Generalized granuloma annulare in an infant clinically manifested as papules and atrophic macules: A case report.

BACKGROUND: Granuloma annulare (GA) has diverse clinical manifestations including papules, plaques, and nodules on the extremities that are skin-colored, pink, or purple. Approximately 15% of all GA cases are considered generalized GA. CASE SUMMARY: Herein, we describe the case of a pediatric patient who initially presented with papules and later developed generalized atrophic macules. Upon examination, two different morphologic lesions were histopathologically confirmed: Epithelioid nodular GA and scattered histiocytic infiltrative GA. This patient exhibited rare clinical manifestations that differed throughout the course of the disease. The varying histopathological types and clinical manifestations of GA may be linked to the different stages of the disease. CONCLUSION: This rare case demonstrates the different histopathological features of different stages and clinical manifestations of granuloma annulare in an infant.

Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming.

Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.

Development and validation of a nomogram to predict cancer-specific survival in nonsurgically treated elderly patients with prostate cancer.

Prostate Cancer (PC) is the most common male nonskin tumour in the world, and most diagnosed patients are over 65 years old. The main treatment for PC includes surgical treatment and nonsurgical treatment. Currently, for nonsurgically treated elderly patients, few studies have evaluated their prognostic factors. Our aim was to construct a nomogram that could predict cancer-specific survival (CSS) in nonsurgically treated elderly PC patients to assess their prognosis-related independent risk factors. Patient information was obtained from the Surveillance, Epidemiology and End Results (SEER) database, and our target population was nonsurgically treated PC patients who were over 65 years old. Independent risk factors were determined using both univariate and multivariate Cox regression models. A nomogram was built using a multivariate Cox regression model. The accuracy and discrimination of the prediction model were tested using the consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve. Decision curve analysis (DCA) was used to examine the potential clinical value of this model. A total of 87,831 elderly PC patients with nonsurgical treatment in 2010-2018 were included in the study and were randomly assigned to the training set (N = 61,595) and the validation set (N = 26,236). Univariate and multivariate Cox regression model analyses showed that age, race, marital status, TNM stage, chemotherapy, radiotherapy modality, PSA and GS were independent risk factors for predicting CSS in nonsurgically treated elderly PC patients. The C-index of the training set and the validation set was 0.894 (95% CI 0.888-0.900) and 0.897 (95% CI 0.887-0.907), respectively, indicating the good discrimination ability of the nomogram. The AUC and the calibration curves also show good accuracy and discriminability. We developed a new nomogram to predict CSS in elderly PC patients with nonsurgical treatment. The model is internally validated with good accuracy and reliability, as well as potential clinical value, and can be used for clinical aid in decision-making.

[Leukemia Genotype Analysis of Children with Acute Lymphoblastic Leukemia in Yunnan Area].

OBJECTIVE: To analyze 43 leukemia genes in children with acute lymphoblastic leukemia (ALL) in Yunnan province, and provide the basis for the diagnosis and treatment of children with ALL in this area. METHODS: The clinical data of 428 children with newly diagnosed ALL in Yunnan area from January 2015 to December 2020 were retrospectively analyzed. Multiple nested PCR technology was used to detect 43 common leukemia genes. RESULTS: Among the 428 children with ALL, 159 were positive for leukemia genes, with a positive rate of 37.15% (159/428), and a total of 15 leukemia genes were detected. Among the 159 leukemia gene-positive children, ETV6-RUNX1+ accounted for 25.79% (41/159), followed by E2A-PBX1+ and BCR-ABL+, accounting for 24.53% (39/159) and 23.27% (37/159) respectively. MLL+ accounted for 6.29% (10/159), WT1+ accounted for 4.40% (7/159), IKZF1 gene deletion and CRLF2+ accounted for 3.77% (6/159) respectively. The positive rate of MLL (46.15%) was the highest in ＜1-year old group, the positive rate of ETV6-RUNX1 (10.56%) was the highest in 1-10-year old group, and BCR-ABL+ rate (23.65%) was the highest in >10-year old group. The distribution of leukemia genes in different age groups was statistically significant (P <0.05). CONCLUSION: The most common fusion gene of children with ALL in Yunnan is ETV6-RUNX1, followed by E2A-PBX1 and BCR-ABL.

