Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth.

Cancer immunotherapy has seen significant success in the last decade for cancer management by enhancing endogenous cancer immunity. However, immunotherapies developed thus far have seen limited success in the majority of high-grade serous carcinoma (HGSC) ovarian cancer patients. This is largely due to the highly immunosuppressive tumour microenvironment of HGSC and late-stage identification. Thus, novel treatment interventions are needed to overcome this immunosuppression and complement existing immunotherapies. Here, we have identified through analysis of > 600 human HGSC tumours a critical role for Let-7i in modulating the tumoural immune network. Tumoural expression of Let-7i had high positive correlation with anti-cancer immune signatures in HGSC patients. Confirming this role, enforced Let-7i expression in murine HGSC tumours resulted in a significant decrease in tumour burden with a significant increase in tumour T cell numbers in tumours. In concert with the improved tumoural immunity, Let-7i treatment also significantly increased CD86 expression in antigen presenting cells (APCs) in the draining lymph nodes, indicating enhanced APC activity. Collectively, our findings highlight an important role of Let-7i in anti-tumour immunity and its potential use for inducing an anti-tumour effect in HGSC.

miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration.

Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53-/- and IG10 murine HGSC models. Increasing miR-146a expression in tumors improved anti-tumor immune responses by decreasing immune suppressive neutrophils and increasing CTL infiltration. Mechanistically, miR-146a targets IL-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6 adaptor molecules of the transcription factor nuclear factor κB signaling pathway in ID8-p53-/- cells and decreases production of the downstream neutrophil chemoattractant, C-X-C motif chemokine ligand 1. In addition to HGSC, tumoral miR-146a expression also correlates strongly with CTL infiltration in other cancer types including thyroid, prostate, breast, and adrenocortical cancers. Altogether, our findings highlight the ability of miR-146a to overcome immune suppression and improve CTL infiltration in tumors.

Nano-therapeutics for modulating the tumour microenvironment: Design, development, and clinical translation.

Nanoparticles (NPs) that permit active targeting promise to play a key role in cancer therapy moving forward. However, in order to successfully advance into clinic, these delivery platforms not only must target individual tumoural cellular components but also require safe, efficient and scalable production. Herein, we review recent and innovative targeted nanoparticle delivery strategies to individual TME components, including cancer-associated blood and lymphatic vessels, pericytes, cancer associated fibroblasts, and cancer stem cells. In contrast to traditional therapies that promote widespread ablation, emerging nano-strategies that specifically modulate different cell populations of the TME, such as targeting pericytes and endothelial cells for vascular normalization, are proving to effectively deliver therapeutics to tumours. Additionally, new smart targeted NPs with transformable characteristics responsive to specific tumour microenvironmental cues demonstrate enhanced spatiotemporal control over cell targeting and therapeutic release. However, translating these therapies to the clinic requires overcoming several significant barriers such as failure to recapitulate the human TME in animal models and issues with NP targeting efficacy, safety and scalable production. We discuss recent efforts to overcome these challenges and innovative means to reduce off-target toxicities. We also highlight important deficiencies in current NP development and offer new perspectives on the design of pre-clinical and clinical trials to accelerate clinical translation of targeted NP platforms.

Novel therapeutic approaches for targeting TB and HIV reservoirs prevailing in lungs.

INTRODUCTION: Coinfection with Mycobacterium tuberculosis is the leading cause of death in HIV positive patients. In 2017, about 0.3 million HIV positive people died of tuberculosis. There is high load of mycobacteria and HIV in the lungs and eradication of the same is vital for patient survival. AREAS COVERED: This review focuses on the pathogenesis of HIV-TB coinfection and the current management approaches of this coinfection. It presents a detailed discussion of current investigations in novel drug delivery systems for effective targeting of HIV-TB lung reservoirs, especially via pulmonary drug delivery. Additionally, emphasis is given to the need of HIV-TB cotargeting, an unmet need in management of HIV-TB coinfection. EXPERT OPINION: To achieve the goal of complete eradication of HIV-TB reservoirs in lungs requires focused research strategies to be undertaken in the area of pulmonary delivery systems. These endeavors could eventually lead to better patient compliance and improved treatment outcomes. The treatment regimen of HIV-TB coinfection is associated with a major drawback of low therapeutic concentration of drugs in lungs. Nanotechnology provides an excellent platform for delivery of anti-TB and anti-HIV drugs via the pulmonary route thereby serving as a viable and effective means of managing the mycobacterial and HIV reservoirs in the lungs.

Selective drug deposition in lungs through pulmonary drug delivery system for effective management of drug-resistant TB.

INTRODUCTION: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is a major health issue and continues to be a global health concern. Despite significant advancements in treatment modalities, ~1.6 million deaths worldwide occur due to TB infection. This is because of tuberculosis reservoirs in the alveoli making it a challenge for the formulation scientist to target this. AREAS COVERED: This review recent investigations on the forefront of pulmonary drug delivery for managing MDR-TB and XDR-TB. Novel delivery systems like liposomes, niosomes, employing carbohydrate, and -coated molecules via conjugation to selectively deliver the drugs to the lung TB reservoir via pulmonary administration are discussed. EXPERT OPINION: Poor patient adherence to treatment due to side effects and extended therapeutic regimen leads to drug-resistant TB. Thus, it is essential to design novel strategies this issue by developing new chemical entities and/or new delivery systems for delivery to the lungs, consequently reducing the side effects, the frequency and the duration of treatment. Delivery of drugs to enhance the efficacy of new/existing anti-TB drugs to overcome the resistance and enhance patient compliance is underway.

