Until recently, the intrinsically high level of cross-talk between immune cells, the complexity of immune cell development, and the pleiotropic nature of cytokine signaling have hampered progress in ...understanding the mechanisms of immunosuppression by which tumor cells circumvent native and adaptive immune responses. One technology that has helped to shed light on this complex signaling network is the cytokine antibody array, which facilitates simultaneous screening of dozens to hundreds of secreted signal proteins in complex biological samples. The combined applications of traditional methods of molecular and cell biology with the high-content, high-throughput screening capabilities of cytokine antibody arrays and other multiplexed immunoassays have revealed a complex mechanism that involves multiple cytokine signals contributed not just by tumor cells but by stromal cells and a wide spectrum of immune cell types. This review will summarize the interactions among cancerous and immune cell types, as well as the key cytokine signals that are required for tumors to survive immunoediting in a dormant state or to grow and spread by escaping it. Additionally, it will present examples of how probing secreted cell–cell signal networks in the tumor microenvironment (TME) with cytokine screens have contributed to our current understanding of these processes and discuss the implications of this understanding to antitumor therapies.
Display omitted
Objective To isolate a strain of lysing carbapenem-resistant Klebsiella pneumoniae phage, and explore its biological characteristics and whole genome information. Methods The phage was isolated and ...purified from waste water of the General Hospital of Western Theater Command Hospital by the double-layer agar plate method. The morphology of phage was observed by transmission electron microscopy, and its biological properties and in vitro antibacterial activity were determined. Whole-genome sequencing was used to analyze its structural characteristics, and a phylogenetic evolutionary tree and the comparative genomic analysis was conducted to analyze the evolutionary relationships of phage. Results A virulent phage was isolated and named vB_KpnP1, which formed a 2~3 mm transparent circular spot surrounded by a distinct halo; Electron microscopy showed that the head size of the phage was about 68.2 nm×64.3 nm, and the tail length was about 11 nm; The head of the phage was a regular icosahedron with a non-contracti
Oncolytic viruses have been emerging as a promising therapeutic option for cancer patients, including lung cancer. Orf virus (ORFV), a DNA parapoxvirus, can infect its natural ungulate hosts and ...transmit into humans. Moreover, the ORFV has advantages of low toxicity, high targeted, self-amplification and can induce potent Th1-like immunity. This study explored the therapeutic potential of ORFV infection for human lung cancer therapy and investigated the molecular mechanisms. We used a previously described ORFV NA1/11 strain and tested the oncolysis of ORFV NA1/11 in two lines of lung cancer cells
in vitro
and
in vivo
. Treatment of both cell lines with ORFV NA1/11 resulted in a decrease in cell viability by inducing cell cycle arrest in G2/M phase, suppressing cyclin B1 expression and increasing their apoptosis in a caspase-dependent manner. The ORFV NA1/11-infected lung cancer cells were highly immunogenic. Evidently, ORFV NA1/11 infection of lung cancer cells induced oncolysis of tumor cells to release danger-associated molecular patterns, and promoted dendritic cell maturation, and CD8 T cell infiltration in the tumors by enhancing CXCL16 secretion. These findings may help to understand the molecular mechanisms of ORFV oncolysis and aid in the development of novel therapies for lung cancer.
The collaborative problem solving theory helps learners build on one another's ideas by reinforcing the problems that others have stated, identifying the barriers that led to the problems, finding ...evidence-based and innovative solutions, suggesting actions, and evaluating the actions. Method The new instructions asked students to label their responses with no more than two of the keywords in the subject line of the discussion forum: “problems,” “barriers,” “solutions,” “actions,” or “evaluation.” “Evaluation” meant to judge and analyze the result of an action(s).
To systematically explore potential biomarkers which can predict disease severity in COVID-19 patients and prevent the occurrence or development of severe COVID-19, the levels of 440 factors were ...analyzed in patients categorized according to COVID-19 disease severity; including asymptomatic, mild, moderate, severe, convalescent and healthy control groups. Factor candidates were validated by ELISA and functional relevance was uncovered by bioinformatics analysis. To identify potential biomarkers of occurrence or development of COVID-19, patient sera from three different severity groups (moderate, severe, and critical) at three time points (admission, remission, and discharge) and the expression levels of candidate biomarkers were measured. Eleven differential factors associated with disease severity were pinpointed from 440 factors across 111 patients of differing disease severity. The dynamic changes of GDF15 reflect the progression of the disease, while the other differential factors include TRAIL R1, IGFBP-1, IGFBP-4, VCAM-1, sFRP-3, FABP2, Transferrin, GDF15, IL-1F7, IL-5Rα, and CD200. Elevation of white blood cell count, neutrophil count, neutrophil-lymphocyte ratio (NLR), Alanine aminotransferase and Aspartate aminotransferase, low lymphocyte and eosinophil counts in the severe group were associated with the severity of COVID-19. GDF15 levels were observed to be associated with the severity of COVID-19 and the dynamic change of GDF15 levels was closely associated with the COVID-19 disease progression. Therefore, GDF15 might serve as an indicator of disease severity in COVID-19 patients.