A novel anti-IL-33 antibody recognizes an epitope FVLHN of IL-33 and has a therapeutic effect on inflammatory diseases.

As a crucial member of the Interleukin-1 (IL-1) family, IL-33 plays an indispensable role in modulating inflammatory responses. Here, we developed an effective anti-human IL-33 monoclonal antibody (mAb) named 5H8. Importantly, we have identified an epitope (FVLHN) of IL-33 protein as a recognition sequence for 5H8, which plays an important role in mediating the biological activity of IL-33. We observed that 5H8 significantly suppressed IL-33-induced IL-6 expression in bone marrow cells and mast cells in a dose-dependent manner in vitro. Furthermore, 5H8 effectively relievedHDM-induced asthma and PR8-induced acute lung injury in vivo. These findings indicate that targeting the FVLHN epitope is critical for inhibiting IL-33 function. In addition, wedetected that the Tm value of 5H8 was 66.47℃ and the KD value was 173.0 pM, which reflected that 5H8 had good thermal stability and high affinity. Taken together, our data suggest that our newly developed 5H8 antibody has potential as a therapeutic antibody for treating inflammatory diseases.

Elastic fiber degradation in the development of pediatric granuloma annulare: Report of 39 cases.

BACKGROUND: Granuloma annulare (GA) has diverse clinical manifestations, multiple subtypes, and unknown etiology and pathogenesis. Existing studies regarding GA in children are scarce. AIM: To examine the correlation between clinical manifestation and histopathology of pediatric GA. METHODS: A total of 39 patients under 18 years of age with both a clinical and pathological diagnosis of GA at Kunming Children's Hospital from 2017 to 2022 were retrieved. Their medical records were consulted, and clinical data of the children were recorded and summarized, including gender, age, disease site, etc. Existing wax blocks of skin lesion specimens of children and pathological films were retrieved for further study and relevant histology, including hematoxylin-eosin, Alcian blue, elastic fiber (Victoria blue-Lichon red method), and antacid staining. Finally, the children's clinical manifestations, histopathological results, and special staining characteristics were analyzed. RESULTS: The clinical manifestations of granuloma annulare in children were diverse: 11 cases presented with a single lesion, 25 with multiple lesions, and 3 with generalized lesions. The pathological typing comprised histiocytic infiltration, palisading granuloma, epithelioid nodular, and mixed types in 4, 11, 9, and 15 cases, respectively. Thirty-nine cases were negative for antacid staining. The positive rate of Alcian blue staining was 92.3%, and that of elastic fiber staining was 100%. The degree of elastic fiber dissolution and granuloma annulare histopathological typing were positively correlated (r = 0.432, P < 0.05). No correlation was found between clinical presentation and histopathological typing of the granuloma annulare in children. In the pathological diagnosis of granuloma annulare, the positive elastic fiber staining rate was higher than that of Alcian blue staining. A correlation was found between elastic fiber dissolution degree and histopathological staging. However, the differences in pathological staging may have been related to the pathological manifestation of granuloma annulare at different periods. CONCLUSION: Elastic fiber degradation may be a critical step in the pathogenesis of pediatric granuloma annulare. This is also one of the first studies focused on granuloma annulare in children.

Clinical and whole exome sequencing findings in children from Yunnan Yi minority ethnic group with retinitis pigmentosa: two case reports.

