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Background: The clinical implications of platelet count changes in patients with bronchiolitis throughout hospitalization have not been extensively investigated. We aimed to investigate the significance of platelet count on admission and platelet count changes during hospitalization in pediatric patients with bronchiolitis. Methods: Clinical data from 559 consecutive patients hospitalized for bronchiolitis were collected and compared after grouping according to the platelet count on admission and the delta platelet count during hospitalization (the platelet count on discharge minus the platelet count on admission; Group A, delta platelet count ≤ -50 × 109/L; Group B, -50 × 109/L < delta platelet count ≤ 50 × 109/L; Group C, delta platelet count > 50 × 109/L). Results: Thrombocytosis was found in 122 (21.8%) patients, while 437 (78.2%) patients had a normal platelet count on admission. There was no difference in disease severity between these two groups. Groups A, B, and C comprised 79 (14.1%), 179 (32.0%), and 301 (53.9%) patients, respectively. The patients from Group A had a higher platelet count on admission, a lower platelet count on discharge, and a longer hospitalization duration. These patients had a lower concentration of C-reactive protein, longer periods of oxygen therapy and stay in the pediatric intensive care unit (PICU), and a greater frequency of mechanical ventilation than the patients from Group B or Group C. Notably, among all the patients, the delta platelet count [63 (-3–142) × 109/L] negatively correlated with the numbers of days of oxygen therapy [4.0 (3.0–6.0), day] (r = -0.186, P = 0.027) and stay in the PICU [5.0 (3.0–6.0), day] (r = -0.391, P = 0.001). Conclusions: Repeated assessment of platelet count during hospitalization in pediatric patients with bronchiolitis may provide useful information for disease management.

The purpose of this study was to determine the clinical features of viral pathogens and Mycoplasma pneumoniae in children hospitalized with community-acquired pneumonia (CAP). M. pneumoniae infection was diagnosed by both serology and polymerase chain reaction (PCR). Respiratory viruses were detected by direct immunofluorescence or PCR. Medical records of children younger than 5 years diagnosed with 5-day-old CAP were reviewed. Viral pathogens and/or M. pneumoniae were detected in 388 (15.59%) children in the following three groups: viral monoinfection (n = 321), M. pneumoniae with viral coinfection (n = 17), and M. pneumoniae monoinfection (n = 50). M. pneumoniae monoinfection was characterized by older age, fever, higher neutrophil count, and chest X-ray showing lobar consolidation. Wheezing was more common in children with viral infections. Elevated alanine aminotransferase and aspartate aminotransferase were commonly seen in children with Mycoplasma infections. The median symptom duration in children with viral coinfection was shorter than in the other two groups (both p

BACKGROUND: Viral etiology and atopic characteristics, e.g., allergens and fractional exhaled nitric oxide (FeNO), play essential roles in asthma development. This study aimed to investigate associations among them in children at high risk of developing asthma to guide reliable diagnosis and treatment of wheezing. METHODS: From April 2016 to August 2017, 135 children aged

Background MicroRNAs play roles in the pathogenesis of bronchial asthma. However, the mechanism of miR-29c in allergic asthma remains unclear. This study is to elucidate the regulation of Th cell differentiation by miR-29c in mononuclear macrophages. Methods A total of 52 children with asthma exacerbation and 26 children as controls were enrolled in the study. CD14+ monocytes were isolated from the peripheral blood. Differential expressions of microRNAs were evaluated using microarray analysis and miR-29c expression in monocytes was determined by qRT-PCR. The plasma B7-H3 was determined by ELISA. Transfection studies and luciferase reporter assay were performed to confirm target gene of miR-29c and its function. Results Compared to controls, 88 miRNAs in blood monocytes were up-regulated and 41 miRNAs down-regulated including miR-29c in asthma children. Children with asthma exacerbation had significantly lower level of miR-29c and higher level of plasma B7-H3 compared to controls (both P

