the surgery, and then injected into a sterile collection tube to be stored at -80 ℃. Those proteins extracted from aqueous humor were analyzed by quantitative proteomic mass spectrometry. The differential significance test was performed by Maxquant significances A approach. The differential proteins of the two groups were screened and determined with the conditions of P<0.05 and difference multiple>2. The functions and signal pathway of differential proteins in aqueous humor were annotated in biological big data, on the basis gene ontology (GO) and the Kyoto gene and genomic encyclopedia (KEGG) analyses. Results: There were 3 males and 7 females with an average age of (68±6) years in the APACG group. The cataract group included 2 males and 8 females with an average age of (71±8) years. There were no statistical differences in gender ratio and age between the two groups (both P>0.05). A total of 91 differential proteins were detected in this experiment, including 50 up-regulated proteins (annexinA1, vimentin, S100 calcium binding protein A8, interleukin 6, C reactive protein, laminin ß2, etc.) and 41 down-regulated (keratin 85, γ-crystallin D, syntaxin-binding protein 5, semaphoring 4B, matrilin 2, cathepsin O, cadherin 4, semaphoring 3B, platelet-derived growth factor D, transforming growth factor ß, etc.). On one hand, the functions of differential proteins involved in many aspects. AnnexinA1, CD163, S100 calcium-binding protein A8, C reactive protein, interleukin 6 are involved in the inflammatory reaction, cadherin 4 and laminin ß2 regulate cell adhesion, matrilin 2, vimentin and laminin ß2 participate in tissue fibrosis; on the other hand, KEGG analysis showed that the differential proteins participate diverse signaling pathways such as phosphatidylinositol-3-kinase-protein kinase B signaling pathway, transformation growth factor ß signaling pathway, mitogen activated protein kinase signaling pathway, Toll-like receptor signaling pathway, the nuclear factor κ-light chain enhancer of the activated B cells signaling pathway, focal adhension and extracellular matrix receptor interaction pathway and so on. Conclusions: The expression of annexin A1 is significantly up-regulated in the aqueous humor in APACG, while some other factors such as transformation growth factor ß, cadherin-4, and matrilin 2 are down-regulated. The change of proteins in aqueous humor is related with the outbreak of APACG. (Chin J Ophthalmol, 2019, 55: 687-694).

Genome-wide DNA methylation patterns in coronary heart disease.

BACKGROUND: To better understand the molecular mechanisms of atherosclerosis, we conducted a comparative analysis of DNA methylation patterns in right coronary arteries in the area of advanced atherosclerotic plaques (CAP), great saphenous vein (GSV), and internal mammary artery (IMA) of patients affected by coronary heart disease. METHODS: DNA methylation data (accession number E­GEOD-62867) were divided into three paired groups: CAP vs. IMA, CAP vs. GSV, and IMA vs. GSV. Differentially methylated genes (DMGs) were extracted to analyze the changes in the DMGs in the three different tissues. The gplots package was used for the clustering and heatmap analysis of DMGs. Subsequently, DMG-related pathways were identified using DAVID (Database for Annotation, Visualization and Integrated Discovery) and transcription factors (TFs) were predicted. RESULTS: Based on the filtering criterion of p < 0.05, and a mean beta value difference of ≥0.2, there were 252, 373, and 259 DMGs, respectively, in the CAP vs. IMA, CAP vs. GSV, and IMA vs. GSV groups. Interestingly, the S100A10 gene was hypomethylated in CAP compared with IMA and GSV. Clustering and heatmap analyses suggested that DMGs were segregated into two distinct clusters. Hypermethylated genes in CAP as compared with GSV were only involved in the pathway of fat digestion and absorption, while hypomethylated genes in CAP compared with GSV mainly participated in immune response-associated pathways (cytokine-cytokine receptor interaction, MAPK signaling pathway). CONCLUSION: The DNA methylation differences in vascular tissues of patients with coronary artery disease may provide new insights into the mechanisms underlying the development of atherosclerosis. The functions identified here-cytokine-cytokine receptor interaction, MAPK signaling pathway, DMG (S100A10), and TF (NF-kB)-may serve as potential targets in the treatment of atherosclerosis.

[Efficacy analysis of the endovascular treatment for 175 unruptured vertebrobasilar dissecting aneurysms].

