Comparative Outcomes of Second-line Topoisomerase-I Inhibitor Therapies on Neuroendocrine Carcinoma.

INTRODUCTION: This investigation aims to assess the outcomes for second-line therapies to treat extrapulmonary neuroendocrine carcinoma (EP-NEC) after first-line platinum-based chemotherapy. METHODS: With IRB approval, we conducted a retrospective study of EP-NEC patients that progressed on first-line platinum chemotherapy from 2008 to 2018. Demographic data and treatment-related characteristics were collected and represented as descriptive statistics. The primary endpoints include overall survival (OS) and progression-free survival (PFS). OS and PFS were estimated and stratified by site of primary (gastroenteropancreatic [GEP] versus non-GEP) and type of second-line therapy (irino/topotecan versus others). Log-rank test and Kaplan-Meier curves were used to compare survival distributions between groups. RESULTS: Forty-seven patients met eligibility, with median age 65 (range 31-82), 62% male, and 83% White; 22 were GEP and 25 were non-GEP primary. Thirty patients (63.8%) received second-line therapy where 11 received irinotecan/topotecan (ir/to), while 19 received other agents (temozolomide, other platinum agents, gemcitabine, paclitaxel, pembrolizumab, and sunitinib). The median OS was 10.3 months in the ir/to group versus 13.4 months for other therapies, p = 0.10. The median PFS for ir/to therapy compared to other therapies was 2.0 months versus 1.8 months, respectively, p = 0.72. The OS and PFS with and without ir/to were not significantly different by the primary site (p = 0.61 and p = 0.21). DISCUSSION/CONCLUSION: Many EP-NEC patients undergo second-line therapies. Interestingly, outcomes for ir/to-containing second-line therapies were not statistically different from other agents, regardless of the site of primary. With approval of new second-line therapies for small cell lung cancer, further research in therapeutic options is needed for this aggressive disease.

Host-directed therapies for malaria and tuberculosis: common infection strategies and repurposed drugs.

INTRODUCTION: Malaria and tuberculosis are highly infectious diseases declared a global health emergency by the World Health Organization, and together they account for more than 1.5 million deaths worldwide each year. In the case of both malaria and tuberculosis, emergence of multidrug resistance towards frontline drugs has been reported in the recent past. Therefore, an urgent need exists for the discovery and development of novel drugs or therapies to fight these diseases. AREAS COVERED: We provide a detailed overview of major infection strategies, commonly used by both the parasite Plasmodium and by Mycobacterium tuberculosis (Mtb) during disease development. We also describe selected host-directed drugs which can be repurposed to treat both malaria and tuberculosis, and co-infections. EXPERT OPINION: Investigation of common infection strategies used by both Plasmodium and Mtb, during the development of disease in humans, suggests that they are potential host targets for which to develop host-directed therapies. By taking advantage of these common infection strategies, there is a chance that a number of available drugs can be repurposed to fight both malaria and tuberculosis, and their co-infections.

Host-directed therapies: a potential solution to combat COVID-19.

Coronavirus disease 2019 (COVID-19) characterized by immuno-pathological host responses including pneumonia, lymphopenia, and cytokine storm that leads to severe lung inflammation, developed in acute respiratory distress syndrome (ARDS). In the absence of an effective vaccine or any definitive cure, the use of host-directed therapies is an effective alternative and demanding treatment option in the current pandemic outbreak of COVID-19.

The role of T regulatory cell-associated markers in monitoring tuberculosis treatment completion and failure.

Monitoring tuberculosis (TB) treatment success is crucial for clinical decision-making. The only available tool in this regard is sputum microscopy, but it has demerits. Moreover, in case of smear negatives and extrapulmonary TB, an efficient tool is still sought for. Therefore, we evaluated T regulatory cell (Treg)-associated markers (CD25, CD39, and FoxP3) and cellular subsets in monitoring treatment success in treatment-completed groups. Expression profile of various markers and subsets were compared real time among treatment-naive pulmonary TB patients (TN-PTB), followed-up treatment-completed (TC-fu) cohort, and a not followed-up (TC-nfu) cohort. Peripheral blood mononuclear cells from various groups were incubated overnight and were stained with antibodies for specific markers and studied by flow cytometry. In both the treatment-completed groups, a decline in frequencies of CD25+ marker and CD4+CD25+, CD4+CD25+FoxP3, CD4+CD25+CD39+ Treg was observed with clearance of infection, indicating their potential in monitoring treatment success. However, in the case of treatment failure patient (Tfp), a drastic increase in frequency of CD4+CD25+FoxP3+ Treg subset was found, indicating its usefulness in predicting treatment failure. Although the investigation unveils markers useful in predicting treatment success or failure, the findings from this study needs to be validated in a larger cohort.

