Molecular and Metabolic Regulation of Immunosuppression in Metastatic Pancreatic Ductal Adenocarcinoma

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological hot spots could improve the outcomes of PDAC immunotherapies

Noncoding-RNA-Based Therapeutics with an Emphasis on Prostatic Carcinoma-Progress and Challenges.

Noncoding RNAs (ncRNAs) defy the central dogma by representing a family of RNA molecules that are not translated into protein but can convey information encoded in their DNA. Elucidating the exact function of ncRNA has been a focus of discovery in the last decade and remains challenging. Nevertheless, the importance of understanding ncRNA is apparent since these molecules regulate gene expression at the transcriptional and post-transcriptional level exerting pleiotropic effects critical in development, oncogenesis, and immunity. NcRNAs have been referred to as the dark matter of the nucleus , and unraveling their role in physiologic and pathologic processes will provide vast opportunities for basic and translational research with the potential for significant therapeutic progress. Consequently, strong efforts are underway to exploit the therapeutic utility of ncRNA, some of which have been approved by the US Food and Drug Administration and the European Medicines Agency. The use of ncRNA therapeutics (or vaccines if defined as anti-disease agents) may result in improved curative strategies when used alone or in combination with existing treatments. This review will focus on the role of ncRNA therapeutics in prostatic carcinoma while exploring basic biological aspects of these molecules that represent about 97% of the transcriptome in humans

Quantifying Serum miRNA using DNA-Gold Nanoparticles: A Modern Approach to Diagnosing Pancreatic Cancer

Pancreatic Cancer (PC) is the third leading cause of cancer-related mortality in America with nearly 50,000 deaths annually. Furthermore, PC’s low 5-year survival rate, 11% overall, is highly dependent on the stage during which it is diagnosed and treated. When confined to the pancreas, the 5-year survival rate has been shown to reach as high as 42%, a nearly four-fold increase. Due to significant mortality differences dependent on PC stage, there is an utmost clinical need to diagnose PC as early as possible to maximize the chance of favorable patient outcomes. Most PC diagnostic methods currently involve imaging techniques including x-rays, CT, MRI, US, PET, ERCP. Issues with these techniques include levels of discomfort for the patient and higher costs and commitment to diagnose PC. For this reason, noninvasive diagnostic tests, such as CA 19-9 and CEA antigen blood tests are widely used to better inform patient outcomes. Current blood tests struggle to show appropriate specificity or sensitivity to reliably diagnose PC, including the limited ability to discriminate between benign and malignant tumors. Lacking validity may lead to patients over or under-investing in PC treatment. In comparison to blood antigens, microRNA (miRNA) is a biomarker that can be much more capable of diagnosing PC. The miRNAs consist of strands of around 20 base pairs in length that are transcribed in the body for gene regulation, controlling the expression of over half of our total genes. Aberrant expression of miRNAs are associated with PC. Current diagnostic tests that utilize miRNA biomarkers (e.g., microarray, qPCR) lack the sensitivity and limit of detection (LOD) required to assay normal versus aberrant miRNA levels since they are designed to detect longer nucleotide chains. Current methods are also cumbersome to use as they require extreme precaution and resources to collect data and avoid contamination. We propose new nanoparticle-based DNA-AuNP technology that will run a real time in situ assay of a patient’s serum sample to more reliably inform PC diagnosis early on.https://digitalcommons.unmc.edu/surp2022/1010/thumbnail.jp

Emerging trends for radioimmunotherapy in solid tumors.

Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed

Multiple hepatic lesions in a case of isolated hepatic tuberculosis simulating metastases on 18F-FDG PET/CT imaging

Hepatic tuberculosis is an unusual form of extrapulmonary tuberculosis and constitutes less than 1% of all cases of tuberculosis. Imaging studies for hepatic tuberculosis are nonspecific and mimic primary or metastatic carcinoma. Here we present 18F-FDG PET/CT images of a 25-year-old male patient with isolated hepatic tuberculosis

Pattern of adverse drug reactions reported at a tertiary care teaching hospital in northern India