Background Mycoplasma pneumoniae (M. pneumoniae) is one of the most common causes of community-acquired pneumonia in children. Recent studies demonstrated that the incidence of severe or fatal M. pneumoniae was gradually increasing, which may be related to the excessive inflammation. However, the exact pathogenesis of excessive inflammation in Mycoplasma pneumoniae pneumonia(MPP) is still unclear. This study aimed to reveal the role of miR-29c/B7-H3/Th17 axis in children with MPP. Methods Children hospitalized in Respiratory Department during Jan. 2014 to Dec. 2015 were enrolled. All children enrolled was confirmed with MP infection using real-time PCR and ELISA. Children were excluded if they were co-infected with other pathogens. A total of 52 children with MPP and 26 controls were enrolled. miR-29c expression in monocytes of children with MPP was determined by real-time PCR and soluble B7-H3 (sB7-H3) and IL-17 were determined by ELISA, and explore their clinical significance. miR-29c overexpression and silencing technology and luciferase reporter assay were performed to confirm whether B7-H3 is the direct target of miR-29c. The levels of transcription factor ROR-γt in CD4+ T cells and cytokine IL-17A in supernatant were detected after stimulated by different concentrations of B7-H3 fusion protein in vitro. Results Of all 52 children with MPP, the mean age of the children were 77 ± 33 months, and 23 cases were male accounting for 44.2%. Nineteen cases had pleural effusion accounting for 36.5%. Children with MPP had significantly lower level of miR-29c and higher level of sB7-H3 and IL-17 compared to controls (both P

Background: While HER2 targeted therapeutics have significantly improved outcomes of patients with HER2 overexpressed advanced breast cancer (ABC), c-Met pathway activation serves as a resistance mechanism in about 60% of patients. Neratinib is an irreversible tyrosine kinase inhibitor of the ErbB family of receptors (EGFR, HER2, and HER4) and tepotinib is a tyrosine kinase inhibitor of c-Met. From live extracted cells from patient biopsies, the CELsignia Pathway Activity Test measures in real-time ErbB and c-Met signaling activity and the dynamic response to pathway inhibition by targeted therapy ex vivo. The CELsignia test may identify patients with ABC who would benefit from the combination of neratinib and tepotinib regardless of the molecular breast cancer subtype. Trial Design: We designed a phase Ib/II multi-center, non-randomized, open-label study of combination of neratinib with tepotinib in patients with advanced breast cancer including those with inflammatory breast cancer. The study sites include UT MD Anderson Cancer Center, City of Hope, and The Ohio State University Cancer Center. Four dose levels of neratinib, and two dose levels of tepotinib will be studied in phase Ib to determine the maximum tolerated dose (MTD). Phase II portion of the study will test the early efficacy of neratinib and tepotinib combination in patients with HER2-/HR+ ABC with abnormal HER2 and c-Met signaling activity determined by the CELsignia test. Eligibility: All patients with IBC/ABC will be eligible for the phase Ib. Eligible patients must have measurable metastatic disease per RECIST v1.1 or unresectable disease amenable for biopsy and have had at >1 line of systemic therapy for advanced disease. Patients will have an Eastern Cooperative Oncology Group performance status of 0 to 2. For the phase II component, patients must have hyperactive HER2 and c-Met signaling determined by CELsignia test. Aims: The primary objective of the phase Ib component is to determine the MTD of the combination in previously treated IBC/ABC of any molecular subtype. The primary objective of the phase II component is to determine the overall response rate (ORR) in patients with HER2-/HR+ ABC who have a positive CELsignia test result (described in the Eligibility). Secondary objectives include progression free and overall survival, clinical benefit rate, duration of response, and safety and tolerability. Exploratory objectives will be to assess HER2 and c-Met driven signaling pathways as either hyperactive or abnormally active by CELsignia test. Statistical Methods: The phase I study will be conducted using a Bayesian optimal interval (BOIN) design to establish the MTD and the recommended phase II dose and assess early efficacy of the combination with a maximum of 21 patients. Two dose levels of tepotinib, and four dose levels of neratinib will be studied. The phase II study will assess the ORR using Bayesian optimal phase 2 (BOP2) design to rule out a 10% ORR in favor of a 30% target ORR, with a power of 80% and two-sided 5% significance level. Accrual: Once MTD is determined, up to 29 evaluable CELsignia test positive subjects will be enrolled to the phase II component of the study and an interim analysis will be performed when the total number of enrolled patients reaches 15. We hope to complete the accrual of patients by July 2022 and to schedule the last patient visit by July 2023. Contact information: For more information or to refer a patient, email blim@mdanderson.org, eahobbs@mdanderson.org Citation Format: Evthokia Hobbs, Eric Lindquist, Brian Sullivan, Esther Yoon, Ying Yuan, Angela Marx, Jie Willey, Huiming Sun, Rachel Layman, Daniel Stover, Yuan Yuan, Bora Lim. Neratinib and tepotinib combination in advanced breast cancer and inflammatory breast cancer patients with abnormal HER2 and c-Met pathway activity as measured by the CELsignia signaling pathway activity test [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-04.

