Nanoengineering Solutions for Cancer Therapy: Bridging the Gap between Clinical Practice and Translational Research.

Nanoengineering has emerged as a progressive method in cancer treatment, offering precise and targeted delivery of therapeutic agents while concurrently reducing overall toxicity. This scholarly article delves into the innovative strategies and advancements in nanoengineering that bridge the gap between clinical practice and research in the field of cancer treatment. Various nanoengineered platforms such as nanoparticles, liposomes, and dendrimers are scrutinized for their capacity to encapsulate drugs, augment drug efficacy, and enhance pharmacokinetics. Moreover, the article investigates research breakthroughs that drive the progression and enhancement of nanoengineered remedies, encompassing the identification of biomarkers, establishment of preclinical models, and advancement of biomaterials, all of which are imperative for translating laboratory findings into practical medical interventions. Furthermore, the integration of nanotechnology with imaging modalities, which amplify cancer detection, treatment monitoring, and response assessment, is thoroughly examined. Finally, the obstacles and prospective directions in nanoengineering, including regulatory challenges and issues related to scalability, are examined. This underscores the significance of fostering collaboration among various entities in order to efficiently translate nanoengineered interventions into enhanced cancer therapies and patient management.

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

A Web Application for Predicting Drug Combination Efficacy Using Monotherapy Data and IDACombo.

We recently reported a computational method (IDACombo) designed to predict the efficacy of cancer drug combinations using monotherapy response data and the assumptions of independent drug action. Given the strong agreement between IDACombo predictions and measured drug combination efficacy in vitro and in clinical trials, we believe IDACombo can be of immediate use to researchers who are working to develop novel drug combinations. While we previously released our method as an R package, we have now created an R Shiny application to allow researchers without programming experience to easily utilize this method. The app provides a graphical interface which enables users to easily generate efficacy predictions with IDACombo using provided data from several high-throughput cell line screens or using custom, user-provided data.

Simplicity: web-based visualization and analysis of high-throughput cancer cell line screens.

High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatic skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high-throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity's outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.

Canonical Wnt signaling regulates soft palate development by mediating ciliary homeostasis.

Craniofacial morphogenesis requires complex interactions involving different tissues, signaling pathways, secreted factors and organelles. The details of these interactions remain elusive. In this study, we have analyzed the molecular mechanisms and homeostatic cellular activities governing soft palate development to improve regenerative strategies for individuals with cleft palate. We have identified canonical Wnt signaling as a key signaling pathway primarily active in cranial neural crest (CNC)-derived mesenchymal cells surrounding soft palatal myogenic cells. Using Osr2-Cre;ß-cateninfl/fl mice, we show that Wnt signaling is indispensable for mesenchymal cell proliferation and subsequently for myogenesis through mediating ciliogenesis. Specifically, we have identified that Wnt signaling directly regulates expression of the ciliary gene Ttll3. Impaired ciliary disassembly leads to differentiation defects in mesenchymal cells and indirectly disrupts myogenesis through decreased expression of Dlk1, a mesenchymal cell-derived pro-myogenesis factor. Moreover, we show that siRNA-mediated reduction of Ttll3 expression partly rescues mesenchymal cell proliferation and myogenesis in the palatal explant cultures from Osr2-Cre;ß-cateninfl/fl embryos. This study highlights the role of Wnt signaling in palatogenesis through the control of ciliary homeostasis, which establishes a new mechanism for Wnt-regulated craniofacial morphogenesis.

Simplicity: Web-Based Visualization and Analysis of High-Throughput Cancer Cell Line Screens.

High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatics skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high- throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity's outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.

TGF-ß signaling and Creb5 cooperatively regulate Fgf18 to control pharyngeal muscle development.

