Trametinib potentiates anti-PD-1 efficacy in tumors established from chemotherapy-primed pancreatic cancer cells.

Despite advances in immune checkpoint inhibitors (ICIs), chemotherapy remains the standard therapy for patients with pancreatic ductal adenocarcinoma (PDAC). As the combinations of chemotherapy, including the FOLFIRINOX (5-fluorouracil (5FU), irinotecan, and oxaliplatin) regimen, and ICIs have failed to demonstrate clinical benefit in patients with metastatic PDAC tumors, there is increasing interest in identifying therapeutic approaches to potentiate ICI efficacy in PDAC patients. In this study, we report that neoadjuvant FOLFRINOX-treated human PDAC tumors exhibit increased MEK/ERK activation. We also show elevated MEK/ERK signaling in ex vivo PDAC slice cultures and cell lines treated with a combination of 5FU (F), irinotecan (I), and oxaliplatin (O) (FIO). In addition, we find that the KPC-FIO cells, established from repeated treatment of mouse PDAC cell lines with 6-8 cycles of FIO, display enhanced ERK phosphorylation and demonstrate increased sensitivity to MEK inhibition in vitro and in vivo. Significantly, the KPC-FIO cells develop tumors with a pro-inflammatory immune profile similar to human PDAC tumors following neoadjuvant FOLFIRINOX treatment. Furthermore, we found that the MEK inhibitor Trametinib enables additional infiltration of highly functional CD8+ T cells into the KPC-FIO tumors and potentiates the efficacy of anti-PD-1 antibody in syngeneic mouse models. Our findings provide a rationale for combining Trametinib and anti-PD-1 antibodies in PDAC patients following neoadjuvant or short-term FOLFIRINOX treatment to achieve effective anti-tumor responses.

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications.

Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.

Corrigendum: Selective Targeting of 4SO4-N-Acetyl-Galactosamine Functionalized Mycobacterium tuberculosis Protein Loaded Chitosan Nanoparticle to Macrophages: Correlation With Activation of Immune System.

[This corrects the article DOI: 10.3389/fmicb.2018.02469.].

Selective Targeting of 4SO4-N-Acetyl-Galactosamine Functionalized Mycobacterium tuberculosis Protein Loaded Chitosan Nanoparticle to Macrophages: Correlation With Activation of Immune System.

In the present study, we investigated potential of chitosan-based nanoparticles (CNPs) to deliver loaded therapeutic molecules to pathogen harboring macrophages. We fabricated stable CNPs employing ionic cross-linking method and evaluated their potential to target RAW 264.7 cells. The physicochemical characterization of as-synthesized CNPs was determined using electron microscopy, infrared microscopy and zeta potential measurement. Next, cellular uptake and intracellular localization studies of CNPs were followed in living RAW264.7 cells using confocal microscopy. We found that both Acr-1 loaded (CNP-A) and 4-SO4-GalNAc ligand harboring (CNP-L) chitosan nanoparticle experience increased cellular uptake by Mycobacterium smegmatis infected RAW cells. Following cellular digestion in model macrophage cell line (RAW), CNPs provide an increased immune response. Further, 4-SO4-GalNAc bearing CNP-L exhibits high binding affinity as well as antibacterial efficacy toward M. smegmatis. The data of the present study suggest that CNP-based nanoparticle offer a promising delivery strategy to target infected macrophages for prevention and eradication of intracellular pathogens such as M. smegmatis.

Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages.

Mycobacterium tuberculosis (M.tb) contrives intracellular abode as a strategy to combat antibody onslaught. Additionally, to thrive against hostile ambiance inside host macrophages, the pathogen inhibits phago-lysosomal fusion. Finally, to further defy host cell offensives, M.tb opts for dormant phase, where it turns off or slows down most of its metabolic process as an added stratagem. While M.tb restrains most of its metabolic activities during dormancy, surprisingly latency-associated alpha-crystallin protein (Acr-1) is expressed most prominently during this phase. Interestingly, several previous studies described the potential of Acr-1 to induce the robust immuno-prophylactic response in the immunized host. It is intriguing to comprehend the apparent discrepancy that the microbe M.tb overexpresses a protein that has the potential to prime host immune system against the pathogen itself. Keeping this apparent ambiguity into consideration, it is imperative to unravel intricacies involved in the exploitation of Acr-1 by M.tb during its interaction with host immune cells. The present study suggests that Acr-1 exhibits diverse role in the maturation of macrophages (MΦs) and related immunological responses. The early encounter of bone marrow derived immune cells (pre-exposure during differentiation to MΦs) with Acr-1 (AcrMΦpre), results in hampering of their function. The pre-exposure of naïve MΦs with Acr-1 induces the expression of TIM-3 and IL-10. In contrast, exposure of fully differentiated MΦs to Acr-1 results in their down-modulation and induces the phosphorylation of STAT-1 and STAT-4 in host MΦs. Furthermore, Acr-1 mediated activation of MΦs results in the induction of Th1 and Th17 phenotype by activated T lymphocyte.