Polymeric Lipid Hybrid Nanoparticles: Properties and Therapeutic Applications.

Some of the criteria for selection of a viable nanocarrier formulation currently being explored are the development of a site-specific and bioavailable formulation. Although the literature reports a variety of techniques for fabrication of nanocarrier systems, their stability and scale-up issues are a concern for their prominence in the pharmaceutical industry. The other widely recognized drawbacks of nanoparticulates, i.e., polymeric nanoparticles and lipid vesicular nanoparticles (liposomes), are low circulatory half-lives due to reticuloendothelial system (RES) uptake and leaky architecture leading to burst kinetics. Polymeric lipid hybrid nanoparticles (PLHNs) or lipomers are the recent advancement in nanodrug delivery systems composed of a polymeric core and lipid shell which imparts physicochemical stability and biocompatibility to the nanoparticles. The lipomers are a blend of positive attributes of both liposomes and polymeric nanoparticles wherein their individual innate flaws are negated. An extensive study of PLHN was engineered using single/two or multiple methods carried out for encapsulation efficiency, physicochemical properties, and stability. The influence of shape and composition of PLHN has also shown promising results in terms of reticuloendothelial uptake. These PLHNs have shown to hold a promising place in designing drug delivery systems for the treatment of cancer and infectious diseases as well as for theranostic purposes. The present review article encompasses various types of PLHNs, their physicochemical characteristics, and their applications as future perspectives in strategizing drug delivery to their desired sites of action.

Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies.

INTRODUCTION: Tumor is a heterogeneous mass of malignant cells co-existing with non-malignant cells. This co-existence evolves from the initial developmental stages of the tumor and is one of the hallmarks of cancer providing a protumorigenic niche known as tumor microenvironment (TME). Proliferation, invasiveness, metastatic potential and maintenance of stemness through cross-talk between tumors and its stroma forms the basis of TME. AREAS COVERED: The article highlights the developmental phases of a tumor from dysplasia to the formation of clinically detectable tumors. The authors discuss the mechanistic stages involved in the formation of TME and its contribution in tumor outgrowth and chemoresistance. The authors have reviewed various approaches for targeting TME and its hallmarks along with their advantages and pitfalls. The authors also highlight cancer stem cells (CSCs) that are resistant to chemotherapeutics and thus a primary reason for tumor recurrence thereby, posing a challenge for the oncologists. EXPERT OPINION: Recent understanding of the cellular and molecular mechanisms involved in acquired chemoresistance has enabled scientists to target the tumor niche and TME and modulate and/or disrupt this communication leading to the transformation from a tumor-supportive niche environment to a tumor-non-supporting environment and give synergistic results towards an effective management of cancer.

Current and novel approaches for control of dental biofilm.

Insights in oral demographics have revealed that a significant percentage of population faces chronic incidences of oral diseases. The innervation of these oral manifestations is required because untreated conditions may lead to bone loss in the oral cavity and systemic complications. Conventional treatments include surgery of the affected area followed by its management and/or treatment with antibiotics. However, widely used antibiotics like Triclosan have serious side effects including down-regulation of oral keratinocytes and fibroblasts. Thus, novel treatments with more targeted approaches have been under investigation. Treatment modalities like Viral mediated gene delivery, liposomes, nanoparticles, and nanobubbles not only help in management of oral diseases but also aid in reducing the biofilm formed due to bacterial bioburden in the areas less accessible through oral and conventional means. This review focuses on the limitation of conventional treatments and highlights the recent investigations in the use of the novel treatment approaches in order to increase the patient compliance and alleviation of side effects. The authors have also tried to emphasize on the future perspectives of glucansucrase inhibitors, photodynamic therapy and probiotics as targeted drug delivery systems. However, further investigations are necessary for implementation of these novel approaches in the clinical setup.

Toxic Brain Injury with Nitrobenzene Poisoning.

Acute methemoglobinemia secondary to nitrobenzene ingestion is a rare but well-known clinical entity. It is extremely important to identify such patients as rapid and effective management with methylene blue and other supportive measures will often save these lives. We present a rare and unfortunate case of a girl who developed acute toxic brain injury following nitrobenzene ingestion and succumbed.

Functionalized and graft copolymers of chitosan and its pharmaceutical applications.