The communication between myogenic cells and their surrounding connective tissues is indispensable for muscle morphogenesis. During late embryonic development in mice, myogenic progenitors migrate to discrete sites to form individual muscles. The detailed mechanism of this process remains unclear. Using mouse levator veli palatini (LVP) development as a model, we systematically investigated how a distinct connective tissue subpopulation, perimysial fibroblasts, communicates with myogenic cells to regulate mouse pharyngeal myogenesis. Using single-cell RNAseq data analysis, we identified that TGF-ß signaling is a key regulator for the perimysial fibroblasts. Loss of TGF-ß signaling in the neural crest-derived palatal mesenchyme leads to defects in perimysial fibroblasts and muscle malformation in the soft palate in Osr2Cre;Tgfbr1fl/fl mice. In particular, Creb5, a transcription factor expressed in the perimysial fibroblasts, cooperates with TGF-ß signaling to activate expression of Fgf18. Moreover, Fgf18 supports pharyngeal muscle development in vivo and exogenous Fgf18 can partially rescue myogenic cell numbers in Osr2Cre;Tgfbr1fl/fl samples, illustrating that TGF-ß-regulated Fgf18 signaling is required for LVP development. Collectively, our findings reveal the mechanism by which TGF-ß signaling achieves its functional specificity in defining the perimysial-to-myogenic signals for pharyngeal myogenesis.

Epithelial miR-215 negatively modulates Th17-dominant inflammation by inhibiting CXCL12 production in the small intestine.

MicroRNAs are a class of non-coding short-chained RNAs that control cellular functions by downregulating their target genes. Recent research indicates that microRNAs play a role in the maintenance of gut homeostasis. miR-215 was found to be highly expressed in epithelial cells of the small intestine; however, the involvement of miR-215 in gut immunity remains unknown. Here, we show that miR-215 negatively regulates inflammation in the small intestine by inhibiting CXCL12 production. Mice lacking miR-215 showed high susceptibility to inflammation induced by indomethacin, accompanied by an increased number of Th17 cells in the lamina propria of the small intestine. Our findings provide a rationale for targeting miR-215 as a therapeutic intervention for inflammatory conditions in the small intestine.

Oncogene or tumor suppressor? Long noncoding RNAs role in patient's prognosis varies depending on disease type.

Functional studies of long noncoding RNAs (lncRNAs) are often performed in the context of only a single cancer type. However, the tissue-specific expression patterns of lncRNAs raise the question of whether lncRNA associations identified in one cancer type are relevant to other cancer types. Here, we examine the relationships between the expression levels of 50 cancer-related lncRNAs and survival data from 24 types of cancer in The Cancer Genome Atlas (TCGA) with the goal of identifying prognosis related lncRNAs. Our results suggest that high expression levels of certain lncRNAs are consistently associated with worse/better survival in a number of cancers, while other lncRNAs have different prognostic roles in different types of cancer. Our analysis also identifies 20 novel unadjusted associations that have not been reported before. In addition, in low-grade glioma (LGG), prognostic-related lncRNAs are identified after conditioning on known clinical biomarker and common therapy, revealing that 2 lncRNAs, FOXP4-AS1, and NEAT1, are associated with temozolomide response-a standard-of-care in LGG. Pathway analysis suggests NF-kB/STAT3 signaling pathway enrichment in LGG patients with high NEAT1 expression and DNA repair/myc gene set enrichment in LGG patients with high expression of FOXP4-AS1. Our work demonstrates the context dependency of lncRNAs across cancer types and highlights a number of lncRNAs as potential novel cancer prognosis markers.

Comparison of Japanese and Indian intestinal microbiota shows diet-dependent interaction between bacteria and fungi.