Genome sequencing, assembly, annotation and analysis of Staphylococcus xylosus strain DMB3-Bh1 reveals genes responsible for pathogenicity.

BACKGROUND: Staphylococcus xylosus is coagulase-negative staphylococci (CNS), found occasionally on the skin of humans but recurrently on other mammals. Recent reports suggest that this commensal bacterium may cause diseases in humans and other animals. In this study, we present the first report of whole genome sequencing of S. xylosus strain DMB3-Bh1, which was isolated from the stool of a mouse. RESULTS: The draft genome of S. xylosus strain DMB3-Bh1 consisted of 2,81,0255 bp with G+C content of 32.7 mol%, 2623 predicted coding sequences (CDSs) and 58 RNAs. The final assembly contained 12 contigs of total size 2,81,0255 bp with N50 contig length of 4,37,962 bp and the largest contig assembled measured 7,61,338 bp. Further, an interspecies comparative genomic analysis through rapid annotation using subsystem technology server was achieved with Staphylococcus aureus RF122 that revealed 36 genes having similarity with S. xylosus DMB3-Bh1. 35 genes encoded for virulence, disease and defense and 1 gene encoded for phages, prophages and transposable elements. CONCLUSIONS: These results suggest co linearity in genes between S. xylosus DMB3-Bh1 and S. aureus RF122 that contribute to pathogenicity and might be the result of horizontal gene transfer. The study indicates that S. xylosus DMB3-Bh1 may be a potential emerging pathogen for rodents.

Erratum to: Genome sequencing, annotation and comparative genomic analysis of Shigella dysenteriae strain SD1D.

[This corrects the article DOI: 10.1186/1757-4749-6-28.].

Genome sequencing, annotation and comparative genomic analysis of Shigella dysenteriae strain SD1D.

BACKGROUND: Shigellosis is an acute form of gastroenteritis caused by the bacteria belonging to the genus Shigella. It is the most common cause of morbidity and mortality in children. Shigella belongs to the family Enterobactericeae, which is a Gram-negative and rod shaped bacterium. In the present study, we report the draft genome of Shigella dysenteriae strain SD1D, which was isolated from the stool sample of a healthy individual. RESULTS: Based on 16S rRNA gene sequence and phylogenetic analysis, the strain SD1D was identified as Shigella dysenteriae. The draft genome of SD1D consisted of 45, 93, 159 bp with a G + C content of 50.7%, 4, 960 predicted CDSs, 75 tRNAs and 2 rRNAs. The final assembly contained 146 contigs of total length 45, 93, 159 bp with N50 contig length of 77, 053 bp; the largest contig assembled measured 3, 85, 550 bp. CONCLUSIONS: We have for the first time performed the whole genome sequencing of Shigella dysenteriae strain SD1D. The comparative genomic analysis revealed several genes responsible for the pathogenesis, virulence, defense, resistance to antibiotics and toxic compounds, multidrug resistance efflux pumps and other genomic features of the bacterium.

Genome sequencing, annotation and analysis of Salmonella enterica sub species salamae strain DMA-1.

BACKGROUND: The genus Salmonella is Gram-negative which belongs to the family Enterobacteriaceae. In this study, we have sequenced the whole genome of the strain DMA-1, which was isolated from mouse stool sample and identified as Salmonella enterica subspecies salamae. RESULTS: The strain DMA-1 was closely related at the 16S rRNA gene sequence level with the members of the genus Salmonella: Salmonella enterica subspecies salamae DSM 9220T (100%), followed by Salmonella enterica subspecies diarizonae (99.1%), Salmonella enterica subspecies enterica (99.0%) and Salmonella enterica subspecies indica (98.5%). We obtained the draft genome of S. enterica subspecies salamae strain DMA-1 with a size of 4,826,209 bp and mean G+C content of 52.0 mol%. CONCLUSIONS: We for the first time, sequenced the entire genome of the strain DMA-1 which was isolated from the mouse stool sample and identified it as Salmonella enterica, sub species salamae. Further, we subjected the whole genome sequencing data for annotation that revealed several genes responsible for the pathogenesis, virulence, defense, metabolism and other genomic features.