Antibody-drug conjugates: the paradigm shifts in the targeted cancer therapy

Cancer is one of the deadliest diseases, causing million of deaths each year globally. Conventional anti-cancer therapies are non-targeted and have systemic toxicities limiting their versatile applications in many cancers. So, there is an unmet need for more specific therapeutic options that will be effective as well as free from toxicities. Antibody-drug conjugates (ADCs) are suitable alternatives with the right potential and improved therapeutic index for cancer therapy. The ADCs are highly precise new class of biopharmaceutical products that covalently linked a monoclonal antibody (mAb) (binds explicitly to a tumor-associated surface antigen) with a customized cytotoxic drug (kills cancer cells) and tied via a chemical linker (releases the drug). Due to its precise design, it brings about the target cell killing sparing the normal counterpart and free from the toxicities of conventional chemotherapy. It has never been so easy to develop potential ADCs for successful therapeutic usage. With relentless efforts, it took almost a century for scientists to advance the formula and design ADCs for its current clinical applications. Until now, several ADCs have passed successfully through preclinical and clinical trials and because of proven efficacy, a few are approved by the FDA to treat various cancer types. Even though ADCs posed some shortcomings like adverse effects and resistance at various stages of development, with continuous efforts most of these limitations are addressed and overcome to improve their efficacy. In this review, the basics of ADCs, physical and chemical properties, the evolution of design, limitations, and future potentials are discussed

Antimicrobial Resistance: A Growing Serious Threat for Global Public Health

Antibiotics are among the most important discoveries of the 20th century, having saved millions of lives from infectious diseases. Microbes have developed acquired antimicrobial resistance (AMR) to many drugs due to high selection pressure from increasing use and misuse of antibiotics over the years. The transmission and acquisition of AMR occur primarily via a human-human interface both within and outside of healthcare facilities. A huge number of interdependent factors related to healthcare and agriculture govern the development of AMR through various drug-resistance mechanisms. The emergence and spread of AMR from the unrestricted use of antimicrobials in livestock feed has been a major contributing factor. The prevalence of antimicrobial-resistant bacteria has attained an incongruous level worldwide and threatens global public health as a silent pandemic, necessitating urgent intervention. Therapeutic options of infections caused by antimicrobial-resistant bacteria are limited, resulting in significant morbidity and mortality with high financial impact. The paucity in discovery and supply of new novel antimicrobials to treat life-threatening infections by resistant pathogens stands in sharp contrast to demand. Immediate interventions to contain AMR include surveillance and monitoring, minimizing over-the-counter antibiotics and antibiotics in food animals, access to quality and affordable medicines, vaccines and diagnostics, and enforcement of legislation. An orchestrated collaborative action within and between multiple national and international organizations is required urgently, otherwise, a postantibiotic era can be a more real possibility than an apocalyptic fantasy for the 21st century. This narrative review highlights on this basis, mechanisms and factors in microbial resistance, and key strategies to combat antimicrobial resistance

Antibody-drug conjugates: the paradigm shifts in the targeted cancer therapy

Cancer is one of the deadliest diseases, causing million of deaths each year globally. Conventional anti-cancer therapies are non-targeted and have systemic toxicities limiting their versatile applications in many cancers. So, there is an unmet need for more specific therapeutic options that will be effective as well as free from toxicities. Antibody-drug conjugates (ADCs) are suitable alternatives with the right potential and improved therapeutic index for cancer therapy. The ADCs are highly precise new class of biopharmaceutical products that covalently linked a monoclonal antibody (mAb) (binds explicitly to a tumor-associated surface antigen) with a customized cytotoxic drug (kills cancer cells) and tied via a chemical linker (releases the drug). Due to its precise design, it brings about the target cell killing sparing the normal counterpart and free from the toxicities of conventional chemotherapy. It has never been so easy to develop potential ADCs for successful therapeutic usage. With relentless efforts, it took almost a century for scientists to advance the formula and design ADCs for its current clinical applications. Until now, several ADCs have passed successfully through preclinical and clinical trials and because of proven efficacy, a few are approved by the FDA to treat various cancer types. Even though ADCs posed some shortcomings like adverse effects and resistance at various stages of development, with continuous efforts most of these limitations are addressed and overcome to improve their efficacy. In this review, the basics of ADCs, physical and chemical properties, the evolution of design, limitations, and future potentials are discussed