BACKGROUND: Retinitis pigmentosa is a group of rare hereditary retinal dystrophy diseases that lead to difficulty seeing at night, progressive loss of peripheral field vision (tunnel vision), and eventual loss of central vision. However, a genetic cause cannot be determined in approximately 60% of cases. CASE PRESENTATION: Two non-consanguineous Yi minority ethnic group families who have a 6.4-year-old boy and a 0.5-year-old boy, respectively, were recruited for genetic diagnosis. Here, we used whole-exome sequencing to detect mutations in the genes of the probands of the retinitis pigmentosa families, and Sanger sequencing to confirm the causal mutations identified by whole exome sequencing. In addition, we report two cases with retinitis pigmentosa caused by RDH12 (c.524C > T) and PRPF4 (c.1273G > A) pathogenic mutations. CONCLUSIONS: These results might extend the mutation spectrum of known retinitis pigmentosa genes and give these two Yi minority ethnic group families from Yunnan more precise genetic counseling and more specific prognoses.

Characterization of Serotypes and Molecular Drug Resistance Patterns of Haemophilus influenzae in Kunming Children.

The present study aimed to determine the capsular serotype distribution and antimicrobial drug resistance patterns of Haemophilus influenzae from children in the Kunming region of China. This information could guide policymakers in clinical treatment. In the present study, H. influenzae isolates were tested for their serotypes, antimicrobial susceptibility pattern, and presence of ß-lactamases. One-hundred forty-eight H. influenzae strains isolated from children 0-2 years old were investigated for capsular types by glass slide agglutination and molecular methods, and biotyped by the biochemical reactions. The drug resistance-encoding genes TEM-1, ROB-1, and the ftsI gene mutations PBP3-3, and PBP3-BLN were detected with real-time quantitative polymerase chain reaction (qPCR). The prevalence of ß-lactamase-producing strains (60.3%) was significantly higher (p < 0.05) than non-enzyme-producing strains. ß-Lactamase-producing strains were multidrug resistant to various antibiotics such as ampicillin, tetracycline, sulfamethoxazole/trimethoprim, chloramphenicol, cefuroxime, and cefaclor. Among ß-lactamase-producing strains, the detection rates of the TEM-1, PBP3-BLN, PBP3-s, and ROB-1 were 54.1%, 18.9%, 11.8%, and 6.9%, respectively. The biotyping results show that most H. influenzae strains were of type II and III. Non-typeable H. influenzae (NTHi) accounted for 89.3% of the strains. NTHi strains were the most prevalent in this region; most belonged to biological types II and III. ß-Lactamase-positive ampi-cillin-resistant (BLPAR) strains were prevalent among H. influenzae isolates in this region.

Molecular characterization of coxsackievirus B5 from the sputum of pneumonia children patients of Kunming, Southwest China.

BACKGROUND: CVB5 can cause respiratory infections. However, the molecular epidemiological information about CVB5 in respiratory tract samples is still limited. Here, we report five cases in which CVB5 was detected in sputum sample of pneumonia children patients from Kunming, Southwest China. METHODS: CVB5 isolates were obtained from sputum samples of patients with pneumonia. Whole-genome sequencing of CVB5 isolates was performed using segmented PCR, and phylogenetic, mutation and recombination analysis. The effect of mutations in the VP1 protein on hydration were analyzed by Protscale. The tertiary models of VP1 proteins were established by Colabfold, and the effect of mutations in VP1 protein on volume modifications and binding affinity were analyzed by Pymol software and PROVEAN. RESULTS: A total of five CVB5 complete genome sequences were obtained. No obvious homologous recombination signals comparing with other coxsackie B viruses were observed in the five isolates. Phylogenetic analysis showed that the five CVB5 sputum isolates were from an independent branch in genogroup E. Due to the mutation, the structure and spatial of the VP1 protein N-terminus have changed significantly. Comparing to the Faulkner (CVB5 prototype strain), PROVEAN revealed three deleterious substitutions: Y75F, N166T (KM35), T140I (KM41). The last two of the three deleterious substitutions significantly increased the hydrophobicity of the residues. CONCLUSIONS: We unexpectedly found five cases of CVB5 infection instead of rhinoviruses infection during our routine surveillance of rhinoviruses in respiratory tract samples. All five patients were hospitalized with pneumonia symptoms and were not tested for enterovirus during their hospitalization. This report suggests that enterovirus surveillance in patients with respiratory symptoms should be strengthened.