The bacterial species living in the gut mediate many aspects of biological processes such as nutrition and activation of adaptive immunity. In addition, commensal fungi residing in the intestine also influence host health. Although the interaction of bacterium and fungus has been shown, its precise mechanism during colonization of the human intestine remains largely unknown. Here, we show interaction between bacterial and fungal species for utilization of dietary components driving their efficient growth in the intestine. Next generation sequencing of fecal samples from Japanese and Indian adults revealed differential patterns of bacterial and fungal composition. In particular, Indians, who consume more plant polysaccharides than Japanese, harbored increased numbers of Prevotella and Candida. Candida spp. showed strong growth responses to the plant polysaccharide arabinoxylan in vitro. Furthermore, the culture supernatants of Candida spp. grown with arabinoxylan promoted rapid proliferation of Prevotella copri. Arabinose was identified as a potential growth-inducing factor in the Candida culture supernatants. Candida spp. exhibited a growth response to xylose, but not to arabinose, whereas P. copri proliferated in response to both xylose and arabinose. Candida spp., but not P. copri, colonized the intestine of germ-free mice. However, P. copri successfully colonized mouse intestine already harboring Candida. These findings demonstrate a proof of concept that fungal members of gut microbiota can facilitate a colonization of the intestine by their bacterial counterparts, potentially mediated by a dietary metabolite.

MiR-155 induction in microglial cells suppresses Japanese encephalitis virus replication and negatively modulates innate immune responses.

BACKGROUND: Microglial cells, which are resident macrophages of the central nervous system, play important roles in immune responses and pathogenesis. Japanese encephalitis virus (JEV) is a neurotropic virus that infects microglial cells in brain. Several microRNAs including miR-155 and miR-146a play an important role in defining the microglia inflammatory profile. In this study, we have investigated the effect of miR-155 and miR-146a modulation on JEV infection as well as innate immune responses in human microglial cells. METHODS: In vitro studies were performed in JEV-infected human microglial CHME3 cells. miR-155 or miR-146a were overexpressed and total RNA and protein were extracted following JEV-infection. Expression of genes involved in innate immune responses was studied by PCR array, quantitative real-time PCR (qPCR), western blot and Fluorescence activated cell sorter (FACS). JEV replication was monitored by studying the viral RNA by qPCR, protein by western blot, and titres by plaque assay. RESULTS: Overexpression of miR-155 in CHME3 cells resulted in significantly reduced JEV replication whereas miR-146a overexpression had an insignificant effect. Additionally, interferon regulatory factor 8 (IRF8) and complement factor H (CFH) were induced during JEV infection; however, this induction was attenuated in miR-155 overexpressing cells following JEV infection. Further, JEV-induced NF-κB regulated downstream gene expression was attenuated. Interestingly, an increased level of CD45, a negative regulator of microglia activation and a reduced phosphorylated-Signal Transducers and Activators of Transcription (p-STAT1) expression was observed in miR-155 overexpressing cells upon JEV infection. CONCLUSION: Induction of miR-155 in human microglial cells may negatively modulate JEV-induced innate immune gene expression and may have a beneficial role in limiting JEV replication in human microglial cells.

Exiguobacterium himgiriensis sp. nov. a novel member of the genus Exiguobacterium, isolated from the Indian Himalayas.

The taxonomic position of an orange coloured bacterium, strain K22-26(T) isolated from a soil sample was studied using a polyphasic approach. The organism had phenotypic and chemotaxonomic properties consistent with its allocation into the genus Exiguobacterium. Phylogenetic analysis of the 16S rRNA gene sequence showed that strain K22-26(T) belongs to the genus Exiguobacterium and was related to Exiguobacterium aurantiacum DSM 6208(T) (99.0 %) Exiguobacterium mexicanum DSM 16483(T) (98.6 %), Exiguobacterium aquaticum (98.6 %), Exiguobacterium aestuarii DSM 16306(T) (98.1 %), Exiguobacterium profundum DSM 17289(T) (98.1 %) and Exiguobacterium marinum DSM 16483(T) (97.9 %), whereas sequence similarity values with respect to other Exiguobacterium species with validly published names were between 92.5-94.0 %. The major polar lipids detected were phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The major menaquinone was determined to be MK-7 (83 %) whereas MK-8 (11 %) and MK-6 (6 %) occur in smaller amounts. The peptidoglycan of the strain was found to contain L-lysine as the diagnostic diamino acid. The major fatty acids detected were iso C13:0 (11.2 %), anteiso C13:0 (15.4 %), iso C15:0 (13.2 %) and iso C17:0 (16.1 %). However, analysis of the DNA-DNA relatedness confirmed that strain K22-26(T) belongs to a novel species. The G + C content of the strain K22-26(T) was determined to be 50.1 mol %. The novel strain was distinguished from closely related type species of the genus Exiguobacterium using DNA-DNA relatedness and phenotypic data. Based on these differences, the strain K22-26(T) should be classified as a novel species of the genus Exiguobacterium, for which the name Exiguobacterium himgiriensis sp. nov. strain K22-26(T) (= MTCC 7628(T) = JCM 14260(T)) is proposed.