Background: Adverse drug reactions (ADRs) are among the leading cause of morbidity and mortality in hospital setup. This study was conducted with the aim of understanding the pattern and occurrence of ADRs to minimize their risk and safeguard public health.Methods: This study is a retrospective analysis of pattern of ADRs reported at ADR monitoring centre (AMC) in a tertiary care hospital. A total of 207 spontaneous ADR reports collected over a period of 18 months were analysed for pattern and type of reactions, demographic profile of patients, organ system affected by ADRs, causative drugs, route of drug administration, severity of reaction, their outcome, management and causality assessment.Results: Most common age group affected by ADRs was 41-50 years with almost equal involvement of male and female gender. Cutaneous reactions involving skin like rashes and itching were most common ADRs. The most common causative drug for ADRs were antimicrobials agents like Penicillin and Cephalosporin group of antibiotics. Orally administered drugs were most commonly involved in causing ADRs. Most of the ADRs belonged to Type A category, were non-serious and moderate in severity. Most of the patients recovered from the ADRs on stopping the suspected drug. On assessing the causality, most of the ADRs were probable with the suspected drugs.Conclusions: Most of the patients recover from ADRs with appropriate and timely intervention, but it is important to understand the pattern and occurrence of ADRs for patient safety and this is possible only with an effective and robust pharmacovigilance system

A New Biometric Template Protection using Random Orthonormal Projection and Fuzzy Commitment

Biometric template protection is one of most essential parts in putting a biometric-based authentication system into practice. There have been many researches proposing different solutions to secure biometric templates of users. They can be categorized into two approaches: feature transformation and biometric cryptosystem. However, no one single template protection approach can satisfy all the requirements of a secure biometric-based authentication system. In this work, we will propose a novel hybrid biometric template protection which takes benefits of both approaches while preventing their limitations. The experiments demonstrate that the performance of the system can be maintained with the support of a new random orthonormal project technique, which reduces the computational complexity while preserving the accuracy. Meanwhile, the security of biometric templates is guaranteed by employing fuzzy commitment protocol.Comment: 11 pages, 6 figures, accepted for IMCOM 201

GPCRs and Fibroblast Heterogeneity in Fibroblast-Associated Diseases

G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of most targeted receptors . About one-third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast-mediated diseases. This review highlights the importance of designing and adaptation of next-generation strategies such as GPCR-omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies

RNA-Based Therapies: A Cog in the Wheel of Lung Cancer Defense

Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biology. The critical regulatory role of different RNAs in multiple cancer pathways makes them a rich source of targets and innovative tools for developing anticancer therapies. The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclinical and early clinical evaluation against LC. In the last decade, RNA-based therapies have substantially expanded and tested in clinical trials for multiple malignancies, including LC. This article describes the current understanding of various aspects of RNA-based therapeutics, including modern platforms, modifications, and combinations with chemo-/immunotherapies that have translational potential for LC therapies

MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells.

INTRODUCTION: Current studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs. METHOD: In the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue and normal breast tissue by immunostaining. RESULTS: MUC4 promotes proliferation, anchorage-dependent and-independent growth of TNBC cells, augments TNBC cell migratory and invasive potential in vitro, and enhances tumorigenicity and metastasis in vivo. In addition, our studies demonstrated that MUC4 up-regulates the EGFR family of proteins, and augments downstream Erk1/2, PKC-γ, and FAK mediated oncogenic signaling. Moreover, our studies also showed that knockdown of MUC4 in TNBC cells induced molecular changes suggestive of mesenchymal to epithelial transition. We also demonstrated in this study, for the first time, that knockdown of MUC4 was associated with reduced expression of EGFR and ErbB3 (EGFR family proteins) in TNBC cells, suggesting that MUC4 uses an alternative to ErbB2 mechanism to promote aggressiveness. We further demonstrate that MUC4 is differentially over-expressed in invasive TNBC tissues compared to normal breast tissue. CONCLUSIONS: MUC4 mucin expression is associated with TNBC pathobiology, and its knockdown reduced aggressiveness in vitro, and tumorigenesis and metastasis in vivo. Overall, our findings suggest that MUC4 mucin promotes invasive activities of TNBC cells by altering the expression of EGFR, ErbB2, and ErbB3 molecules and their downstream signaling