CmMYB44 might interact with CmAPS2-2 to regulate starch metabolism in oriental melon fruit.

Sugar content is one of the determining factors for melon fruit maturity. Studies have shown that starch gradually degrades during fruit ripening, resulting in sugar accumulation. But the specific relationship between starch metabolism and sucrose accumulation was still unknown. Here, the starch and sugar contents, the activities of key enzymes and the expression patterns of genes related to starch-sucrose metabolism were determined in the fruit of high sugar and starch variety 'HS' and low sugar and starch variety 'LW'. It was found that starch accumulated during fruit development process, and then degraded at 30 days after anthesis (DAA), which was synchronized with sucrose accumulation in 'HS' fruit, while starch and sucrose contents were always at a lower level during 'LW' fruit maturation. Furthermore, starch metabolism-related enzymes (Adenine dinucleotide phosphate -glucose pyrophosphorylase (AGPase), α-amylase (AMY), ß-amylase (BMY)) and the key enzymes for sucrose accumulation (sucrose phosphate synthase (SPS) and sucrose synthase (SS)) were significantly increased at ripening stage of 'HS' fruit, and their activities were consistent with the expressions of CmAPS2-2, CmAMY2, CmBAM1, CmBAM9 and CmSPS1. However, the contents of starch and sucrose and the activities of AGPase and SPS in 'LW' fruit didn't change significantly. We discovered an R2R3-type MYB transcription factor, CmMYB44, screened from yeast one hybrid library, could directly bind to the promoter of CmAPS2-2 to inhibit its transcription. These results revealed that the targeted down-regulation of CmAPS2-2 by CmMYB44 might be involved in the starch accumulation process, which affect the flavor quality of oriental melon fruit.

Clinical impact of c-KIT and CEBPA mutations in 33 patients with corebinding factor (Non-M3) acute myeloid leukemia.

BACKGROUND: Corebinding factor acute myeloid leukemia (CBF-AML) is the most common cytogenetic subtype of pediatric AML. CBF-AML is associated with a relatively favorable outcome, although the relapse rate of approximately 40% indicates a high degree of clinical heterogeneity. The clinical impact of additional cytogenetic aberrations, including c-KIT and CEBPA mutations, in pediatric CBF-AML has not been well characterized, especially in the multi-ethnic region of Yunnan Province in China. METHODS: In this study, we retrospectively analyzed the clinical features, gene mutations, and prognoses of 72 pediatric patients newly diagnosed with non-M3 AML in Kunming Children's Hospital, China, from January 1, 2015 to May 31, 2020. RESULTS: Of the 72 pediatric patients with AML, 46% (33/72) had CBF-AML. Thirteen patients with CBF-AML (39%) had c-KIT mutations, five (15%) had CEBPA mutations, and eleven (33.3%) had no other cytogenetic aberrations. The c-KIT mutations, resulting from single nucleotide substitutions and small insertions or deletions, occurred in exons 8 and 17. All of the CBF-AML-associated CEBPA mutations were single mutations and occurred in patients with RUNX1-RUNX1T1 fusion. We found no significant differences in the clinical data between CBF-AML patients with c-KIT or CEBPA mutations and CBF-AML patients without other aberrations, and no prognostic significance was established for these mutations. CONCLUSION: Our study is the first to report the clinical impact of c-KIT and CEBPA mutations in pediatric patients with non-M3 CBF-AML from the multi-ethnic Yunnan Province, China. c-KIT and CEBPA mutations occurred at a higher frequency in CBF-AML cases and were associated with unique clinical characteristics; however, no potential molecular prognostic markers were identified.

