Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models

Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted.

RNAi-Based Approaches for Pancreatic Cancer Therapy

Pancreatic cancer is one of the most lethal forms of cancer, predicted to be the second leading cause of cancer-associated death by 2025. Despite intensive research for effective treatment strategies and novel anticancer drugs over the past decade, the overall patient survival rate remains low. RNA interference (RNAi) is capable of interfering with expression of specific genes and has emerged as a promising approach for pancreatic cancer because genetic aberrations and dysregulated signaling are the drivers for tumor formation and the stromal barrier to conventional therapy. Despite its therapeutic potential, RNA-based drugs have remaining hurdles such as poor tumor delivery and susceptibility to serum degradation, which could be overcome with the incorporation of nanocarriers for clinical applications. Here we summarize the use of small interfering RNA (siRNA) and microRNA (miRNA) in pancreatic cancer therapy in preclinical reports with approaches for targeting either the tumor or tumor microenvironment (TME) using various types of nanocarriers. In these studies, inhibition of oncogene expression and induction of a tumor suppressive response in cancer cells and surrounding immune cells in TME exhibited a strong anticancer effect in pancreatic cancer models. The review discusses the remaining challenges and prospective strategies suggesting the potential of RNAi-based therapeutics for pancreatic cancer.

Role of the Immune System Elements in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a relatively rare disease, but, today, its incidence tends to increase. The severe course of the disease and poor patient survival rate make PAH a major diagnostic and therapeutic challenge. For this reason, a thorough understanding of the pathogenesis of the disease is essential to facilitate the development of more effective therapeutic targets. Research shows that the development of PAH is characterized by a number of abnormalities within the immune system that greatly affect the progression of the disease. In this review, we present key data on the regulated function of immune cells, released cytokines and immunoregulatory molecules in the development of PAH, to help improve diagnosis and targeted immunotherapy.

Challenges Associated with Pancreas and Kidney Retransplantation—A Retrospective Analysis

Simultaneous pancreas and kidney transplantation (SPK) is an accepted treatment for diabetic patients with renal failure, and is associated with increased survival and quality of life for recipients. There are only a few publications on the outcomes of simultaneous pancreas–kidney retransplantation (Re-SPK) after previous SPK and the loss of function of both grafts. A total of 55 patients with type 1 diabetes mellitus underwent pancreas retransplantation at our center between January 1994 and March 2021. Twenty-four of these patients underwent Re-SPK after a previous SPK. All 24 operations were technically feasible. Patient survival rate after 3 months, 1 year, and 5 years was 79.2%, 75%, and 66.7%, respectively. The causes of death were septic arterial hemorrhage (n = 3), septic multiorgan failure (n = 2), and was unknown in one patient. Pancreas and kidney graft function after 3 months, 1 year, and 5 years were 70.8% and 66.7%, 66.7% and 62.5%, and 45.8% and 54.2%, respectively. Relaparotomy was performed in 13 out of 24 (54.2%) patients. The results of our study show that Re-SPK, after previously performed SPK, is a technical and immunological challenge, associated with a significantly increased mortality and complication rate; therefore, the indication for Re-SPK should be very strict. Careful preoperative diagnosis is indispensable.

Overcoming the challenges in the treatment of glioblastoma via nanocarrier based drug delivery approach

Background: Glioblastoma multiforme is the most malignant form of high-grade astrocytoma. Clinically it is characterized as 4thgrade of astrocytoma having necrotic tissue and hyperplastic blood vessel. It is observed to be the most frequent adult brain tumor representing an overall 15.4% of all brain tumors and about 60-75% of the entire astrocytoma. There are limited therapies available and the most widely used therapy includes surgical intrusion followed by radiotherapy plus chemotherapy (paclitaxel, temozolomide, docetaxel, etc); with an overall patient survival rate from 6–14 months. Various studies have proved that nanoformulations offer considerable advantages like enhanced drug solubility, targeted activity, and attenuated side effects. Objective: The key objective of this review article is to exemplify numerous studies carried out using nanocarriers for overcoming the challenges associated with the treatment of glioblastoma. It also describes the pathways associated with the induction, initiation, and progression of glioblastoma. Methods: Research articles that focused on the use of nanocarrier-based drug delivery approach for the treatment of various glioblastoma were collected from different search engines, such as Google Scholar, Science Direct, and PubMed using keywords like glioblastoma, nanocarriers, Brain delivery, etc. Results: Nanocarriers have shown enormous potential in overcoming the challenges associated with the treatment of glioblastoma. Conclusion: Broad research is still needed so that these nanocarriers can be used clinically for the welfare of mankind, in the management of glioblastoma, in near future.