Efficacy of T Regulatory Cells, Th17 Cells and the Associated Markers in Monitoring Tuberculosis Treatment Response.

Treatment monitoring is an essential aspect for tuberculosis (TB) disease management. Sputum smear microscopy is the only available tool for monitoring, but it suffers from demerits. Therefore, we sought to evaluate markers and cellular subsets of T regulatory (Treg) cells and T helper (Th) 17 cells in pulmonary TB patients (PTB) for TB treatment monitoring. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro (with purified protein derivative (PPD)) overnight which was followed by a polychromatic flow cytometry approach to study Treg and Th17 markers and cellular subsets in PTB (n = 12) undergoing antituberculous treatment (ATT). The baseline levels of these markers and cellular subsets were evaluated in normal healthy subjects (NHS). We observed a significant decrease in the expression of CD25 (p<0.01) marker and percentage of T-cell subsets like CD4+CD25+ (p<0.001) and CD4+CD25+CD39+ (p<0.05) at the end of intensive phase (IP) as well as in the continuation phase (CP) of ATT. A decrease in CD25 marker expression and percentage of CD4+CD25+ T cell subset showed a positive correlation to sputum conversion both in high and low sputum positive PTB. In eight PTB with cavitary lesions, only CD4+CD25+FoxP3 Treg subset manifested a significant decrease at the end of CP. Thus, results of this study show that CD25 marker and CD4+CD25+ T cells can serve as better markers for monitoring TB treatment efficacy. The Treg subset CD4+CD25+FoxP3 may be useful for prediction of favorable response in PTB with extensive lung lesions. However, these findings have to be evaluated in a larger patient cohort.

T regulatory cells: Achilles' heel of Mycobacterium tuberculosis infection?

T regulatory cells (Treg) constitute a specialized subset of T cells that play a pivotal role in preventing the occurrence of autoimmune diseases by suppressing deleterious activities of immune cells. Contrarily, they can have adverse effect on immune response against infectious diseases where Treg weaken the host immunity leading to enhanced microbial load and thereby increase in severity of the disease. Here, we have attempted to review plethora of information documenting prevalence of Treg in tuberculosis (TB) and their involvement in progression and immunopathogenesis of the disease. Further, we have laid emphasis on the possible use of Treg as a biomarker for determining the TB treatment efficacy. Also, we have discussed the probable contribution of Treg in dampening the efficacy of BCG, the anti-TB vaccine. Finally, we have speculated some of the possible strategies which might be explored by exploiting Treg for enhancing the efficacy of TB management.

Physicochemical properties of the modeled structure of astacin metalloprotease moulting enzyme NAS-36 and mapping the druggable allosteric space of Heamonchus contortus, Brugia malayi and Ceanorhabditis elegans via molecular dynamics simulation.

Nematodes represent the second largest phylum in the animal kingdom. It is the most abundant species (500,000) in the planet. It causes chronic, debilitating infections worldwide such as ascariasis, trichuriasis, hookworm, enterobiasis, strongyloidiasis, filariasis and trichinosis, among others. Molecular modeling tools can play an important role in the identification and structural investigation of molecular targets that can act as a vital candidate against filariasis. In this study, sequence analysis of NAS-36 from H. contortus (Heamonchus contortus), B. malayi (Brugia malayi) and C. elegans (Ceanorhabditis elegans) has been performed, in order to identify the conserved residues. Tertiary structure was developed for an insight into the molecular structure of the enzyme. Molecular Dynamics Simulation (MDS) studies have been carried out to analyze the stability and the physical properties of the proposed enzyme models in the H. contortus, B. malayi and C. elegans. Moreover, the drug binding sites have been mapped for inhibiting the function of NAS-36 enzyme. The molecular identity of this protease could eventually demonstrate how ex-sheathment is regulated, as well as provide a potential target of anthelmintics for the prevention of nematode infections.