Blood transcriptomics reveal systemic eosinophilic and neutrophilic inflammation patterns in patients with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic sinonasal disease characterized by heterogeneous inflammation. However, the presence of systemic inflammation heterogeneity in CRSwNP patients remains unknown. This study aims to profile transcriptomic alterations in the blood of CRSwNP patients and characterize the CRSwNP heterogeneity based on blood transcriptomic biomarkers. METHODOLOGY: Patients with CRSwNP were prospectively recruited from three hospitals and chronologically divided into exploratory (n=123) and independent validation (n=46) cohorts. Transcriptomic profiles were generated by whole blood mRNA sequencing and subjected to patient clustering, differential expression, and pathway analysis. Differences in immune pattern and clinicopathologic features between clusters were assessed. A transcriptomic signature was defined and applied to an independent cohort to validate the findings. RESULTS: CRSwNP patients showed diverse blood transcriptomic profiles versus healthy controls, or when stratified by tissue and blood eosinophils and asthma comorbidity. Transcriptome-wide correlation analysis revealed a transcriptional signature associated with blood eosinophil levels, consisting of nine T2-related genes (CLC, SIGLEC8, ALOX15, IL5RA, PTGDR2, CCL23, CCR3, EPX and IL1RL1). Three distinct clusters with differing systemic eosinophilic and neutrophilic inflammation patterns and asthma comorbidity were identified based on transcriptomic profiling of T2 and T1/3-related blood biomarkers. A 36-gene signature was developed by machine learning and accurately predicted the three CRSwNP subtypes. Validation on an independent cohort confirmed the prediction robustness. CONCLUSIONS: There is heterogeneous systemic inflammation associated with eosinophilic and neutrophilic patterns in patients with CRSwNP. Endotyping based on blood transcriptomic biomarkers might lead to more personalized treatment strategies for CRSwNP in the future.

Fumarate Restrains Alveolar Bone Restoration via Regulating H3K9 Methylation.

Nonresolving inflammation causes irreversible damage to periodontal ligament stem cells (PDLSCs) and impedes alveolar bone restoration. The impaired tissue regeneration ability of stem cells is associated with abnormal mitochondrial metabolism. However, the impact of specific metabolic alterations on the differentiation process of PDLSCs remains to be understood. In this study, we found that inflammation altered the metabolic flux of the tricarboxylic acid cycle and induced the accumulation of fumarate through metabolic testing and metabolic flux analysis. Transcriptome sequencing revealed the potential of fumarate in modulating epigenetics. Specifically, histone methylation typically suppresses the expression of genes related to osteogenesis. Fumarate was found to impede the osteogenic differentiation of PDLSCs that exhibited high levels of H3K9me3. Various techniques, including assay for transposase-accessible chromatin with high-throughput sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing, were used to identify the target genes regulated by H3K9me3. Mechanistically, accumulated fumarate inhibited lysine-specific demethylase 4B (KDM4B) activity and increased H3K9 methylation, thus silencing asporin gene transcription. Preventing fumarate from binding to the histone demethylase KDM4B with α-ketoglutarate effectively restored the impaired osteogenic capacity of PDLSCs and improved alveolar bone recovery. Collectively, our research has revealed the significant impact of accumulated fumarate on the regulation of osteogenesis in stem cells, suggesting that inhibiting fumarate production could be a viable therapeutic approach for treating periodontal diseases.

[Clinical characteristics, treatment strategy, and clinical outcomes in type 2 intestinal failure].

Objective: To evaluate the characteristics, clinical management and clinical outcomes of type 2 intestinal failure (IF). Methods: A descriptive case-control study was carried out. The inclusion criteria were as follows: (1) the diagnosis of IF was performed according to the European Society for Parenteral and Enteral Nutrition (ESPEN) consensus statement. (2) using a requirement for parenteral nutrition (PN) of 28 days or more as surrogate marker. (3) a multidisciplinary team (MDT) included surgeons, nutritionist, pharmacist, stoma therapists, and critical care physicians. (4) complete laboratory data. Patients with type 1 and type 3 IF and those who do not cooperate with follow-up. All the data of 67 type II IF were collected from the database in Sir Run Run Shaw Hospital from Jan 2016 to Dec 2023. The pathophysiology, clinical management, and outcomes of type II IF were analyzed. Results: A total of 67 type II IF were included. The median age was 54 (15-83) with 43 males and 24 females. The body mass index was (17.5±3.8) kg/m2, the incidence of malnutrition was 67.2% (45/67), the incidence of sarcopenia was 74.6% (50/67), the median number of previous surgeries was 2.0 (1-13), and the median duration time of PN was 2.1 (1-12) months. The underlying disease of type 2 IF included 36 Crohn`s disease, 2 ulcerative colitis, 3 radiation enteritis, 2 intestinal Behcet's disease, 4 mesenteric infarction, 1 aggressive fibromatosis, 5 abdominal cocoon syndrome, 5 gastrointestinal perforation, 1 hernia, 4 intestinal dysmotility, and 4 other reasons (gastrointestinal tumor, trauma, and non-Hodgkin's lymphoma). According to the pathophysiology of IF, there were 33 intestinal fistula, 12 intestinal dysmotility, 6 mechanical obstruction, 13 short bowel syndrome, and 3 extensive small bowel mucosal disease. After treatment with MDT, 67 patients with type 2 IF received nutritional support therapy for intestinal rehabilitation treatment, of which 36 patients recovered with oral diet or enteral nutrition, 31 patients underwent reconstructive surgery after intestinal rehabilitation treatment failure. The median duration time of reconstructive surgery was 2.7 (1-9) months. 24 patients recovered intestinal autonomy after surgery, with 7 deaths, including 6 deaths due to abdominal infections and 1 case of intestinal dysmotility with abiotrophy and liver failure. Conclusion: Standardized multidisciplinary treatment plays an important role in type II intestinal failure, and it promotes patients with intestinal failure regain enteral autonomy.

