Bayskovgaard8824
vascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P less then 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P less then 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.The cyclin-dependent kinase 6 (CDK6) regulates the transition through the G1-phase of the cell cycle, but also acts as a transcriptional regulator. As such CDK6 regulates cell survival or cytokine secretion together with STATs, AP-1 or NF-κB. In the hematopoietic system, CDK6 regulates T cell development and promotes leukemia and lymphoma. CDK4/6 kinase inhibitors are FDA approved for treatment of breast cancer patients and have been reported to enhance T cell-mediated anti-tumor immunity. The involvement of CDK6 in T cell functions remains enigmatic. We here investigated the role of CDK6 in CD8+ T cells, using previously generated CDK6 knockout (Cdk6 -/-) and kinase-dead mutant CDK6 (Cdk6 K43M) knock-in mice. RNA-seq analysis indicated a role of CDK6 in T cell metabolism and interferon (IFN) signaling. To investigate whether these CDK6 functions are T cell-intrinsic, we generated a T cell-specific CDK6 knockout mouse model (Cdk6 fl/fl CD4-Cre). T cell-intrinsic loss of CDK6 enhanced mitochondrial respiration in CD8+ T cells, but did not impact on cytotoxicity and production of the effector cytokines IFN-γ and TNF-α by CD8+ T cells in vitro. Loss of CDK6 in peripheral T cells did not affect tumor surveillance of MC38 tumors in vivo. Similarly, while we observed an impaired induction of early responses to type I IFN in CDK6-deficient CD8+ T cells, we failed to observe any differences in the response to LCMV infection upon T cell-intrinsic loss of CDK6 in vivo. This apparent contradiction might at least partially be explained by the reduced expression of Socs1, a negative regulator of IFN signaling, in CDK6-deficient CD8+ T cells. Therefore, our data are in line with a dual role of CDK6 in IFN signaling; while CDK6 promotes early IFN responses, it is also involved in the induction of a negative feedback loop. These data assign CDK6 a role in the fine-tuning of cytokine responses.The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.
The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the coronavirusdisease of 2019(COVID-19) that killed more than 3.5 million people till now. The cytokine storm induced in severe COVID-19 patients causes hyper-inflammation, is the primary reason for respiratory and multi-organ failure and fatality. This work uses a rational computational strategy to identify the existing drug molecules to target host pathways to reduce the cytokine storm.
We used a "
" consist of 36 genes induced by SARS-CoV-2 infection and associated with cytokine storm. In order to attenuate the cytokine storm, potential drug molecules were searched against
. Our study identified that drug molecule andrographolide, naturally present in a medicinal plant
, has the potential to bind with crucial proteins to block the TNF-induced NFkB1 signaling pathway responsible for cytokine storm in COVID-19 patients. The molecular docking method showed the binding of andrographolide with TNF and covalent binding with NFkB1 proteins of the TNF signaling pathway.
We used a rational computational approach to repurpose existing drugs targeting host immunomodulating pathways. Our study suggests that andrographolide could bind with TNF and NFkB1 proteins, block TNF-induced cytokine storm in COVID-19 patients, and warrant further experimental validation.
We used a rational computational approach to repurpose existing drugs targeting host immunomodulating pathways. Our study suggests that andrographolide could bind with TNF and NFkB1 proteins, block TNF-induced cytokine storm in COVID-19 patients, and warrant further experimental validation.Cutaneous leishmaniasis caused by L. braziliensis induces a pronounced Th1 inflammatory response characterized by IFN-γ production. Even in the absence of parasites, lesions result from a severe inflammatory response in which inflammatory cytokines play an important role. Different approaches have been used to evaluate the therapeutic potential of orally administrated heat shock proteins (Hsp). These proteins are evolutionarily preserved from bacteria to humans, highly expressed under inflammatory conditions and described as immunodominant antigens. Tolerance induced by the oral administration of Hsp65 is capable of suppressing inflammation and inducing differentiation in regulatory cells, and has been successfully demonstrated in several experimental models of autoimmune and inflammatory diseases. We initially administered recombinant Lactococcus lactis (L. lactis) prior to infection as a proof of concept, in order to verify its immunomodulatory potential in the inflammatory response arising from L. brazilie autoimmune diseases, as well as in chronic infections that cause inflammatory disease.
