Nanotechnology Synergised Immunoengineering for Cancer

Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic. As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies avail in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment

Liposomal nanotheranostics for multimode targeted in vivo bioimaging and near‐infrared light mediated cancer therapy

Developing a nanotheranostic agent with better image resolution and high accumulation into solid tumor microenvironment is a challenging task. Herein, we established a light mediated phototriggered strategy for enhanced tumor accumulation of nanohybrids. A multifunctional liposome based nanotheranostics loaded with gold nanoparticles (AuNPs) and emissive graphene quantum dots (GQDs) were engineered named as NFGL. Further, doxorubicin hydrochloride was encapsulated in NFGL to exhibit phototriggered chemotherapy and functionalized with folic acid targeting ligands. Encapsulated agents showed imaging bimodality for in vivo tumor diagnosis due to their high contrast and emissive nature. Targeted NFGL nanohybrids demonstrated near infrared light (NIR, 750 nm) mediated tumor reduction because of generated heat and Reactive Oxygen Species (ROS). Moreover, NFGL nanohybrids exhibited remarkable ROS scavenging ability as compared to GQDs loaded liposomes validated by antitumor study. Hence, this approach and engineered system could open new direction for targeted imaging and cancer therapy.publishersversionpublishe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Effect of Environmental Changes on Phenology and Reproductive Biology of Sida cordifolia with Special Reference to the Temperature and Relative Humidity

Impact of environmental factors (temperature and relative humidity) on phenology and reproductive biology of a medicinal plant Sida cordifolia L. growing at district Agra was studied. The study revealed that phenological events (leaf fall, leaf renewal, flowering and fruiting) varied considerably with the fluctuations in temperature and relative humidity. Flowering was observed throughout the year with maximum in the months of February-April (11.8 – 38.3ºC) and August-September (24.4- 33.9ºC). Floral biology studies showed that pollen viability, pollen-ovule ratio and fruit-set percentage was greatly reduced with rise or fall in temperature and relative humidity. The maximum pollen fertility (71%), fruit-set (70- 90%) and pollen-ovule ratio (190:1) was recorded in the month of March when temperature was ranging between 15.1-32.6ºC with 22- 76% RH. With the fall in temperature in the month of January (6.8 - 17.9ºC) the pollen fertility was reduced to 52%. At the end of April 32.5- 45.3ºC with 16- 43% RH, the plants under observation exhibited a gradual decline in fruit-set percentage (45- 55%). The anthesis, anther dehiscence and stigma receptivity also varied during the entire flowering period. As the temperature rises, the anthesis takes place earlier and the time of anther dehiscence and stigma receptivity changed accordingly. In this investigation it was found that the changes in temperature and relative humidity during the entire flowering period was associated with the variation in different phenological and reproductive events in the Sida cordifolia plant

Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes

Background: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. Results: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. Conclusions: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.ZonMWNetherlands Organization for Health Research and Development 40-00812-98-10042Maag Lever Darm stichting WO09-62NIHUnited States Department of Health & Human Services National Institute

Comprehensive Review on Current Interventions, Diagnostics, and Nanotechnology Perspectives against SARS-CoV-2

COVID-19 has dramatically challenged the healthcare system of almost all countries. The authorities are struggling to minimize the mortality along with ameliorating the economy downturn. Unfortunately, till now, there has been no promising medicine or vaccine available. Herein, we deliver a perspective of nanotechnology for increasing the specificity and sensitivity of current interventional platforms towards the urgent need of quickly deployable solutions. This review summarizes the recent involvement of nanotechnology from the development of biosensor to fabrication of multifunctional nanohybrid system practiced for respiratory and deadly viruses, along with the recent interventions and current understanding about SARS-CoV2

The somatic mutation paradigm in congenital malformations: Hirschsprung disease as a model

Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested—whole blood, dermal fibroblasts or saliva—but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to ‘missing heritability’ in developmental defects