[Risk factors for nosocomial infection of carbapenem-resistant Klebsiella pneumoniae in children: a single-center matched case-case-control study]. / å„¿ç«¥ç¢³é’éœ‰çƒ¯ç±»è€è¯è‚ºç‚Žå ‹é›·ä¼¯èŒåŒ»é™¢æ„ŸæŸ“çš„å±é™©å› ç´ åˆ†æžï¼šå•ä¸­å¿ƒé å¯¹ç— ä¾‹-ç— ä¾‹-å¯¹ç §ç ”ç©¶.

OBJECTIVES: To identify risk factors for carbapenem-resistant Klebsiella pneumoniae (CRKP) infection and death in hospitalized children in pediatric hospitals, and to provide a basis for the prevention and control of such infection. METHODS: This is a matched case-case-control study. The medical data of 81 children with CRKP infection and 81 children with carbapenem-sensitive Klebsiella pneumoniae (CSKP) infection who were hospitalized in Kunming Children's Hospital from January 2019 to October 2021 were retrospectively analyzed. A total of 162 children without CRKP or CSKP infection were enrolled as the control group. The association of underlying disease, previous hospitalization exposure, and current hospitalization exposure with CRKP infection and death was identified. RESULTS: Compared with the control group, there was a higher correlation between the history of hospitalization in the past 3 months and CRKP and CSKP infections (OR=14.25 and 10.07 respectively, P<0.01). The use of carbapenem in the past 3 months (OR=16.54, P<0.01) and central venous catheterization during the current hospitalization (OR=33.03, P<0.01) were risk factors for CRKP infection. The use of carbapenem in the past 3 months (OR=28.33, P<0.01) and empirical antibiotic use during the current hospitalization (OR=14.5, P<0.01) were risk factors for death of the children with CRKP infection. CONCLUSIONS: The history of hospitalization and the history of treatment with carbapenems in the past 3 months and invasive procedure after admission are leading influencing factors for CRKP infection and prognosis. It is necessary for pediatric hospitals to conduct CRKP screening on admission, standardize antibiotic use, and strengthen nosocomial infection surveillance, so as to decrease the incidence of CRKP infection.

Changes in molecular characteristics and antimicrobial resistance of invasive Staphylococcus aureus infection strains isolated from children in Kunming, China during the COVID-19 epidemic.

Invasive Staphylococcus aureus (S. aureus) infection is associated with high rates of mortality in children. No studies have been reported on invasive S. aureus infection among children in Kunming, China, and it remains unknown whether the COVID-19 epidemic has affected S. aureus prevalence in this region. Thus, this study investigated the changes in molecular characteristics and antimicrobial resistance of invasive S. aureus strains isolated from children in Kunming during 2019-2021. In total, 66 invasive S. aureus strains isolated from children were typed by multilocus sequence typing (MLST), spa, and Staphylococcal cassette chromosome mec (SCCmec), and antimicrobial resistance and virulence genes were analyzed. A total of 19 ST types, 31 spa types and 3 SCCmec types were identified. Thirty nine (59.09%) strains were methicillin-sensitive S. aureus (MSSA) and 27 (40.91%) strains were methicillin-resistant S. aureus (MRSA). The most common molecular type was ST22-t309 (22.73%, 15/66), followed by ST59-t437 (13.64%, 9/66). In 2019 and 2021, the dominant molecular type was ST22-t309, while in 2020, it was ST59-t437. After 2019, the dominant molecular type of MRSA changed from ST338-t437 to ST59-t437. All strains were susceptible to tigecycline, ciprofloxacin, moxifloxacin, vancomycin, quinopudine-dafoputin, linezolid, levofloxacin, and rifampicin. From 2019 to 2021, the resistance to penicillin and sulfamethoxazole initially decreased and then increased, a trend that contrasted with the observed resistance to oxacillin, cefoxitin, erythromycin, clindamycin, and tetracycline. Sixteen antimicrobial resistance profiles were identified, with penicillin-tetracycline-erythromycin-clindamycin-oxacillin-cefoxitin being the most common, and the antimicrobial resistance profiles varied by year. The carrier rates of virulence genes, icaA, icaD, hla, fnbA, fnbB, clfA, clfB, and cna were 100.00%. Furthermore, sak, pvl, icaC, icaR, fib, lip, hlb, hysA, sea, seb, and tsst-1 had carrier rates of 96.97, 92.42, 87.88, 69.70, 84.85, 62.12, 56.06, 50, 37.87, 30.30, and 7.58%, respectively. Since COVID-19 epidemic, the annual number of invasive S. aureus strains isolated from children in Kunming remained stable, but the molecular characteristics and antimicrobial resistance profiles of prevalent S. aureus strains have changed significantly. Thus, COVID-19 prevention and control should be supplemented by surveillance of common clinical pathogens, particularly vigilance against the prevalence of multidrug-resistant and high-virulence strains.