Objective: To analyze the clinical characteristics, clinical effect and follow-up outcome of the different endovascular treatment techniques in the treatment of unruptured vertebrobasilar dissecting aneurysms (VBDAs). Methods: The clinical data of 160 consecutive patients (175VBDAs) from January 2012 to December 2016 in Beijing Tiantan hospital were retrospectively analyzed.All of the 175 aneurysms were treated with endovascular embolization, including 115 stent-assisted coils, 27 simple stents, 21 blood flow diverting devices, and 12 parent arteries occlusion.The imaging and clinical follow-up were performed after the operation. Results: Headache including cervical-occipital pain(43.1%)was the most common clinical manifestation.The incidence of perioperative complications was 3.75%, no intraoperative bleeding and no deaths.The imaging findings of 113 aneurysms were followed up for (9.9±7.3) months.Of the 71 stent-assisted coils, 62 recovered well and 9 relapsed; of the 19 aneurysms treated with simple stent, 4 recovered well, 11 improved, 2 stable and 2 relapsed; of the 15 aneurysms treated by the blood flow diverting devices, 4 recovered and 11 improved; all of the 8 aneurysms with parent arteries occlusion recovered well.A total of 144 patients were follow-up (17.3±16.6) months by the Modified Rankin Scale(mRS) score: 140 patients were 0-2 score and 4 patients were 3-6 score. Conclusions: The clinical manifestations of the unruptured VBDAs are complex, and the headache is the most common clinical symptom.Endovascular treatment for the treatment of unruptured VBDAs is safe and feasible.The principle of individualization should be followed during embolization.

[Urothelial carcinoma-associated 1 enhances tamoxifen resistance in breast cancer cells through competitively inhibiting miR-18a].

OBJECTIVE: To investigate how urothelial carcinoma-associated 1 (UCA1) and miR-18a modulates acquired tamoxifen resistance and the relevant mechanisms in estrogen receptor (ER) positive cancer cells. METHODS: qRT-PCR was performed to detect UCA1 and miR-18a expression in breast cancer cells. Dual luciferase assay was performed to detect the binding between miR-18a and UCA1 3'UTR. Tamoxifen sensitive MCF-7 cells were transfected with UCA1 expression vector or miR-18a inhibitors. Tamoxifen resistant LCC9 and BT474 cells were transfected with UCA1 siRNA or miR-18a mimics. CCK-8 assay was performed to detect cell viability. Soft agar assay was performed to assess cell colony formation. Flow cytometric analysis was performed to check cell cycle distribution. RESULTS: UCA1 was significantly upregulated in tamoxifen resistant LCC2, LCC9, and BT474 cells than in tamoxifen sensitive MCF-7 cells. UCA1 expression was significantly upregulated in MCF-7 cells after treatment with 0.1 µmol/L tamoxifen. UCA1 overexpression enhanced cell viability of MCF-7 cells after tamoxifen treatment, while UCA1 siRNA significantly suppressed viability of LCC9 and BT474 cells after tamoxifen treatment. In MCF-7 cells, compared with vector control+tamoxifen group, the average cell colony number and colony size of the UCA1+tamoxifen group was 19.0% more and 29.0% larger respectively, while the proportions of the cells in G1 phase and in S phase were 7.3% lower and 6.7% higher respectively. In BT474 cells, compared with siRNA control+tamoxifen group, the average cell colony number and colony size of the si-UCA1+tamoxifen group were 54.0% less and 42.0% smaller respectively, while the proportions of the cells in G1 phase and in S phase were 9.0% higher and 6.2% lower respectively. UCA1 directly interacted with miR-18a and reduced its expression in ER positive breast cancer cells. Knockdown of miR-18a increased viability of MCF-7 cells after tamoxifen treatment, while miR-18a overexpression significantly reduced viability of BT474 cells after tamoxifen treatment. In MCF-7 cells, compared with miRNA inhibitor control+tamoxifen group, the average cell colony number and colony size of the miR-18a inhibitor+tamoxifen group were 15.0% more and 33.0% larger respectively, while the proportions of the cells in G1 phase and in S phase were 8.8% lower and 5.3% higher respectively. In BT474 cells, compared with miRNA control+tamoxifen group, the average cell colony number and colony size of the miR-18a mimics+tamoxifen group were 47.0% less and 25.0% smaller respectively, while the proportions of the cells in G1 phase and in S phase were 13.3% higher and 7.9% lower respectively. CONCLUSION: UCA1 can increase tamoxifen resistance of ER positive breast cancer cells via competitively inhibiting of miR-18a.

[Myoclonus and it's associated factors in Creutzfeldt-Jakob disease].