DEPDC1/ EEF1A1 complex promotes the progression of human osteosarcoma via downregulation of FOXO3a

This study deciphers a potentially critical interplay of DEPDC1-EEF1A1-FOXO3a axis during the osteosarcoma progression. Bioinformatics analysis of documented 25,035 genes for differentially expressed genes were accompanied by transcriptional and translational examinations of clinical osteosarcoma specimens and osteosarcoma cell lines to assess the roles and interactions of DEPDC1, EEF1A1, and FOXO3a in the tumor cells proliferation and prognosis. Gene expression profile analysis and clinical tests revealed highly expressed DEPDC1 in human osteosarcoma cells and tumor tissues. Vector-mediated silence of DEPDC1 resulted in halted osteosarcoma cell proliferation, promoted apoptosis, and ceased tumor metastasis. Immunoprecipitation assay confirmed that EEF1A1 directly bind to DEPDC1 protein through three binding regions. Further, DEPDC1/EEF1A1 complex significantly decreased the expression of FOXO3a at transcription and translation levels, which subsequently promoted the proliferation of osteosarcoma cells and tumor metastasis. Correlation studies exhibited that overexpression of DEPDC1/EEF1A1 complex in the clinical specimens negatively correlated with the patient survival rate. In conclusion, DEPDC1-EEF1A1-FOXO3a axis plays as a critical pathway that regulates the progression and prognosis of osteosarcoma.

A mini review on the pathogenesis, diagnosis and treatment options for COVID-19

: Coronavirus disease 2019 (COVID-19) is a serious viral disease caused by SARS-CoV-2, associated with a high morbidity and mortality, and represents the greatest public health crisis worldwide. Despite recent efforts for developing novel antiviral agents, no specific drugs are approved for management and treatment of COVID-19. The immune responses to viral infection followed by cytokine storm and acute respiratory distress syndrome are serious issues that may cause death in patients with severe COVID-19. Therefore, developing a novel therapeutic strategy for management of COVID-19 is urgently needed to control the virus spread and improving patient survival rate and clinical outcomes. In this mini review, we summarize the symptoms, pathogenesis and therapeutic approaches that are currently being used to managing the spread of SARS-CoV-2.

Revolution to Reticence, Halsted and The History of Mastectomy

The mastectomy techniques used to treat breast cancer patients today are a product of thousands of years of discovery. Early mentions of breast excision and cauterization can be found in Ancient Egyptian and Indian texts dating back to 3000 B.C. Formally developed by Halsted in 1894, the radical mastectomy marked an important innovation in breast cancer therapy. Employment of the technique nearly doubled the patient survival rate. Since Halsted’s time, the uses for this technique have also changed. Less invasive surgeries such as lumpectomies are often preferred by patients, with radical mastectomy surgeries now commonly used for prophylaxis. This article explores the significance of Halsted’s innovation, while providing contextual evidence that examines the noteworthy events that both precede and follow it. It also examines how Halsted’s innovation rose and later fell from public favour.

Convalescent plasma therapy: A promising solution for SARS-CoV-2 outbreak

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has caused more than 18 million confirmed cases and 700000 deaths worldwide after the outbreak in November 2019 (COVID-19). It has been considered as most pathogenic infection under this category. Till date none of the therapeutics or prophylaxis measures have been claimed by any researcher which could cure the patient suffering from the SARS-CoV-2 infection. There is an urgent need for any alternative and effective way of disease management for COVID-19. However, convalescent plasma therapy (CPT) has gain attention of researchers with significant improvement of patient survival rate. Interestingly, there are numerous examples where CPT has proven its potential upon post-exposure prophylaxis and/or treatment in various diseases including COVID-19. This review summarizes the essential elements related to CPT, its past clinical evidences and application of CPT for the management of SARS-CoV-2 infection during COVID-19. We used the published literatures from PubMed, EMBASE and Medline databases until 31st May 2020.

m5C RNA Methylation Primarily Affects the ErbB and PI3K–Akt Signaling Pathways in Gastrointestinal Cancer

5-Methylcytosine (m5C) is a kind of methylation modification that occurs in both DNA and RNA and is present in the highly abundant tRNA and rRNA. It has an important impact on various human diseases including cancer. The function of m5C is modulated by regulatory proteins, including methyltransferases (writers) and special binding proteins (readers). This study aims at comprehensive study of the m5C RNA methylation-related genes and the main pathways under m5C RNA methylation in gastrointestinal (GI) cancer. Our result showed that the expression of m5C writers and reader was mostly up-regulated in GI cancer. The NSUN2 gene has the highest proportion of mutations found in GI cancer. Importantly, in liver cancer, higher expression of almost all m5C regulators was significantly associated with lower patient survival rate. In addition, the expression level of m5C-related genes is significantly different at various pathological stages. Finally, we have found through bioinformatics analysis that m5C regulatory proteins are closely related to the ErbB/PI3K–Akt signaling pathway and GSK3B was an important target for m5C regulators. Besides, the compound termed streptozotocin may be a key candidate drug targeting on GSK3B for molecular targeted therapy in GI cancer.