Diagnostic value of bone marrow cell morphology in visceral leishmaniasis-associated hemophagocytic syndrome: Two case reports.

BACKGROUND: Visceral leishmaniasis related-hemophagocytic lymphohistiocytosis (VL-HLH) is a hemophagocytic syndrome caused by Leishmania infection. VL-HLH is rare, especially in nonendemic areas where the disease is severe, and mortality rates are high. The key to diagnosing VL-HLH is to find the pathogen; therefore, the Leishmania must be accurately identified for timely clinical treatment. CASE SUMMARY: We retrospectively analyzed the clinical data, laboratory examination results, and bone marrow cell morphology of two children with VL-HLH diagnosed via bone marrow cell morphology at Kunming Children's Hospital of Yunnan, China. Both cases suspected of having malignant tumors at other hospitals and who were unresponsive to treatment were transferred to Kunming Children's Hospital. They are Han Chinese girls, one was 2 years old and the other one is 9 mo old. They had repeated fevers, pancytopenia, hepatosplenomegaly, hypertriglyceridemia, and hypofibrinogenemia over a long period and met the HLH-2004 criteria. Their HLH genetic test results were negative. Both children underwent chemotherapy as per the HLH-2004 chemotherapy regimen, but it was ineffective and accompanied by serious infections. We found Leishmania amastigotes in their bone marrow via morphological examination of their bone marrow cells, which showed hemophagocytic cells; thus, the children were diagnosed with VL-HLH. After being transferred to a specialty hospital for treatment, the condition was well-controlled. CONCLUSION: Morphological examination of bone marrow cells plays an important role in diagnosing VL-HLH. When clinically diagnosing secondary HLH, VL-HLH should be considered in addition to common pathogens, especially in patients for whom HLH-2004 chemotherapy regimens are ineffective. For infants and young children, bone marrow cytology examinations should be performed several times and as early as possible to find the pathogens to reduce potential misdiagnoses.

DLEU1 promotes cell survival by preventing DYNLL1 degradation in esophageal squamous cell carcinoma.

BACKGROUND: Emerging evidence has highlighted the critical roles of long noncoding RNAs (lncRNAs) in tumor development and progression. However, the biological functions and underlying mechanisms of DLEU1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: LncRNA expression in ESCC tissues was explored using lncRNA microarray datasets. The functional roles of DLEU1 in ESCC were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down and immunoprecipitation assays were performed to demonstrate the potential mechanisms of DLEU1. RESULTS: In a screen for differentially expressed lncRNAs in ESCC, we determined that DLEU1 was one of the most overexpressed lncRNAs in ESCC tissues and that upregulated DLEU1 expression was associated with a worse prognosis. Functional assays showed that DLEU1 promoted tumor growth by inhibiting cell apoptosis. Mechanistically, DLEU1 could bind and stabilize DYNLL1 by interfering with RNF114-mediated ubiquitination and proteasomal degradation. The DLEU1/DYNLL1 axis subsequently upregulated antiapoptotic BCL2 and promoted cell survival. Furthermore, DLEU1 upregulation was at least partly facilitated by promoter hypomethylation. Notably, targeting DLEU1 sensitized ESCC cells to cisplatin-induced death. CONCLUSIONS: Our findings suggest that DLEU1-mediated stabilization of DYNLL1 is critical for cell survival and that the DLEU1/DYNLL1 axis may be a promising therapeutic target for ESCC.