INTRODUCTION: Chitosan is the second most abundant natural polysaccharide. It belongs a family of polycationic polymers comprised of repetitive units of glucosamine and N-acetylglucosamine. Its biodegradability, nontoxicity, non-immunogenicity and biocompatibility along with properties like mucoadhesion, fungistatic and bacteriogenic have made chitosan an appreciated polymer with numerous applications in the pharmaceutical, comestics and food industry. However, the limited solubility of chitosan at alkaline and neutral pH limits its widespread commercial use. This can be circumvented by fabrication of chitosan by graft copolymerization with acyl, alkyl, monomeric and polymeric moieties. Areas covered: Modifications like quarterization, thiolation, acylation and grafting result in copolymers with higher mucoadhesion strength, increased hydrophobic interactions (advantageous in hydrophobic drug entrapment), and increased solubility in alkaline pH, the ability for adsorption of metal ions, protein and peptide delivery and nutrient delivery. Insights on methods of polymerization, including atomic transfer radical polymerization and click chemistry are discussed. Applications of such modified chitosan copolymers in medical and surgical, and drug delivery, including nasal, oral and buccal delivery have also been covered. Expert opinion: Despite a number of successful investigations, commercialization of chitosan copolymers still remains a challenge. Further advancements in polymerization techniques may address the unmet needs of the healthcare industry.

Oral Squamous Cell Carcinoma: Current Treatment Strategies and Nanotechnology-Based Approaches for Prevention and Therapy.

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer; it involves damage to oral epithelial cells due to accumulation of multiple genetic mutations in the cells. OSCC remains major cause of morbidity and mortality in patients with head and neck cancers. Tobacco, smoking, alcohol consumption alone or with chewing tobacco, and betel quid are potential carcinogens contributing to the high occurrence of OSCC. Current treatment modalities for OSCC like chemoradiotherapy, surgery, EGFR inhibitors and COX-2 inhibitors, and photodynamic therapy have led to the major problems related to non-specific cell death. Nanoengineered systems offer solutions to these problems that not only minimize the major drawbacks of nonspecific cell death but also maximize the efficacy of the cancer therapeutic agents. Various efficacious nanotechnology-based carrier systems are being widely investigated for their potential in OSCC treatment: polymeric nanoparticles, polymeric micelles, nanoemulsions and layered nanoemulsions, nanoliposomes, solid lipid nanoparticles and nanolipid carriers, cyclodextrin complexes, hydrogels, metallic nanoparticles, nanocarbon tubes, and receptor mediated drug delivery systems. We highlight the etiology, line of the treatment and chemopreventive measures related to OSCC. We focus on data available in the research carried out worldwide in past 15 years related to the management of OSCC.

A study of 113 cases of genital ulcerative disease and urethral discharge syndrome with validation of syndromic management of sexually transmitted diseases.

AIMS: To validate syndromic management of cases having genital ulcerative disease (GUD) and urethral discharge syndrome (UDS). MATERIALS AND METHODS: A study of 113 cases of GUD and UDS was carried out in the Department of Skin and VD from March 2011 to August 2012. All cases having history and clinical evidence suggestive of GUD and UDS were included in the study. RESULTS: According to syndromic diagnosis, GUD herpetic syndrome was the most common 71 (62.27%), followed by GUD non-herpetic syndrome 25 (21.89%) and UDS 17 (14.91%). Out of 71 cases clinically diagnosed as GUD herpetic, 16 (22.53%) were validated by immunoglobulin M (IgM) anti herpes simplex virus-2 (HSV) serology, 14 (19.71%) by Tzanck smear and 3 (4.22%) by both. 24 (33.80%) were Reactive plasma Reagin (RPR)(<1:8) reactive and trepenomma palidum haem-agglutination positive. Out of total 25 clinically diagnosed GUD non herpetic cases, 22 (88%) were validated by laboratory tests Out of 17 cases of UDS, 15 (88%) were validated by smear. CONCLUSION: Sensitivity and specificity of clinically diagnosed syndrome is not so high particularly for GUD herpetic syndrome Continuous monitoring of diagnostic component of syndromic approach is key to success of STD control program.

Active learning of neuron morphology for accurate automated tracing of neurites.

Automating the process of neurite tracing from light microscopy stacks of images is essential for large-scale or high-throughput quantitative studies of neural circuits. While the general layout of labeled neurites can be captured by many automated tracing algorithms, it is often not possible to differentiate reliably between the processes belonging to different cells. The reason is that some neurites in the stack may appear broken due to imperfect labeling, while others may appear fused due to the limited resolution of optical microscopy. Trained neuroanatomists routinely resolve such topological ambiguities during manual tracing tasks by combining information about distances between branches, branch orientations, intensities, calibers, tortuosities, colors, as well as the presence of spines or boutons. Likewise, to evaluate different topological scenarios automatically, we developed a machine learning approach that combines many of the above mentioned features. A specifically designed confidence measure was used to actively train the algorithm during user-assisted tracing procedure. Active learning significantly reduces the training time and makes it possible to obtain less than 1% generalization error rates by providing few training examples. To evaluate the overall performance of the algorithm a number of image stacks were reconstructed automatically, as well as manually by several trained users, making it possible to compare the automated traces to the baseline inter-user variability. Several geometrical and topological features of the traces were selected for the comparisons. These features include the total trace length, the total numbers of branch and terminal points, the affinity of corresponding traces, and the distances between corresponding branch and terminal points. Our results show that when the density of labeled neurites is sufficiently low, automated traces are not significantly different from manual reconstructions obtained by trained users.