Objective: To analyze features and the related factors of myoclonus of 47 patients with probable or possible Creutzfeldt-Jakob disease (CJD). Methods: All patients diagnosed with"suspected CJD" and hospitalized in Xuanwu Hospital from January 2013 to November 2015 were included, and their clinical information and myoclonus features were analyzed. Age, clinical, course and manifestation, EEG, MRI, CSF14-3-3 features between myoclonus positive group and negative group were compared, and the correlation between myoclonus features and these factors was analyzed using Spearman correlation analyses. Results: (1) Occurrence rate of extrapyramidal symptoms (P=0.028), visual impairment (P=0.025) and dyssomnia (P=0.004) were higher in myoclonus positive group, the differences were significant. Spearman correlation analysis showed that myoclonus was related to extrapyramidal symptoms (P=0.024), visual impairment (P=0.030) and dyssomnia (P=0.001). (2) EEG features showed no significant difference between myoclonus positive and negative group. The 17 myoclonus positive patients were divided into three subgroups, typical EEG change group 52.94%(9/17), atypical EEG change group 23.53%(4/17) and no EEG change group 23.53%(4/17). Difference of myoclonus and other clinical manifestations were not significant among the three subgroups(P>0.05); correlation analysis also found no statistically significant correlation between myoclonus and EEG (P=0.201). Conclusions: Myoclonus often occurs after the damage of locomotor system (including pyramidal tract, extracorticospinal tract and cerebellum) among CJD patients, and it is related to extrapyramidal symptoms , visual impairment and dyssomnia . There is undefined correlation between myoclonus and periodic sharp wave complexes (PSWC) in EEG.

[Feature of magnetic resonance imaging in patients with Creutzfeldt-Jakob disease].

Objective: To assess the imaging features of 43 patients diagnosed as clinically possible or probable Creutzfeldt-Jakob disease (CJD) for providing referential information and experience on applications of MRI in the clinical diagnosis and treatment of CJD. Method: All patients who were diagnosed with "suspected CJD" and hospitalized in Xuanwu Hospital from January 2013 to November 2015 were collected, and their clinical information and MRI imaging features were analyzed retrospectively. Results: Totally 62 patients with "suspected CJD" were rectruited in this study, and 43 of them were diagnosied as probable and possible CJD when they were discharged.The typical MRI feature of CJD patients was "cortical ribbon" sign in MR DWI sequences and/or high signal in cortex or bilateral basal ganglia.In all patients, the simple coritcal involvement was the highest(76.47%, 26/34), followed by the cortical cortex and basal ganglia(23.53%, 8/34). MRI positive group had more prominent extrapyramidal symptoms than MRI negative group (26/31 vs 9/12, P=0.015), but no statistical difference in clinic feature was found between the group with simple cortex affected and the group with both cortex and bilateral basal ganglia affected (P>0.05). Conclusions: MRI images of patients with CJD have special characteristics and have corresponding changes when the patients are in different stages of disease. In combination with the clinical evaluation of disease progression, brain microscopic pathological changes of CJD patients can be assessed by regularly brain MRI examination.

SERS detection of R6G based on a novel graphene oxide/silver nanoparticles/silicon pyramid arrays structure.

We present a novel surface-enhanced Raman scattering (SERS) substrate based on graphene oxide/silver nanoparticles/silicon pyramid arrays structure (GO/Ag/PSi). The SERS behaviors are discussed and compared by the detection of R6G. Based on the contrast experiments with PSi, GO/PSi, Ag/PSi and GO/AgA/PSi as SERS substrate, the perfect bio-compatibility, good homogeneity and chemical stability were confirmed. We also calculated the electric field distributions using Finite-difference time-domain (FDTD) analysis to further understand the GO/Ag/PSi structure as a perfect SERS platform. These experimental and theoretical results imply that the GO/Ag/PSi with regular pyramids array is expected to be an effective substrate for label-free sensitive SERS detections in areas of medicine, food safety and biotechnology.

Effects of BCL2 transfection on the cell cycle and proliferation of human GES-1 cells.