m6Am Methyltransferase PCIF1 Regulates Periodontal Inflammation.

N6,2'-O-dimethyladenosine (m6Am), a common mRNA modification in eukaryotic capped mRNAs, plays a pivotal role in cellular functions and disease progression. However, its involvement in host inflammation remains elusive. Here, we demonstrate that loss of m6Am methyltransferase phosphorylated CTD interacting factor 1 (PCIF1) attenuates periodontal inflammation in whole-body and myeloid lineage-specific knockout mouse models. Pcif1 deletion inhibits macrophage phagocytosis and migration through m6Am-Csf1r signaling. In addition, colony-stimulating factor-1 receptor (CSF1R) is identified as a potential target for the treatment of periodontitis. We thus reveal a previously unrecognized role for PCIF1-mediated m6Am modification in governing macrophage responses and periodontal inflammation.

[A multicenter study on effect of delayed chemotherapy on prognosis of Burkitt lymphoma in children].

Objective: To analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma (BL) and their influence on prognosis. Methods: Retrospective cohort study. Clinical data of 591 children aged ≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma (CNCL) was collected. The patients were treated according to the protocol CNCL-BL-2017. According to the clinical characteristics, therapeutic regimen was divided into group A, group B and group C .Based on whether the total chemotherapy time was delayed, patients were divided into two groups: the delayed chemotherapy group and the non-delayed chemotherapy group. Based on the total delayed time of chemotherapy, patients in group C were divided into non-delayed chemotherapy group, 1-7 days delayed group and more than 7 days delayed group. Relationships between delayed chemotherapy and gender, age, tumor lysis syndrome before chemotherapy, bone marrow involvement, disease group (B/C group), serum lactate dehydrogenase (LDH) > 4 times than normal, grade Ⅲ-Ⅳ myelosuppression after chemotherapy, minimal residual disease in the interim assessment, and severe infection (including severe pneumonia, sepsis, meningitis, chickenpox, etc.) were analyzed. Logistic analysis was used to identify the relevant factors. Kaplan-Meier method was used to analyze the patients' survival information. Log-Rank was used for comparison between groups. Results: Among 591 patients, 504 were males and 87 were females, the follow-up time was 34.8 (18.6,50.1) months. The 3-year overall survival (OS) rate was (92.5±1.1)%,and the 3-year event-free survival (EFS) rate was (90.5±1.2)%. Seventy-three (12.4%) patients were in delayed chemotherapy group and 518 (87.6%) patients were in non-delayed chemotherapy group. The reasons for chemotherapy delay included 72 cases (98.6%) of severe infection, 65 cases (89.0%) of bone marrow suppression, 35 cases (47.9%) of organ dysfunction, 22 cases (30.1%) of tumor lysis syndrome,etc. There were 7 cases of chemotherapy delay in group B, which were seen in COPADM (vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases) and CYM (methotrexate+cytarabine+intrathecal injection,3 cases) stages. There were 66 cases of chemotherapy delay in group C, which were common in COPADM (28 cases) and CYVE 1 (low dose cytarabine+high dose cytarabine+etoposide+methotrexate, 12 cases) stages. Multinomial Logistic regression analysis showed that the age over 10 years old (OR=0.54,95%CI 0.30-0.93), tumor lysis syndrome before chemotherapy (OR=0.48,95%CI 0.27-0.84) and grade Ⅲ-Ⅳ myelosuppression after chemotherapy (OR=0.55,95%CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group ((79.4±4.9)% vs. (94.2±1.1)%, (80.2±4.8)% vs. (92.0±1.2)%,both P<0.05). The 3-year OS rate of the group C with chemotherapy delay >7 days (42 cases) was lower than that of the group with chemotherapy delay of 1-7 days (22 cases) and the non-delay group (399 cases) ((76.7±6.9)% vs. (81.8±8.2)% vs. (92.7±1.3)%, P=0.002).The 3-year OS rate of the chemotherapy delay group (9 cases) in the COP (vincristine+cyclophosphamide+prednisone) phase was lower than that of the non-chemotherapy delay group (454 cases) ((66.7±15.7)% vs. (91.3±1.4)%, P=0.005). Similarly, the 3-year OS rate of the chemotherapy delay group (11 cases) in the COPADM1 phase was lower than that of the non-chemotherapy delay group (452 cases) ((63.6±14.5)% vs. (91.5±1.3)%, P=0.001). Conclusions: The delayed chemotherapy was related to the age over 10 years old, tumor lysis syndrome before chemotherapy and grade Ⅲ-Ⅳ myelosuppression after chemotherapy in pediatric BL. There is a significant relationship between delayed chemotherapy and prognosis of BL in children.

[Applications of artificial intelligence for imaging-driven diagnosis and treatment of bone and soft tissue tumors].

Bone and soft tissue tumors occur in the musculoskeletal system, and malignant bone tumors of bone and soft tissue account for 0.2% of all human malignant tumors, and if not diagnosed and treated in a timely manner, patients may be at risk of a poor prognosis. Image interpretation plays an increasingly important role in the diagnosis of bone and soft tissue tumors. Artificial intelligence (AI) can be applied in clinical treatment to integrate large amounts of multidimensional data, derive models, predict outcomes, and improve treatment decisions. Among these methods, deep learning is a widely employed technique in AI that predominantly utilizes convolutional neural networks (CNN). The network is implemented through repeated training of datasets and iterative parameter adjustments. Deep learning-based AI models have successfully been applied to various aspects of bone and soft tissue tumors, encompassing but not limiting in image segmentation, tumor detection, classification, grading and staging, chemotherapy effect evaluation, recurrence and prognosis prediction. This paper provides a comprehensive review of the principles and current state of AI in the medical image diagnosis and treatment of bone and soft tissue tumors. Additionally, it explores the present challenges and future prospects in this field.

[The efficacy and safety of ibrutinib in the treatment of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia].

Objective: To explore the efficacy and safety of ibrutinib for the treatment of newly treated and relapsed refractory (R/R) lymphoplasmacytic lymphoma (LPL) /Waldenström macroglobulinemia (WM) . Methods: Retrospectively collected clinical data of 98 cases of newly treated and R/R LPL/WM patients who received ibrutinib treatment at the Hematology & Blood Diseases Hospital of the Chinese Academy of Medical Sciences from March 2016 to June 2023, and analyzed their efficacy and safety. Results: A total of 98 LPL/WM patients were included, which consisted of 45 newly treated patients and 53 R/R patients. Of these, 74 were males (75.5%) and the cohort had a median age of 64 (42-87) years. Eighty-eight patients were eligible for efficacy evaluation with a median treatment time of 20.8 (2.1-55.0) months, a major remission rate (MRR) of 78.4%, and an overall response rate (ORR) of 85.2%. The MRR and ORR of the newly treated patients were 78.4% and 86.5%, respectively, whereas the MRR and ORR of the R/R patients were 78.4% and 84.3%, respectively. There were no statistically significant differences in MRR and ORR between the initial treatment and R/R patients (all P values >0.05) . The median follow-up period was 29.1 (2.9-50.3) months and the median overall survival time for newly treated and R/R patients was not reached. The median progression-free survival time was 23.5 (95% CI 10.5-36.5) months and 45.0 (95% CI 34.0-56.0) months, respectively, with no statistically significant differences (all P values >0.05) . There were 25 deceased patients and no deaths were related to ibrutinib treatment. The main adverse reactions of ibrutinib were thrombocytopenia (5.1%) , pneumonia (8.1%) , and hyperuricemia (21.4%) . The incidence of atrial fibrillation was 2.0%. Conclusion: Ibrutinib exhibits good efficacy and safety for newly treated and R/R LPL/WM patients.

[Prevalence and intervention effect of arteriovenous graft stenosis].

Objective: To evaluate the prevalence, intervention methods and effect of arteriovenous graft (AVG) stenosis. Methods: The clinical data of patients who received AVG in the Blood Purification Center, the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022 were retrospectively analyzed. The patency rate, prevalence and intervention effect of AVG stenosis were analyzed. Results: A total of 475 patients aged (55.5±11.8) years were included, and there were 193 male cases (40.6%) and 282 female cases (59.4%). The patients were followed up for [M (Q1, Q3)] 19 (12, 30) months, and the primary, assisted primary and secondary patency were 14 (5, 27), 27 (13, 55), and 59 (33, 65) months, respectively. There were 799 access events which needed intervention, with a total standardized intervention rate of 0.90 per patient-year. Totally, 431(53.9%, 431/799) stenosis events occurred in 207 AVG. Among 422 AVG stenosis events with complete clinical data, 57.8% (244/422) were multi-site stenosis and 42.2% (178/422) were single-site stenosis. The most common sites of stenosis were graft-vein anastomosis (47.6%, 340/715), venous outflows (22.7%, 162/715), and puncture zone (20.0%, 143/715). In the 414 stenosis with intact follow-up data, 90.8% (376/414) were treated by balloon angioplasty, 8.5% (35/414) received covered stent insertion, and 0.7% (3/414) were intervened by open surgery. Clinical success rate was 98.1% (406/414). The primary patency time after endovascular treatment was 6 (4, 12) months. Covered stent significantly increased post-intervention primary patency time compared withballoon angioplasty [6 (3, 7) months vs 3 (1, 4) months, P=0.020]. Conclusions: Stenosis is the most common complication of AVG, and the most common sites are graft-vein anastomosis, venous outflows, and puncture zone. Intervention of AVG stenosis has a high clinical success rate, and a relatively low post-intervention patency. Covered stent insertion improves the post-intervention patency of AVG, which has a poor effect using balloon expansion.

[Application of the blastomere count variations "skip value" in the embryo AI assessment].

Objective: To explore the correlation between blastomere count variations "skip value" which extracted from by time-lapse technology (TLT) combined with artificial intelligence (AI) and morphological features of in vitro fertilization (IVF) embryo, and to test its feasibility in clinical applications. Methods: This study was a diagnostic experiment (AI reassessment of embryo transferred patients), a total of 6 545 embryos from 1 226 patients who underwent IVF at the Women and Children's Hospital of Chongqing Medical University from December 2020 to December 2021 were retrospectively analyzed, of which 2 869 embryos were attempted to cultured to blastocyst stage by TLT. The embryo dynamic map (EDM) was drawn by Embryo Viewer, a TLT recording software, based on embryo developmental kinetics. The self-developed AI embryo evaluation software identified and recorded the number of cleavages in real time during embryonic development, and compared with the EDM, the correlation between the skip value formed by the change of cleavage sphere counts and the outcomes of the embryos was analyzed. The correlation among skip value, morphological score of embryo, implantation rate and live birth rate were performed by Spearman and step-up logistic regression. The receiver operating characteristic (ROC) curve was selected for reporting there relationship of skip value and morphology. Finally, predicting power of skip value for implantation and live birth rate were performed by ROC analysis. Results: The total skip values extracted from the blastomere count of embryos (72 hours post-fertilization) were negatively correlated with abnormal cleavage, blastocyst formation rate, day 3 (D3)-cell score, uneven size and fragmentation (the ß values were -0.268, -0.116, -0.213, -0.159 and -0.222, respectively; all P<0.001); positively correlated with D3-cell number (ß=0.034; P<0.001); negatively correlated with blastocyst formation rate and implantation rate (OR=0.97, 95%CI: 0.93-0.99, P=0.034; OR=0.96, 95%CI: 0.93-0.98, P=0.044). The power of predicting implantation were similar between the order selection of skip values and traditional morphology criteria [area under curve (AUC): 0.679 vs 0.620]. Live birth rate were negatively correlated with female age (OR=0.91, 95%CI: 0.88-0.93; P<0.001), D3 general score (OR=0.77, 95%CI: 0.59-0.99; P=0.045) and order selection of skip values (OR=0.98, 95%CI: 0.96-0.99; P=0.038), while positively correlated with retrieved oocyte number and endometrial thickness in embryo transferred (OR=1.08, 95%CI:1.05-1.11, P<0.001; OR=1.09, 95%CI:1.06-0.12, P<0.001, respectively) from multivariate regression analysis, and the power of predicting live birth was 0.666 for AUC. Conclusions: The skip value and its order form is a systematic quantification of embryo development, correlated with embryo developmental quality and clinical outcome. It could be an addition parameter for embryo culture and selection.

The gene CmPYL6 strongly contributes to cold tolerance in oriental melon.