Background This study set out to evaluate the clinical significance and diagnostic effectiveness of serological tests and real-time polymerase chain reactions (RT-PCR) in children of different age groups and disease durations infected with Mycoplasma pneumoniae (MP). Methods Pediatric patients with lower respiratory tract infection (LRTI) confirmed by polymerase chain reaction (PCR) were enrolled and subjected to bronchoalveolar lavage fluid PCR (BALF-PCR) for MP infection. The diagnostic values of the serum immunoglobulin M (IgM) test, paired sera immunoglobulin G (IgG) test, RT PCR applied to nasopharyngeal aspirates (NPA-PCR), and combined IgM and NPA-PCR test were evaluated. Results When BALF PCR was used as the gold standard, the MP positivity rate of combined IgM and NPA PCR was 78.85%in children aged 3-5 years. The positivity rates of IgM, NPA PCR, and combined IgM and NPA PCR in children older than 5 years were 71.21%, 72.72%, and 84.85%, respectively. The detection rate of combined IgM and NPA PCR was consistent with BALF PCR (Kappa =0.727). The MP positivity rates of combined IgM and NPA PCR at 1-2 weeks was as high as 91.11%, and was consistent with the BALF PCR (Kappa =0.756). Moreover, the positivity rates of IgM or NPA PCR at 2-3 weeks were 63.16%, and were consistent with each other (Kappa =0.771). Conclusions Combined IgM and NPA PCR is the optimal test to confirm MP infection among children aged 3-5 years in cases with a disease duration of less than2 weeks, and either NPA PCR or IgM is recommended for children older than 5 years with a disease duration of 2-3 weeks. Keywords Mycoplasma pneumoniae pneumonia (MPP); diagnosis; children; age; disease duration.

Objective The objective of this study was to assess epidemiological and clinical features of human bocavirus (HBoV) coinfection with other viruses. Method Children coinfected with HBoV between January 2012 and December 2014 were enrolled and retrospectively reviewed. Result A total of 984 patients were stratified into five groups: HBoV infection alone (n = 249), respiratory syncytial virus (RSV) infection alone (n = 649), HBoV coinfection with RSV (n = 28), with human rhinovirus (HRV) (n = 39) and with other virus (n = 19). Length of hospitalization was longer in HBoV coinfection with RSV group than HBoV (9.0 days vs. 7.0 days, p = 0.001), RSV (9.0 days vs. 8.0 days, p = 0.016) infection alone group. Pneumonia was more common in the HBoV coinfection with RSV group compared with the HBoV, RSV infection alone group, respectively (75.0% vs. 44.2%, 31.3%, p Conclusion HBoV coinfection with RSV increases HBoV infection severity.

Background This study aimed to investigate the occurrence of Cytomegalovirus (CMV) DNA in the Bronchoalveolar lavage fluid (BALF) of children with recurrent wheezing and to identify associations with certain patient clinical characteristics. Methods In this cross-sectional study, pediatric patients (age

Background The purpose of this study is to explore the correlations of interleukin 36 (IL-36) and Soluble B7-H3 (sB7-H3) levels in bronchoalveolar lavage fluid (BALF) with clinical characteristics and laboratory findings. Methods A total of 35 children with M. pneumnoiae pneumonia (MPP) and 15 control subjects were enrolled. BALF concentrations of sB7-H3 and IL-36 were detected using enzyme-linked immunosorbent assays and clinical profiles of children with MPP were obtained. Results Children with MPP had significantly higher levels of sB7-H3 and IL-36 compared to control subjects (both P

