Broad-spectrum mono- and combinational drug therapies for global viral pandemic preparedness

Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by analyzing conserved druggable virus-host interactions, mechanisms of action and immunomodulatory properties of broad-spectrum antivirals (BSAs), routes of BSA delivery, and BSA interactions with other antivirals. Based on the analysis we developed scoring systems, which allowed us to predict novel BSAs and BSA-containing drug combinations (BCCs). Thus, we have developed a new strategy to broaden the spectrum of BSA indications and predict novel mono- and combinational therapies that can help better prepare for imminent future viral outbreaks.

Assessment of Ceftazidime-Avibactam 30/20-μg Disk, Etest versus Broth Microdilution Results When Tested against Enterobacterales Clinical Isolates

Multidrug-resistant Gram-negative bacteria, especially for extended-spectrum β-lactamases-producing and carbapenemase-producing Enterobacterales , are disseminating rapidly around the world. Treatment options for these infections are limited, which prompt the development of novel or combinational therapies to combat the infections caused by multidrug-resistant pathogens.

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40–60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.

Investigation of Hypoglycemic Peptides Derived from Conserved Regions of adMc1 to Reveal Their Antidiabetic Activities

Diabetes mellitus is the most common chronic disorder and leading cause of renal, neurological, and gastrointestinal manifestations in developed and developing countries. Despite of many drugs and combinational therapies, the complications of diabetes are still listed due to severe consequences of those drugs. In past few years, plant-derived drugs draw special attention due to their higher efficacy and fewer side-effects. Momordica charantia also known as bitter melon is referred as an antidiabetic and hypoglycemic plant in native populations of Asia and East Africa. In current study, an in silico approach was used to evaluate the interactions and binding patterns of plant-derived peptides devised from a hypoglycemic protein adMc1 of M. charantia as potential inhibitor of DPP-IV, SGLT1, and GLUT2 receptor proteins. The study has described a novel approach to investigate hypoglycemic peptides to cure diabetes. A total of eighty tetra-, penta-, and hexapeptides were devised from conserved regions of adMc1 homologs. The molecular docking approach using MOE software was employed to reveal inhibiting potentials of devised peptides against three selected proteins. Out of 30 shortlisted ligands six peptides (i.e. SMCG, DECC, TTIT, RTTI, ARNL and TVEV) accomplished the criteria of being good drug candidates against selected receptor proteins following the drugability assessment test. The overall results are acceptable on the basis of ADMET profiling for being good drug candidates against selected proteins.

The Role of Hypoxia in Glioblastoma Radiotherapy Resistance

Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O2 partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future.

RONC-21. IDENTIFICATION OF EPIGENETIC DRUGS AS RADIOSENSITIZERS IN PEDIATRIC HIGH-GRADE GLIOMAS

Pediatric high-grade gliomas (pHGG) are malignant brain tumors with a high mortality rate. Radiotherapy (RT) is one of the cornerstones of current pHGG treatment, while the efficacy of chemotherapeutics remains inferior. The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increase the effect of RT in pHGG treatment. Since recent studies revealed pHGG to be epigenetically dysregulated, we tested 148 epigenetic drugs on eight primary pHGG models in the presence and absence of RT, to assess their radiosensitizing potential. Based on synergy scores, we found 22 compounds that resulted in enhanced cytotoxicity in the presence of RT. The effect of these compounds on pHGG was further investigated by tracking spheroid growth microscopically for 30 days, identifying four molecules that stopped spheroid-expansion solely in combination with RT (p=<0.001, multilevel regression). Parallel cell-viability assays reported identical results. Furthermore, tumor migration in 3D matrigel growth assays, using non-toxic doses of the four identified compounds, revealed that two compounds (the selective HDAC-inhibitors; chidamide and entinostat) stop the infiltrative growth characteristics of pHGG cells, exclusively in combination with RT. RNA-Seq data showed that entinostat and chidamide inhibit DNA-repair pathways like the Fanconi anemia cascade and homologous recombination. Since we anticipate that entinostat- or chidamide-induced radiosensitization can be enhanced by blocking kinase-driven escape mechanisms, we are currently conducting a kinome-wide CRISPR/Cas9 knockout screen in three primary pHGG models to develop combinational therapies. These results highlight entinostat and chidamide as potential radiosensitizers in pHGG treatment.

Recent Progresses in Organic-Inorganic Nano Technological Platforms for Cancer Therapeutics

Nanotechnology offers promising tools in interdisciplinary research areas and getting an upsurge of interest in cancer therapeutics. Organic nanomaterials and inorganic nanomaterials bring revolutionary advancement in cancer eradication process. Oncology is achieving new heights under nano technological platform by expediting chemotherapy, radiotherapy, photo thermodynamic therapy, bio imaging and gene therapy. Various nanovectors have been developed for targeted therapy which acts as “Nano-bullets” for tumor cells selectively. Recently combinational therapies are catching more attention due to their enhanced effect leading towards the use of combined organicinorganic nano platforms. The current review covers organic, inorganic and their hybrid nanomaterials for various therapeutic action. The technological aspect of this review emphasizes on the use of inorganic-organic hybrids and combinational therapies for better results and also explores the future opportunities in this field.

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.