The current simple and crude facilities make melon production more susceptible to cold stress during off-season cultivation in China. The ABA signalling pathway is an important target for breeding cold-tolerant melon. Cold-tolerant No. 330 and cold-sensitive No. 410 oriental melon genotypes were used to analyse the relationship between ABA and cold tolerance. 12 CmPYLs, ABA receptors, were identified from the melon genome database according to sequence alignment and phylogenetic analysis. Gene function of CmPYL6 in cold tolerance was analysed using VIGS in No. 330 and overexpression in Arabidopsis WT. A total of 12 CmPYL members contain the representative domain and conserved sites. Under cold treatment, No.330 seedlings had lower electrolyte leakage and MDA content, higher ABA content and CmPYL6 expression than seedlings of No. 410. Exogenous application of ABA upregulated expression of CmPYL6 and enhanced cold tolerance of both genotypes, while inhibiting ABA accumulation reduced expression of CmPYL6 and cold tolerance of both genotypes. CmPYL6-silenced No. 330 seedlings had reduced cold tolerance, increased electrolyte leakage and MDA content as well as limited proline and soluble sugar content, while CmPYL6 overexpressed transgenic Arabidopsis plants had enhanced cold tolerance, with limited electrolyte leakage and MDA content, as well as increased proline and soluble sugar content. The CmPYL6 gene is probably an important ABA receptor in regulating cold tolerance of oriental melon. Our study provides a direction for improving breeding of cold tolerance of oriental melon.

[Mechanisms by which Mettl3 regulates pericyte-myofibroblast transdifferentiation through PI3K/AKT signaling pathway].

Objective: To investigate the role and underlying mechanisms of methyltransferase (Mettl) 3 in the process of angiotensin Ⅱ (Ang Ⅱ)-induced pericyte-to-myofibroblast transdifferentiation and renal fibrosis. Methods: C57BL/6J mice were used, in cell experiments, mouse renal pericytes were isolated and cultured using magnetic bead sorting. These pericytes were then induced to transdifferentiate into myofibroblasts with 1×106 mmol/L Ang Ⅱ, which was the Ang Ⅱ group, while pericytes cultured in normal conditions served as the control group. Successful transdifferentiation was verified by immunofluorescence staining, Western blotting, and real-time reverse transcription PCR (RT-qPCR) for α-smooth muscle actin (α-SMA). The levels of m6A modifications and related enzymes (Mettl3, Mettl14), Wilms tumor 1-associated protein (WTAP), fat mass and obesity protein (FTO), ALKBH5, YTHDF1, YTHDF2, YTHDC1, YTHDC2, YTHDC3 were assessed by Dot blot, RT-qPCR and Western blot. Mettl3 expression was inhibited in cells using lentivirus-mediated Mettl3-shRNA transfection, creating sh-Mettl3 and Ang Ⅱ+sh-Mettl3 groups, while lentivirus empty vector transfection served as the negative control (Ang Ⅱ+sh-NC group). The impact of Ang Ⅱ on pericyte transdifferentiation was observed, and the expression of downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway proteins, including PI3K, AKT, phosphorylated AKT at serine 473 (p-AKT (S473)), and phosphorylated AKT at threonine 308 (p-AKT (T308)), were examined. PI3K gene transcription was inhibited by co-culturing cells with actinomycin D, and the half-life of PI3K mRNA was calculated by measuring residual PI3K mRNA expression over different co-culture time. The reversibility of Mettl3 inhibition on Ang Ⅱ-induced pericyte-to-myofibroblast transdifferentiation was assessed by adding the AKT activator SC79 to the Ang Ⅱ+sh-Mettl3 group. In animal experiments, mice were divided into these groups: sham group (administered 0.9% sterile saline), Ang Ⅱ group (infused with Ang Ⅱ solution), sh-Mettl3 group (injected with Mettl3 shRNA lentivirus solution), Ang Ⅱ+sh-Mettl3 group (infused with Ang Ⅱ solution and injected with Mettl3 shRNA lentivirus solution), and Ang Ⅱ+sh-Mettl3+SC79 group (administered Ang Ⅱ solution and Mettl3 shRNA lentivirus, with an additional injection of SC79). Each group consisted of six subject mice. Blood pressure was measured using the tail-cuff method before and after surgery, and serum creatinine, urea, and urinary albumin levels were determined 4 weeks post-surgery. Kidney tissues were collected at 28 days and stained using hematoxylin-eosin (HE) and Masson's trichrome to assess the extent of renal fibrosis. Results: Primary renal pericytes were successfully obtained by magnetic bead sorting, and intervened with 1×106 mmol/L Ang Ⅱ for 48 hours to induce pericyte-to-myofibroblast transdifferentiation. Dot blot results indicated higher m6A modification levels in the Ang Ⅱ group compared to the control group (P<0.05). RT-qPCR and Western blot results showed upregulation of Mettl3 mRNA and protein levels in the Ang Ⅱ group compared to the control group (both P<0.05). In the Ang Ⅱ+sh-Mettl3 group, Mettl3 protein expression was lower than that in the Ang Ⅱ group, with reduced expression levels of α-SMA, vimentin, desmin, fibroblast agonist protein (FAPa) and type Ⅰ collagen (all P<0.05). Compared to the control group, PI3K mRNA expression level was elevated in the Ang Ⅱ group, along with increased p-AKT (S473) and p-AKT (T308) expressions. In the Ang Ⅱ+sh-Mettl3 group, PI3K mRNA expression and p-AKT (S473) and p-AKT (T308) levels were decreased (all P<0.05). The half-life of PI3K mRNA was shorter in the Ang Ⅱ+sh-Mettl3 group than that in the Ang Ⅱ+sh-NC group (2.34 h vs. 3.42 h). The ameliorative effect of Mettl3 inhibition on Ang Ⅱ-induced pericyte-to-myofibroblast transdifferentiation was reversible by SC79. Animal experiments showed higher blood pressure, serum creatinine, urea, and 24-hour urinary protein levels, and a larger fibrosis area in the Ang Ⅱ group compared to the sham group (all P<0.05). The fibrosis area was smaller in the Ang Ⅱ+sh-Mettl3 group than that in the Ang Ⅱ group (P<0.05), but increased again upon addition of SC79. Conclusion: Mettl3-mediated RNA m6A epigenetic regulation is involved in Ang Ⅱ-induced pericyte-to-myofibroblast transdifferentiation and renal fibrosis, potentially by affecting PI3K stability and regulating the PI3K/AKT signaling pathway.

[Analysis of the relationship between solar greenhouse operation and occupational high incidence diseases].

Objective: To understand the health status of solar greenhouse workers, to provide scientific basis for the development of occupational high incidence diseases prevention and control strategies. Methods: In July 2019, a random cluster sampling method was used to select 245 workers engaged in solar greenhouse vegetable cultivation in Daba Village, Jingyuan County, Baiyin City, Gansu Province as the solar greenhouse operation group. Matched by gender, age, marital status, body mass index (BMI), 282 people from adjacent Shaliang Village who did not engage in solar greenhouse operation were selected as the control group. Field investigation and health examination were carried out among the study subjects. The general situation, facial features examination results, ophthalmic examination results, bone and joint examination results and skin examination results were compared between the two groups. And the multiple logistic regression analysis was used to analyze the influencing factors of abnormal bone and joint examination (upper limbs, lower limbs, hands and spine bone joints) in study subjects. Results: There were statistically significant differences in smoking age and alcohol consumption between the two groups (P<0.001). Compared with the control group, the abnormal detection rates of nose examination, throat examination, slit lamp examination, conjunctival examination, lower limb bone joint examination, hand bone joint examination, spine examination, head and neck skin examination, trunk skin examination, upper limb skin examination, and lower limb skin examination in the solar greenhouse operation group were higher, and the differences were statistically significant (χ(2)=11.53, 7.94, 9.92, 27.93, 79.32, 81.42, 9.43, 6.79, 9.76, 4.34, 8.29, P<0.05). Multivariate logistic regression analysis showed that after adjusting for gender, age, marital status, education level, BMI, compared with the control group, solar greenhouse operation was a risk factor for abnormal bone and joint examination (OR=1.178, 95%CI: 1.151-2.143, P=0.001) . Conclusion: Solar greenhouse operation has a certain harmful effect on health of workers, and solar greenhouse workers have an increased risk of abnormal diseases of upper limbs, lower limbs, hands and spine bone joints.

[Interim efficacy of a multicenter cohort study for China Net Childhood Lymphoma mature B-cell lymphoma 2017 regimen in the treatment of pediatric High-grade-B cell lymphoma].