Here, we investigated the role of one gene that has been previously associated with human prostate carcinoma cells-myelodysplasia/myeloid leukemia factor 1 interacting protein (MLF1IP)-in order to better ascertain its role in human prostate carcinogenesis. The prostate cancer cell line PC-3 was lentivirally transfected to silence endogenous MLF1IP gene expression, which was confirmed by real-time quantitative PCR (RT-qPCR). Cellomics ArrayScan VTI imaging and MTT assays were conducted to assess cell proliferation. Cell cycle phase arrest and apoptosis were assayed by flow cytometry. Colony formation was assessed by fluorescence microscopy. MLF1IP gene expression was also analyzed by RT-qPCR in sixteen prostate cancer tissue samples and six healthy control prostate tissue samples from human patients. Cell proliferation was significantly inhibited in MLF1IP-silenced cells relative to control cells. G1 phase, S and G2/M phase cell counts were not significantly changed in MLF1IP-silenced cells relative to control cells. Apoptosis was significantly increased in MLF1IP-silenced cells, while MLF1IP-silenced cells displayed a significantly reduced number of cell colonies, compared to control cells. The 16 human prostate cancer tissue samples revealed no clear upregulation or downregulation in MLF1IP gene expression. MLF1IP significantly promotes prostate cancer cell proliferation and colony formation and significantly inhibits apoptosis without affecting cell cycle phase arrest. Further study is required to conclusively determine whether MLF1IP is upregulated in human prostate cancer tumors and to determine the precise cellular mechanism(s) for MLF1IP in prostate carcinogenesis.

Mycoplasma pneumoniae (M. pneumoniae) is an important pathogen of community-acquired pneumonia in children, but the epidemiology and clinical features of M. pneumoniae infection in infants are reported in only a few studies. This study aims to evaluate possible age-related differences in the presenting clinical features in infants with M. pneumoniae infection.24-month longitudinal study on lower respiratory tract infection (LRTI) caused by M. pneumoniae, confirmed by both serology and polymerase chain reaction, was performed. Medical records of patients were reviewed for demographic, clinical and microbiological characteristics.Out of 2174 infants with LRTI admitted to the Children's Hospital Affiliated to Soochow University in Jiangsu Province, 80 were diagnosed with M. pneumoniae infection. We found that 15 were aged 1 to5 months; 29 were aged 5 to9 months; and 36 were aged 9 to12 months. M. pneumoniae infection mainly occurred in August to October. The presence of fever with a maximum temperature of39.0 °C for ≥3 days was more common in the 9 to12 month age group (P 0.05). Laboratory tests showed that the infants aged 9-12 months had a higher peripheral leukocyte (P = 0.035) and neutrophil (P = 0.015) count and a higher CRP level (P = 0.041). Moreover, the median length of hospitalization for infants aged 1 to5 months was shorter than that in the other two groups.Our work provides important clinical information about infants with M. pneumoniae infection and highlights that younger infants with M. pneumoniae infection may have a milder clinical course than older infants.

The vascular endothelium responds to infection by destabilizing endothelial cell–cell junctions to allow fluid and cells to pass into peripheral tissues, facilitating clearance of infection and tissue repair. During sepsis, endotoxin and other proinflammatory molecules induce excessive vascular leak, which can cause organ dysfunction, shock, and death. Current therapies for sepsis are limited to antibiotics and supportive care, which are often insufficient to reduce morbidity and prevent mortality. Previous attempts at blocking inflammatory cytokine responses in humans proved ineffective at reducing the pathologies associated with sepsis, highlighting the need for a new therapeutic strategy. The small GTPase ARF6 is activated by a MyD88–ARNO interaction to induce vascular leak through disruption of endothelial adherens junctions. In this study, we show that the MyD88–ARNO–ARF6–signaling axis is responsible for LPS-induced endothelial permeability and is a destabilizing convergence point used by multiple inflammatory cues. We also show that blocking ARF6 with a peptide construct of its N terminus is sufficient to reduce vascular leak and enhance survival during endotoxic shock, without inhibiting the host cytokine response. Our data highlight the therapeutic potential of blocking ARF6 and reducing vascular leak for the treatment of inflammatory conditions, such as endotoxemia.