Chest CT revealed bronchiectasis and superimposed infection (Fig. 1 A1-A3). ...the preliminary diagnosis was as follows: 1) septic shock; 2) severe community-acquired pneumonia; 3) acute respiratory ...distress syndrome (ARDS); 4) chronic obstructive pulmonary disease (COPD). ...she was discharged from the hospital after 5 days and was asked to continue sulfamethoxazole treatment (0.96g QID). Abbreviations ICU intensive care unit NGS next-generation sequencing ARDS acute respiratory distress syndrome COPD chronic obstructive pulmonary disease BALF bronchoalveolar lavage fluid MALDI-TOF MS the matrix-assisted laser desorption/ionization-time of flight mass spectrometry (c) detection COPD chronic obstructive pulmonary disease MRI magnetic resonance imaging BCYE buffered charcoal-yeast extract Appendix A Supplementary data The following is the Supplementary data to this article: 16S rRNA gene sequencing results suggested that Nocardia amamiensis had the highest sequence similarity with this strain, with a consistency of 99.92%, and coverage of 100%.Multimedia component 1Multimedia component 1 Appendix A Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tmaid.2024.102710.
Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor κB (NF-κB) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, ...we describe a NF-κB inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early in infected cells. Infection with ORFV073 gene deletion virus (OV-IA82Δ073) led to increased accumulation of NF-κB essential modulator (NEMO), marked phosphorylation of IκB kinase (IKK) subunits IKKα and IKKβ, IκBα and NF-κB subunit p65 (NF-κB-p65), and to early nuclear translocation of NF-κB-p65 in virus-infected cells (≤ 30 min post infection). Expression of ORFV073 alone was sufficient to inhibit TNFα induced activation of the NF-κB signaling in uninfected cells. Consistent with observed inhibition of IKK complex activation, ORFV073 interacted with the regulatory subunit of the IKK complex NEMO. Infection of sheep with OV-IA82Δ073 led to virus attenuation, indicating that ORFV073 is a virulence determinant in the natural host. Notably, ORFV073 represents the first poxviral virion-associated NF-κB inhibitor described, highlighting the significance of viral inhibition of NF-κB signaling very early in infection.
Sepsis is a common critical illness in intensive care unit (ICU) and an important risk factor for intensive care unit-acquired weakness (ICU-AW). The objective of the study is to analyze the risk ...factors of ICU-AW in septic patients.
A total of 264 septic patients admitted to the General Hospital of the Western Theater Command from January 2018 to April 2022 were included in this study. The cohort was divided into 2 groups according to the presence or absence of ICU-AW. Clinical characteristics included age, sex, body mass index, length of ICU stay, multiple organ dysfunction syndrome, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ), mechanical ventilation time, intubation, tracheotomy, protective constraint, lactic acid, fasting blood glucose, etc. The clinical characteristics of sepsis were evaluated using logistic regression analysis.
A total of 114 septic patients suffered ICU-AW during their ICU stay. Multivariate binary logistic regression analysis showed that APACHE Ⅱ score, mechanical ventilation time, protective constraint, and lactic acid were independent risk factors for ICU-AW in septic patients. The areas under the receiver operating characteristic curve (AUCs) were 0.791, 0.740 and 0.812, all P < 0.05, and the optimal cut-off values were 24 points, 5 days and 2.12 mmol/L, respectively.
A high APACHE Ⅱ score, long mechanical ventilation time, protective constraint and high lactate concentration are independent risk factors for ICU-AW in septic patients. An APACHE Ⅱ score greater than 24 points, mechanical ventilation time longer than 5 days and lactate concentration higher than 2.12 mmol/L are likely to cause ICU-AW.
The parapoxvirus Orf virus (ORFV) has long been recognized as one of the valuable vectors in researches of oncolytic virus. In order to develop a potential therapeutic strategy for breast cancer ...based on the oncolytic virotherapy
ORFV, firstly we explore the oncolytic effects of ORFV. Our research showed that ORFV exerts anti-tumor effects
by inducing breast cancer cell G2/M phase arrest and cell apoptosis.
experiments were carried out, in which we treated 4T1 tumor-bearing BALB/C mice
intratumoral injection of ORFV. ORFV can exert anti-tumor activity by regulating tumor microenvironment (TME) and inducing a host immune response plus directly oncolytic effect. The CRISPR-Cas9 knockout library targeting 507 kinases was used to screen out PAK4, which is beneficial to the anti-tumor effect of ORFV on breast cancer cells. PF-3758309 is a potent PAK4-targeted inhibitor. Co-using of ORFV and PF-3758309 as a combination treatment produces its anti-tumor effects through inhibition of cell viability, induction of apoptosis and suppression of cell migration and invasion
. The results of
experiments showed that the tumor growth of mice in the combination treatment group was significantly inhibited, which proved that the combination treatment exerts an effective anti-tumor effect
. In summary, we have clarified the oncolytic effect of ORFV on breast cancer, and found that the combination of ORFV and PAK4 inhibitor can effectively improve the oncolytic effect of ORFV. We hope our research could provide a new idea for the development of new treatment strategies for breast cancer.
PDF