We investigated the effects of BCL2 transfection on the cell cycle and proliferation of GES-1 cells. A pcDNA3-BCL2 plasmid was used to transfect GES-1 cell line human gastric epithelial cells. Clones were obtained by G418 screening. BCL2-positive cells were identified by fluorescence immunohistochemistry. The pcDNA3-BCL2 vectors carrying the NeoR gene were transfected into GES-1 cells, while the empty plasmid was transfected into the same cells as controls. BCL2-positive clones were screened by neomycin 418 (G418). Flow cytometry was used to detect the cell cycle. Hematoxylin and eosin (H&E) staining revealed morphological changes, and the effects of BCL2 transfection on cell proliferation were analyzed by cell counting and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The plasmid pcDNA3-BCL2 was identified by restriction enzyme digestion. Different degrees of BCL2 gene expression were detected in all seven clones. BCL2 was expressed mainly in the cytoplasm and the nuclear membrane. There were significantly more S-phase cells in the transfection group than in the controls. The morphology did not change after H&E staining. Cell growth was faster than in the controls after transfection for 6 days. At 24, 48, and 72 h after transfection, the A values were 4.15 ± 0.31, 5.98 ± 0.56, and 8.94 ± 0.79; those of the controls were 3.01 ± 0.20, 4.76 ± 0.52, and 7.69 ± 0.84; there was a significant difference between the two groups (P < 0.05). BCL2 transfection increased GES-1 cells in the S phase; the GES-1 cells were stable and BCL2 expression was high, which promoted cell proliferation.

[Analysis of pediatric heart transplantation supported by extracorporeal membrane oxygenation].

Objective: To summarize the clinical characteristics of patients with end-stage heart failure who receive heart transplant under extracorporeal membrane oxygenation (ECMO) support. Methods: The clinical data of 12 pediatric patients who received heart transplant with ECMO support in the Seventh Medical Center of Chinese People's Liberation Army General Hospital and Guangdong Provincial People's Hospital, from January 2019 to December 2023 was collected. The data included sex, age, weight, diagnosis, pre-ECMO lactate level, left ventricular ejection fraction (LVEF), vasoactive-inotropic score (VIS), and preoperative ECMO running time. Surgical data included cold ischemia time of the donor heart, cardiopulmonary bypass time, intraoperative use of immunosuppressant, postoperative use of ECMO, duration of postoperative ECMO, rate of successful weaning from ECMO, and survival discharge rate. The paired t-test was performed to compare cardiac function indices before and after left ventricular decompression. Results: The 12 patients ranged in age from 1.1 to 15.8 years, and weighted from 8 to 63 kg. Ten children were diagnosed with dilated cardiomyopathy, one with myocardial underdensification, and one with a novel heterozygous mutation of the SCN5A gene causing overlap syndrome complicated by fatal arrhythmia. Before ECMO, the lactate ranged from 0.6 to>15.0 mmol/L, the LVEF from 6.5% to 43%, and VIS from 3 to 108. Four patients underwent left ventricular decompression supported by preoperative ECMO, and their pulse pressure was significantly increased after decompression ((17.8±2.1) vs. (9.8±1.5) mmHg, 1 mmHg=0.133 kPa, t=11.31, P=0.001), while there was no apparent change in LVEF ((26.8±4.4)% vs. (24.9±4.9)%, t=1.75, P=0.178). A total of 7 children received a second run of ECMO after surgery and 3 of them successfully weaned off ECMO and survived to discharge. In the entire cohort, 10 were successfully weaned from ECMO and 8 survived to discharge. Conclusions: For children with end-stage heart failure supported by ECMO, left ventricular decompression can significantly improve pulse pressure. These patients will eventually require heart transplantation.

A sero-epidemiological survey of Chinese Babesia motasi for small ruminants in China.

Babesia motasi BQ1 (Lintan) was first isolated from Haemaphysalis qinghaiensis collected in Gannan Tibet Autonomous Region, Gansu province in April 2000. In this study, a total of 3,204 serum samples from small ruminants in 22 provinces located in different districts of China were tested for antibodies against merozoite antigens from cultured B. motasi BQ1 (Lintan) by enzyme-linked immunosorbent assay. This method can survey the prevalence of low-pathogenic Chinese B. motasi. The results of this survey indicated that the average positive rate was 43.5 %, and the positive rates of investigated provinces were significantly different from 6.1 to 91.0 %, and the infections had been found in all provinces investigated. Our data provide large important information regarding the current sero-prevalence of B. motasi in China.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

The incidences of adverse events in small-cell lung cancer patients after radiotherapy and immunotherapy treatment: a systematic review and meta-analysis.