Soluble Sema4D Level Is Positively Correlated with Sema4D Expression in PBMCs and Peripheral Blast Number in Acute Leukemia.

Semaphorin 4D (Sema4D) is highly expressed in various cancers and leukemia. It is involved in the development of acute leukemia. A high level of soluble Sema4D is also present in the plasma of acute leukemia patients. However, it remains unknown whether Sema4D is associated with the clinical characteristics of acute leukemia. In this study, Sema4D expression was examined in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of patients with acute leukemia, and it was highly expressed in the PBMCs of B-acute lymphoblastic leukemia (ALL), T-ALL, and acute myeloid leukemia (AML) patients and in the BMMCs of B-ALL and AML patients but not in the BMMCs of T-ALL patients. Sema4D expression was higher in the PBMCs of T-ALL patients than in the PBMCs of B-ALL or AML patients. In addition, Sema4D expression in BMMCs was reduced in B-ALL patients during the chemotherapy process. It was lower in remission patients than in newly diagnosed and patients without remission. In acute leukemia, soluble Sema4D level in serum is positively correlated with Sema4D expression in PBMCs, leukocyte number, and peripheral blast number. Those results suggest that the levels of Sema4D and its soluble form are associated with acute leukemia development and may be regarded as a potential biomarker in pediatric acute leukemia.

ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-ß-Smad2/3 Signaling-Mediated Lung Fibroblast Activation.

Pulmonary fibrosis is a group of life-threatening diseases with limited therapeutic options. The involvement of cannabinoid type 1 receptors (CB1R) has been indicated in fibrotic diseases, but whether or not the activation of CB1R can be a benefit for fibrosis treatment is controversial. In this study, we investigated the effects of arachidonoylcyclopropylamide (ACPA), as a selective CB1R agonist, on bleomycin (BLM)-induced pulmonary fibrosis. We showed that ACPA treatment significantly improved the survival rate of BLM-treated mice, alleviated BLM-induced pulmonary fibrosis, and inhibited the expressions of extracellular matrix (ECM) markers, such as collagen, fibronectin, and α-SMA. The enhanced expressions of ECM markers in transforming growth factor-beta (TGF-ß)-challenged primary lung fibroblasts isolated from mouse lung tissues were inhibited by ACPA treatment in a dose-dependent manner, and the fibroblast migration triggered by TGF-ß was dose-dependently diminished after ACPA administration. Moreover, the increased mRNA levels of CB1R were observed in both lung fibroblasts of BLM-induced fibrotic mice in vivo and TGF-ß-challenged primary lung fibroblasts in vitro. CB1R-specific agonist ACPA significantly diminished the activation of TGF-ß-Smad2/3 signaling, i.e., the levels of p-Smad2 and p-Smad3, and decreased the expressions of downstream effector proteins including slug and snail, which regulate ECM production, in TGF-ß-challenged primary lung fibroblasts. Collectively, these findings demonstrated that CB1R-specific agonist ACPA exhibited antifibrotic efficacy in both in vitro and in vivo models of pulmonary fibrosis, revealing a novel anti-fibrosis approach to fibroblast-selective inhibition of TGF-ß-Smad2/3 signaling by targeting CB1R.

AMFR drives allergic asthma development by promoting alveolar macrophage-derived GM-CSF production.