Systemic sclerosis (SSc) is an uncommon autoimmune disease that varies with ethnicity. Single nucleotide polymorphisms (SNPs) in the GTFSI, NFKB1, and TYK2 genes have been reported to be associated with SSc in other populations and in individuals with various autoimmune diseases. This study aimed to investigate the association between these SNPs and susceptibility to SSc in a Chinese Han population.
A case-control study was performed in 343 patients with SSc and 694 ethnically matched healthy controls. SNPs in GTF2I, NFKB1, and TYK2 were genotyped using a Sequenom MassArray iPLEX system. Ipatasertib research buy Association analyses were performed using PLINK v1.90 software.
Our study demonstrated that the
rs117026326 T allele and the
rs73366469 C allele were strongly associated with patients with SSc (
= 6.97E-10 and
= 1.33E-08, respectively). Patients carrying the
rs117026326 TT genotype and the
rs73366469 CC genotype had a strongly increased risk of SSc (
= 6.25E-09 and
= 1.67E-08, respectively), and those carrying the
rs1599961 AA genotype had a suggestively significantly increased risk of SSc (
= 0.014). Moreover, rs117026326 and rs73366469 were associated with SSc in different genetic models (additive model, dominant model, and recessive model) (
< 0.05) whereas rs1599961 was associated with SSc in the dominant genetic model but not in the addictive and recessive models (
= 0.0026).
rs2304256 was not significantly associated with SSc in this study.
rs117026326 and rs73366469 SNPs were strongly associated with SSc in this Chinese Han population.
rs1599961 showed a suggestive association with SSc, and no significant association was found between
rs2304256 and SSc in this Chinese Han population.
GTF2I rs117026326 and rs73366469 SNPs were strongly associated with SSc in this Chinese Han population. NFKB1 rs1599961 showed a suggestive association with SSc, and no significant association was found between TYK2 rs2304256 and SSc in this Chinese Han population.
Obesity is a recognized risk factor for low fertility and is becoming increasingly prevalent in many countries around the world. Obesity changes intestinal microbiota composition, causes inflammation of various organs, and also reduces sperm quality. Several microorganisms are present in the testis. However, whether obesity affects the changes of testicular microbiota and whether these changes are related to reduced fertility in obese men remain to be elucidated.
In the present study, a zebrafish obesity model was established by feeding with egg yolk powder. Sperm motility was measured by the Computer Assisted Sperm Analysis system, testicular microbial communities was assessed
16s RNA sequencing, the immune response in zebrafish testis was quantified by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, and the testicular tissue structure was detected by electron microscopy and hematoxylin-eosin staining.
Compared with the control group, zebrafish sperm motility was dramatically reduced, the expression of testicular proinflammatory cytokines in the testes was upregulated, and the blood-testis barrier structure was disrupted in the obese group. In addition, testicular microbiome composition was clearly altered in the obese group.
Obesity alters testicular microbiota composition, and the reason behind the decreased sperm motility in obese zebrafish may be related to changes in the testicular microbial communities.
Obesity alters testicular microbiota composition, and the reason behind the decreased sperm motility in obese zebrafish may be related to changes in the testicular microbial communities.P48/45 is a conserved gametocyte antigen involved in Plasmodium parasite fertilization. A recombinant Plasmodium vivax P48/45 (Pvs48/45) protein expressed in Escherichia coli (E. coli) was highly antigenic and immunogenic in experimental animals and elicited specific transmission-blocking (TB) antibodies in a previous pilot study. Here, a similar Pvs48/45 gene was expressed in Chinese Hamster Ovary (CHO) cells and we compared its immunoreactivity with the E. coli product. Specific antibody titers were determined using plasma from Colombian individuals (n=227) living in endemic areas where both P. vivax and P. falciparum are prevalent and from Guatemala (n=54) where P. vivax is highly prevalent. In Colombia, plasma seroprevalence to CHO-rPvs48/45 protein was 46.3%, while for E. coli-rPvs48/45 protein was 36.1% (p less then 0.001). In Guatemala, the sero prevalence was 24.1% and 14.8% (p less then 0.001), respectively. Reactivity index (RI) against both proteins showed an age-dependent increase. IgG2 was the predominant subclass and the antibody avidity index evaluated by ELISA ranged between 4-6 mol/L.