Objective: To analyze the mid-term efficacy of the China Net Childhood Lymphoma mature B-cell lymphoma 2017 (CNCL-B-NHL-2017) regimen in treating children with high-grade B-cell lymphoma (HGBL). Methods: Clinical and pathological data of HGBL children aged≤18 years admitted to 16 hospitals of the Chinese Children's Lymphoma Collaborative Group (CNCL) from May 2017 to April 2021 were collected retrospectively. They were divided in to high-grade B-cell lymphoma with double hit/triple hit (HGBL-DH/TH) group and high-grade B-cell lymphoma non-specified (HGBL-NOS) group, according to the 2016 version of the World Health Organization (WHO) Hematopoietic and Lymphoid Tissues Cancer Classification. Both groups of patients were treated with stratified chemotherapy by risk according to the CNCL-B-NHL-2017 scheme. The deadline for follow-up was December 31, 2023. All the patients were examined by chromosome fluorescence in situ hybridization (FISH), and the rearrangement of genes MYC, BCL-2 and BCL-6 was confirmed. The clinical and pathological characteristics of patients at disease onset were analyzed, and the therapeutic effects of patients in different clinical stages and risk groups were compared. Survival analysis was drawn by Kaplan Meier method, the log-rank test was used to compare the differences in the cumulative survival rate between different groups, and multivariate Cox regression model was used to identify the prognostic factors. Results: A total of 62 patients were included, with an onset age [M(Q1, Q3)] of 7 (4, 11) years, including 48 males and 14 females. There were 11 (17.7%) patients in stageⅡ, 33(53.2%)patients in stage Ⅲ and 18(29.1%)patients in stage Ⅳ. FISH testing showed that 4 cases (6.5%) were HGBL-DH and 3 (4.8%) were HGBL-TH. The remaining 55 cases (88.7%) were HGBL-NOS, with 18 cases accompanied by MYC rearrangement. There were 7 cases in the HGBL-DH/TH group and 55 cases in the HGBL-NOS group. Thirteen cases (20.9%) were treated with the B1 regimen, 3 cases (4.8%) with B2 regimen, 37 cases (59.6%) with C1 regimen, and 9 cases (14.7%) with the C2 regimen. Forty-eight cases (77.4%) received rituximab therapy at the same time. Five cases (8.0%) progressed during treatment. The follow-up time [M(Q1, Q3)] was 43.5 (36.1, 53.7) months. The complete remission rate was 91.9% (57/62). The 3 year overall survival rate was 93.5% and event-free survival (EFS) rate was 91.9%. The 3-year overall survival rate in the HGBL-NOS group was higher than that in the HGBL-DH/TH group (96.3% vs 71.4%, P=0.011). The 3-year EFS rate of the HGBL-NOS group was higher than that of the HGBL-DH/TH group (94.5% vs 71.4%, P=0.037). In the HGBL-NOS subgroup, the overall survival rate of children with MYC rearrangement was lower (100% vs 88.9%,P=0.039). Multivariate Cox regression analysis showed that central invasion (HR=6.05, 95%CI: 1.96-38.13, P=0.046) was a risk factor for overall survival. Conclusion: CNCL-B-NHL-2017 regimen shows significant effects in the treatment of pediatric HGBL, with a good prognosis.

Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta.

Osteogenesis imperfecta (OI)is a rare genetically heterogeneous disorder caused by changes in the expression or processing of type I collagen. Clinical manifestations include bone fragility, decreased linear growth, and skeletal deformities that vary in severity. In typically growing children, skeletal maturation proceeds in a predictable pattern of changes in the size, shape, and mineralization on the hand and wrist bones that can be followed radiographically known at the bone age. Assessment of bone age can be clinically used to assess time remaining for linear growth, and the onset and duration of puberty, both of which can be useful in determining the timing of some surgeries or the interpretation of other imaging modalities such as bone densitometry. Additionally, deviations in the expected maturation process of the bone age may prompt or assist in the work up of a significant delay or advancement in a child's growth pattern. The primary aim of our study was to determine whether the bone age in children with a skeletal disorder such as OI follow the same pattern and rate of bone maturation compared to a control population. Using participants from the Natural History Study of the Brittle Bone Disorders Consortium, we analyzed 159 left hand and wrist radiographs (bone age) for a cross-sectional analysis and 55 bone ages repeated at approximately 24 months for a longitudinal analysis of skeletal maturation. Bone ages were read by a pediatric endocrinologist and by an automated analysis using a program called BoneXpert. Our results demonstrated that in children with mild-to-moderate OI (types I and IV), the skeletal maturation is comparable to chronological age-mated controls. For those with more severe forms of OI (type III), there is a delayed pattern of skeletal maturation of less than a year (10.5 months CI 5.1-16) P = 0.0012) at baseline and a delayed rate of maturation over the two-year follow up compared to type I (P = 0.06) and type III (P = 0.02). However, despite these parameters being statistically different, they may not be clinically significant. We conclude the bone age, with careful interpretation, can be used in the OI population in a way that is similar to the general pediatric population.

[Genotype and phenotype of WWOX gene related developmental and epileptic encephalopathy].