Alveolar macrophages (AMs) are specialized tissue-resident macrophages that orchestrate the immune response in allergic inflammation and asthma. However, what signals direct AMs to cross talk with other immune cells remains unclear. Here, we report that autocrine motility factor receptor (AMFR), an endoplasmic reticulum-resident E3 ubiquitin ligase, is upregulated in AMs of asthma and is critical for this condition. AMFR deficiency significantly decreased allergy-induced T helper 2 (Th2) and eosinophilic inflammation, with less granulocyte-macrophage colony-stimulating factor (GM-CSF) production in AMs. Mechanistically, following thymic stromal lymphopoietin (TSLP) stimulation, AMFR associated directly with cytokine-inducible SH2-containing protein (CIS), induced the ubiquitination of Lys48-linked polyubiquitination of CIS, and consequently blocked the inhibitory effect of CIS on signal transducer and activator of transcription 5 (STAT5) phosphorylation and the downstream pathway activation in AMs. In conclusion, our results demonstrate that AMFR serves a crucial role in promoting inflammation in asthma through regulating AM function, and may emerge as a new potential drug target for asthma therapy.

Molecular Characterization of the Viral Structural Genes of Human Rhinovirus A11 from Children Hospitalized with Lower Respiratory Tract Infection in Kunming.

BACKGROUND: The human rhinovirus (HRV) is a picornavirus that can cause a variety of respiratory diseases, including the aggravation of chronic respiratory diseases, such as bronchitis, pneumonia, and asthma. Although an increasing number of lower respiratory tract infection cases have been reported with HRV infection in Europe, few such cases have been reported in China. METHODS: The complete genomic sequences of the HRV-A11 epidemic strains were amplified and obtained by segmented polymerase chain reaction (PCR) and sequence, and then the phylogenetic, nucleotide mutation, recombinant, and comparative analyses of amino acid mutations were performed. RESULTS: Phylogenetic analyses showed that the epidemic strains from 3 rare cases of pneumonia belong to the HRV-A11 subgenotypes. All strains were highly similar to strains from the United States. No obvious homologous recombination signals were observed in the epidemic strains. There were 498 nucleotide and 47 amino acid mutations compared with the HRV-A11 prototype strain. Amino acid mutations were observed at the capsid protein region, P1a, RVA2147-2155, and RVA97-114 epitopes of these clinical strains. CONCLUSIONS: We reported the first case of HRV-A11-associated lower respiratory tract infection in China. These mutations in the P1a, HRV A-specific CD8, and CD4 T-cell epitopes might provide a reference for virological surveillance and vaccine development.

Tetraethylthiuram disulphide alleviates pulmonary fibrosis through modulating transforming growth factor-ß signalling.

Idiopathic pulmonary fibrosis (IPF) induces significant morbidity and mortality, for which there are limited therapeutic options available. Here, we found that tetraethylthiuram disulphide (disulfiram, DSF), a derivative of thiuram, used in the treatment of alcohol abuse, has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis via the attenuation of the fibroblast-to-myofibroblast transition, migration, and proliferation of fibroblasts. Furthermore, DSF inhibited the activation of primary pulmonary fibroblasts and fibroblast cell line under transforming growth factor-ß 1 (TGF-ß1) challenge. Mechanistically, the anti-fibrotic effect of DSF on fibroblasts depends on the inhibition of TGF-ß signalling. We further determined that DSF interrupts the interaction between SMAD3 and TGF-ß receptor Ι (TBR Ι), and identified that DSF directly binds with SMAD3, in which Trp326, Thr330, and Cys332 of SMAD3 are critical binding sites for DSF. Collectively, our results reveal a powerful anti-fibrotic function of DSF in pulmonary fibrosis through the inhibition of TGF-ß/SMAD signalling in pulmonary fibroblasts, indicating that DSF is a promising therapeutic candidate for IPF.