Periostin is over expressed in many epithelial malignant cancers, including lung cancer, breast cancer, ovarian cancer and colon cancer. It is related with the progression and migration of breast and ovarian cancer cells in vitro. The aim of this study was to investigate the serum level of periostin in non-small cell lung cancer (NSCLC) and its relationship with established biological and prognostic factors by enzyme-linked-immunosorbent serologic assay. We also observe the function of periostin on the proliferation and migration of human lung adenocarcinoma cell line (A549) and discuss the mechanism. The mean value for serum periostin (POSTN) was elevated in NSCLC patients (242.84 + or - 5.33 pg/ml) compared to the normal healthy volunteers (215.66 + or - 11.67 pg/ml) (p = 0.030). The serum level of periostin of NSCLC patients had no connection with gender, age, pathological type, TNM stage, lymph node status, tumor size and invasiveness. We constructed a plasmid named pEGFP-N1/POSTN expressing full-length human periostin. Transfecting the plasmid to A549 cells and periostin was efficiently expressed in transfected A549 cells. Our data showed that periostin could promote the proliferation and migration of A549 cells by inducing vimentin and N-cadherin expression and downregulating E-cadherin expression. These results strongly suggest that periostin is a novel molecular which play an important role during the progression and development of NSCLC.

Background: Increased CD8+ tumor-infiltrating lymphocytes (TIL) is associated with improved prognosis in triple-negative breast cancer (TNBC) suggesting that T-cell responses at the tumor site can be harnessed for autologous T-cell therapy using TIL expanded ex vivo. Although TIL therapy has been developed for solid tumors such as melanoma, cervical, and ovarian cancer. Moreover, methods facilitating CD8+ TIL expansion from TNBC are desirable given their cytotoxic potential against tumor cells. One approach to address this need is to provide agonist signals through the 4-1BB/CD137 pathway during TIL expansion selectively costimulating CD8+ T-cell activation. In this study, we established a method of expanding TIL from surgical specimens and core biopsies from primary TNBC patients and compared the phenotype and function of these TIL to lymphocytes from peripheral blood. Patients and methods: Eight primary human TNBC tumor samples were obtained by surgical resection or core biopsy after neo-adjuvant chemotherapy. Small (4-6 mm2) tumor fragments were cultured for 28 days in 24-well plates in medium containing 3000 IU/ml IL-2 alone or in combination with 10 µg/ml agonistic anti-4-1BB IgG4 (BMS663513) added at the start of culture. Viable cell numbers and the expression of CD3, CD8, CD4, CD27, CD28, CD56, CD16, Granzyme B, and Perforin were determined by flow cytometry on day 28 after culture. Cytotoxic function of the TIL was evaluated by measuring Caspase 3 cleavage in target cells. Blood samples collected at surgery were immunophenotyped for subsets of T cells and NK cells, and assessed for ability of T cells to synthesize Th1/Th2 cytokines following activation through the T-cell receptor (TCR), and potential of NK cells to kill K562 targets. Results: TIL were successfully expanded from tumor fragments in 6/8 of the cases, with addition of anti-4-1BB greatly increasing the percentage and yield of CD8+CD3+ T cells. CD8+ TIL isolated from cultures receiving 4-1BB costimulation however had decreased CD27 and CD28 expression together with increased cytotoxic T-cell activity. Gene expression analysis also found that TIL from these 4-1BB costimulated cultures had a more differentiated CD8+ T-cell gene profile. Peripheral blood CD3+, CD8+, and CD4+ T cells were lower than those of healthy controls, but TCR-activated cytokine synthesis was not significantly different. Peripheral blood NK cells expressed normal Granzyme A/B and Perforin levels and exhibited normal IFN-? secretion and CD107a-release following exposure to IL-12/IL-18 or with K562 targets. Conclusions: TIL can be reproducibly expanded from TNBC tumors with IL-2 after neo-adjuvant therapy, with CD8+ TIL outgrowth and effector activity increased by provision of 4-1BB/CD137 costimulatory signals during culture initiation. These CD8+ TIL however had a more differentiated phenotype with higher cytotoxic activity. Peripheral blood T-cell and NK cell function was comparable to those of healthy donors. Our results support further development of an autologous TIL expansion protocol after neo-adjuvant therapy for use in an adoptive cell therapy approach to treat TNBC recurrence or metastasis. Citation Format: Michiko Harao, Hui Gao, Jie Qing Chen, Elizabeth A Mittendorf, Gildy V Babiera, Sarah M DeSnyder, Korrene F Rockwood, Savitri Krishnamurthy, Huiming Sun, Jie S Willey, Naoto T Ueno, James M Reuben, Laszlo G Radvanyi. Co-stimulation through 4-1BB/CD137 improves expansion and function of tumor-infiltrating T lymphocytes from primary and metastatic triple-negative breast cancer and inflammatory breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-05.