Objective: To summarize the genotype and clinical phenotype of children with WWOX gene related developmental and epileptic encephalopathy (DEE). Methods: Case series studies. The clinical data of 12 children with WWOX gene related DEE who were admitted to the Neurological Department of Children's Medical Center, Peking University First Hospital from June 2019 to December 2023 were analyzed. The children's characteristics of gene variation, clinical phenotype, auxiliary examination results, treatment and prognosis were analyzed. Results: Among 12 children with WWOX gene related DEE, there were 7 boys and 5 girls, the age of seizure onset ranged from 10 days to 6 months (median 1.8 months). Multiple seizure types were observed, including focal seizures in 10 cases, epileptic spasms in 9 cases, tonic seizures in 4 cases, myoclonic seizures in 1 case. Among 12 cases, 9 cases had multiple seizure types. All 12 cases showed microcephaly and global developmental delay. Video electroencephalography showed slowed background activity in 6 cases, hyperarrhythmia in 6 cases, multifocal discharges in 6 cases, and focal discharges in 1 case. Epileptic spasms were detected in 8 cases, tonic seizures in 4 cases and myoclonic seizures in 1 case. Brain magnetic resonance imaging showed bilateral frontotemporal subarachnoid space widening in 5 cases, deep sulci in 3 cases, bilateral ventricular enlargement in 2 cases, callosal hypoplasia in 5 cases, and delayed white matter myelination in 3 cases. The phenotypes of 12 cases were consistent with the diagnosis of DEE, and 8 of them were diagnosed with infantile epileptic spasm syndrome. All the WWOX gene variants in 12 cases were complex heterozygous variants, including 20 variants, 11 variants and 1 large intragenic WWOX gene deletion (p.Ala149Thr, p.Arg156Ser, p.R167Tfs*8, p.Leu186Val, c.605+5G>A, p.Trp218*, p.His263Arg, p.Leu275fs*19*1, p.N285Kfs*10, p.Ser304Tyr, p.Met326Arg, loss1 exon2-8) had not been reported previously. The age of last follow-up ranged from 11 months to 5 years and 3 months. During the follow-up, 1 case died at the age of 1 year and 10 months, 2 cases were seizure-free, and 9 cases still had seizures after multiple anti-seizure medications. Conclusions: The seizure onset age of children with WWOX gene related DEE is usually less than 6 months, and some of them in neonate. The common seizure types include focal seizures and epileptic spasms. Children usually have microcephaly and global developmental delay. WWOX gene related DEE usually has drug refractory epilepsy.

[Epidemic characteristics of mycoplasma pneumoniae infection and drug-resistant gene mutations in hospitalized children aged 0-17 in Ningbo City from 2019 to 2023].

To analyze the infection and drug-resistant gene 23S rRNA mutations of mycoplasma pneumoniae (Mp) in hospitalized children aged 0-17 in Ningbo City from 2019 to 2023. Throat swabs were collected from hospitalized children with respiratory tract infections in Ningbo University Affiliated Women and Children's Hospital from 2019 to 2023. They were subjected to real-time fluorescence quantitative polymerase chain reaction detection to analyze Mp infection and drug-resistant gene (23S rRNA) mutations. Intergroup comparisons were made by the Chi-square test or Fisher's exact probability method. A total of 18 968 hospitalized children were included, with a total positive rate of 30.37% (5 760/18 968). The total positive rate of drug-resistant gene mutations was 82.45% (4 749/5 760). The positive rate of Mp in male children was 29.26%, which was lower than that in female children (31.67%, χ2=12.948, P<0.001). The positive rate of Mp drug-resistant gene mutations in male children was 82.52%, which was higher than that in female children(82.37%, χ2=0.021, P=0.885). The positive rates of Mp increased with age (χ2=1 722.21, P<0.001). The positive rates of Mp drug-resistant gene mutations also increased with age (χ2=13.152, P<0.001). In the four seasons, the total positive rate of Mp in summer and autumn was significantly higher than that in winter and spring (χ2=1 085.149, P<0.001). Among them, the Mp positive rates in the summer and autumn of 2019 were as high as 38.26% and 34.49%, while in the summer and autumn of 2020, the Mp positive rates were 2.55% and 1.65%, respectively, which were the lowest in previous years. In the summer and autumn of 2023, the Mp positive rates increased to 47.22% and 51.06%. There was no statistically significant difference in the detection rate of Mp drug-resistant gene mutations among the four seasons. In Conclusion, Mp infection was more prevalent in the summer and autumn in Ningbo city and females and children aged 7-17 were more susceptible. The epidemic of Mp infection in Ningbo occurred in the summer of 2019. After the COVID-19 pandemic in 2020, the positive rate of Mp rapidly decreased and later remained in a low incidence state. After the lifting of restrictive prevention and control measures in 2023, the Mp positive rate returned to an epidemic state. The positive rate of Mp drug-resistant gene (23S rRNA) mutations was relatively high.

[Effect of peri-implant soft-tissue phenotype on peri-implant health].

Dental implant is a commonly used therapeutic option for reconstruction of edentulous space. Adequate peri-implant soft tissue is crucial for preventing biological and esthetic complications. Peri-implant soft-tissue phenotypes including supracrestal tissue height, mucosa thickness and keratinized mucosa width could reflect the quality and quantity of peri-implant soft tissue. Different soft-tissue phenotypes might impact the stability of implant restoration through altering the tissue remodeling or inflammatory response. This review will discuss the influence of peri-implant soft-tissue phenotypes on tissue remodeling and inflammatory response after implant placement.