Nitratireductor lucknowense sp. nov., a novel bacterium isolated from a pesticide contaminated soil.

A straw-yellow pigmented bacterium, strain IITR-21(T) was isolated from a pesticide contaminated site and characterized by using a polyphasic taxonomic approach. The organism had morphological and chemotaxonomic properties consistent with its classification in the genus Nitratireductor. Phylogenetic analysis of the 16S rRNA gene sequence showed that the strain IITR-21(T) belongs to the genus Nitratireductor and was moderately related to Nitratireductor indicus C115(T) (97.7%) and Nitratireductor pacificus pht-3B(T) (97.4%), whereas sequence similarity value with the other species including the type species of the genus Nitratireductor, Nitratireductor aquibiodomus showed less than 97.0% similarity. However, the DNA-DNA relatedness values between strain IITR-21(T) and the moderately related taxa N. indicus (59.1%) and N. pacificus (40.4%) were well below the 70% threshold value recommended for the delineation of bacterial species. The G+C content of the DNA was 62.4 mol%. Based on physiological, biochemical tests and genotypic differences between the strain IITR-21(T) and the other two validly published species of the genus Nitratireductor, it is proposed that the strain be classified as a new species of Nitratireductor as Nitratireductor lucknowense sp. nov. The type strain is IITR-21(T) (=MTCC 8354(T )= DSM 24322(T)).

Exiguobacterium aquaticum sp. nov., a member of the genus Exiguobacterium.

A Gram-positive, motile, short rod-shaped, orange pigmented bacterium, designated strain IMTB-3094(T), was isolated from a water sample collected from Tikkar Tal Lake, Haryana, and subjected to detailed polyphasic taxonomic analysis. Strain IMTB-3094(T) possessed most of the phenotypic and chemotaxonomic properties of the genus Exiguobacterium and, based on 16S rRNA gene sequence analysis, was assigned to this genus. Strain IMTB-3094(T) exhibited the highest 16S rRNA gene sequence similarity to Exiguobacterium mexicanum MTCC 7759(T) (99.5 %) followed by Exiguobacterium aurantiacum MTCC 6414(T) (99.1 %), Exiguobacterium aestuarii MTCC 7750(T) (98.0 %), Exiguobacterium profundum MTCC 10851(T) (98.0 %) and Exiguobacterium marinum MTCC 7751(T) (98.0 %). The G+C content of the genomic DNA of strain IMTB-3094(T) was 53.2 mol% and a DNA-DNA relatedness study confirmed that it represents a novel species. The major fatty acids of strain IMTB-3094(T) were iso-C(17 : 0) (16.1 %), anteiso-C(13 : 0) (19.0 %), iso-C(13 : 0) (11.9 %), iso-C(15 : 0) (9.8 %) and iso-C(17 : 1) (12.7 %). The predominant quinones were MK-7 (55.0 %) and MK-6 (26.0 %) with minor amounts of MK-8 (12.0 %). Based on phenotypic, chemotaxonomic and phylogenetic analyses, strain IMTB-3094(T) represents a novel species of the genus Exiguobacterium, for which the name Exiguobacterium aquaticum sp. nov. is proposed. The type strain is IMTB-3094(T) (= MTCC 10958(T) = JCM 17977(T)).