Immunotherapy is important in treating small-cell lung cancer (SCLC), and its anti-tumor effects are better when combined with radiotherapy. However, the toxicity of this combination is little known. This study assessed the incidences of adverse events when adding radiotherapy to ICIs in patients with SCLC. We searched the online databases to identify eligible studies and included nine references. For extensive-stage SCLC patients, the median PFS ranged from 4.5 to 12.5 months, and median OS ranged from 8.4 to NR months, respectively. The incidences of grade 3 or higher pneumonitis, lung infection, diarrhea, and fatal adverse events were 8.7% (95% CI: 5%-14.7%), 6.7% (95% CI: 2.5%-16.5%), 12.6% (95% CI: 7.6%-20%), and 5.1% (95% CI: 2.1%-11.6%), respectively. Our findings suggest that radiotherapy plus ICIs may provide acceptable safety and favorable efficacy for SCLC patients.

Tracing the development of single memory-lineage B cells in a highly defined immune response.

To study the development of B lymphocyte memory, we identified and isolated splenic B cells expressing a highly defined antibody variable region that constitutes a reproducible and predominant component of the memory antibody response to p-azophenylarsonate (Ars). Isolation was achieved during the primary immune response by surface staining and flow cytometry using a specific anti-idiotypic antibody called E4, which recognizes this canonical V region, encoded by one set of V gene segments. The isolated E4+ cells displayed all of the phenotypic characteristics of germinal center centrocytes, including a low level of surface Ig, a lack of surface IgD, a high level of receptor for peanut agglutinin, and expression of mutated antibody V genes. E4+ B cells were first detected in the spleen 7-8 d after primary immunization, reached peak numbers from days 10-13, and waned by day 16. Surprisingly, at their peak, E4+ cells comprised only 40,000 of all splenocytes, and half of these failed to bind Ars. Using this number, we estimate the total number of Ars-specific memory-lineage cells in the spleen to be no more than 50,000 (0.1%) at any one time, and presumably far fewer that are committed to the memory pool. Chromosomal copies of rearranged V genes from single E4+ cells were amplified by nested PCR, and the amplified products were sequenced directly without cloning, using standardized conditions that disclose virtually no Taq polymerase errors. V gene sequence analyses of E4+ cells isolated from single mice confirmed their canonical nature and revealed that they were derived from few precursors. In the average mouse, the E4+ pool was derived from fewer than five canonical precursors. Somatic mutations were found within the V genes of almost all cell isolates. At day 13, a significant fraction of E4+ cells had mutations known to increase antibody affinity for Ars, suggesting they were products of at least one cycle of post-mutational antigen-driven selection. However, the lack of shared mutations by clonally related cells indicated that the selective expansion of mutant subclones typical of memory responses had not yet taken place. This was supported by the observation that half of the E4+ cells failed to bind Ars. Collectively, our results indicate that the memory compartment is a highly selected entity, even at relatively early stages of the primary immune response when somatic mutation and clonal selection are still in progress. If germinal centers are the source of memory B cells, our data suggest that B cell memory may be derived from only a small fraction of all germinal centers.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

BACKGROUND: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. METHODS: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. RESULTS: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children.

BACKGROUND: The Childhood Asthma Control Test (C-ACT) has been proposed as a tool in assessing the level of disease control in asthmatic children. To evaluate the position of C-ACT in the clinical management of asthmatic children, in relationship to the level of airway inflammation as assessed by fractional exhaled nitric oxide (FeNO) and with lung function. METHODS: A total of 200 asthmatic children were included in the study: 47 children with newly diagnosed asthma ('New') and without any regular controller therapy; and 153 children with previously diagnosed asthma, treated according to GINA guidelines, and evaluated during a scheduled follow-up visit ('Follow-up'). Childhood Asthma Control Test, FeNO and lung function [forced expiratory volume 1 (FEV1) and forced vital capacity (FVC)] were evaluated. RESULTS: In New vs Follow-up participants, C-ACT score (P < 0.001), FVC (P < 0.005) and FEV1 (P < 0.05) were significantly lower, and FeNO (P = 0.011) were significantly higher. In New, but not in Follow-up participants, significant correlations were observed between C-ACT score and FeNO (r = -0.51; P < 0.001), FEV1 (r = 0.34; P = 0.022) and FEV1/FVC (r = 0.32; P = 0.03). This lack of correlation in Follow-up visits seemed attributable to dissociation between inadequately controlled asthma by C-ACT ratings with normalization of other measures such as FeNO levels. CONCLUSIONS: This study confirms and expands the concept that C-ACT is complementary to, but not a substitute for, other markers of disease control in asthmatic children, especially in the context of follow-up visits.