Antimicrobial resistance: a growing serious threat for global public health

Antibiotics are among the most important discoveries of the 20th century, having saved millions of lives from infectious diseases. Microbes have developed acquired antimicrobial resistance (AMR) to many drugs due to high selection pressure from increasing use and misuse of antibiotics over the years. The transmission and acquisition of AMR occur primarily via a human–human interface both within and outside of healthcare facilities. A huge number of interdependent factors related to healthcare and agriculture govern the development of AMR through various drug-resistance mechanisms. The emergence and spread of AMR from the unrestricted use of antimicrobials in livestock feed has been a major contributing factor. The prevalence of antimicrobial-resistant bacteria has attained an incongruous level worldwide and threatens global public health as a silent pandemic, necessitating urgent intervention. Therapeutic options of infections caused by antimicrobial-resistant bacteria are limited, resulting in significant morbidity and mortality with high financial impact. The paucity in discovery and supply of new novel antimicrobials to treat life-threatening infections by resistant pathogens stands in sharp contrast to demand. Immediate interventions to contain AMR include surveillance and monitoring, minimizing over-the-counter antibiotics and antibiotics in food animals, access to quality and affordable medicines, vaccines and diagnostics, and enforcement of legislation. An orchestrated collaborative action within and between multiple national and international organizations is required urgently, otherwise, a postantibiotic era can be a more real possibility than an apocalyptic fantasy for the 21st century. This narrative review highlights on this basis, mechanisms and factors in microbial resistance, and key strategies to combat antimicrobial resistance

FOXO3 gene hypermethylation and its marked downregulation in breast cancer cases: A study on female patients

BackgroundFOXO3, a member of the FOX transcription factor family, is frequently described as being deregulated in cancer. Additionally, notable role of FOXO3 can be easily recognized in the process of ageing and survival. Even though various studies have been done to acknowledge the tumour-suppressive or oncogenic role of FOXO3 in cancer, still there exist a lack of understanding in terms of cancer prognosis and treatment. Therefore, to provide better insight, our study aims to evaluate the role and function of FOXO3 in breast cancer in Indian female patients. We examined the FOXO3 expression levels in breast cancer samples by analyzing mRNA and protein expression along with its clinicopathological parameters.ResultsA total of 127 cases of breast cancer with equal normal cases (n=127) were assessed with methylation (MS-PCR), Immunohistochemistry (IHC), mRNA expression using Real-time PCR was analysed and 66.14% cases at mRNA level were found to be downregulated, while 81.10% of cases had little or very little protein expression. Our data state, the promoter hypermethylation of the FOXO3 gene and the downregulated protein expression are significantly correlated (p=0.0004). Additionally, we found a significant correlation between the level of FOXO3 mRNA with ER (p=0.04) and status of lymph node (p=0.01) along with this.ConclusionData suggests the prognostic significance and the tumour-suppressive role of FOXO3 in breast cancer cases studied in India. However, there is a need for the extended research targeting FOXO3 to measure its clinical potential and develop well-defined therapeutic strategies

Conventional methods and future trends in antimicrobial susceptibility testing

Antimicrobial susceptibility testing is an essential task for selecting appropriate antimicrobial agents to treat infectious diseases. Constant evolution has been observed in methods used in the diagnostic microbiology laboratories. Disc diffusion or broth microdilution are classical and conventional phenotypic methods with long turnaround time and labour-intensive but still widely practiced as gold-standard. Scientists are striving to develop innovative, novel and faster methods of antimicrobial susceptibility testing to be applicable for routine microbiological laboratory practice and research. To meet the requirements, there is an increasing trend towards automation, genotypic and micro/nano technology-based innovations. Automation in detection systems and integration of computers for online data analysis and data sharing are giant leaps towards versatile nature of automated methods currently in use. Genotypic methods detect a specific genetic marker associated with resistant phenotypes using molecular amplification techniques and genome sequencing. Microfluidics and microdroplets are recent addition in the continuous advancement of methods that show great promises with regards to safety and speed and have the prospect to identify and monitor resistance mechanisms. Although genotypic and microfluidics methods have many exciting features, however, their applications into routine clinical laboratory practice warrant extensive validation. The main impetus behind the evolution of methods in antimicrobial susceptibility testing is to shorten the overall turnaround time in obtaining the results and to enhance the ease of sample processing. This comprehensive narrative review summarises major conventional phenotypic methods and automated systems currently in use, and highlights principles of some of the emerging genotypic and micro/nanotechnology-based methods in antimicrobial susceptibility testing

Plant metabolite diosmin as the therapeutic agent in human diseases

Plant-derived flavonoids have been the focus of research for many years mainly in the last decade owing to their therapeutic properties. So far, about 4000 flavonoids have been identified from plants and diosmin (a flavone glycoside) is one of them. Online databases, previous studies, and reviews have been used to gather information on anti-oxidant, immunomodulatory, anti-cancer, anti-parasitic, and anti-microbialproperties of diosmin. Effects of diosmin in combination with other flavonoids have been reviewed thoroughly and its administrative routes are also summarized. Additionally, we studied the effect of diosmin on critical protein networks. It exhibits therapeutic effects in diabetes and its associated complications such as neuropathy and dyslipidemia. Combination of diosmin with hesperidin is found to be very effective in the treatment of chronic venous insufficiency and haemorrhoids. Diosmin is an exquisite therapeutic agent alone as well as in combination with other flavonoids

Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation

Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy