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

Extended-interval Dosing of Gentamicin for Treatment of Neonatal Sepsis in Developed and Developing Countries

Serious bacterial infections are the single most important cause of neonatal mortality in developing countries. Case-fatality rates for neonatal sepsis in developing countries are high, partly because of inadequate administration of necessary antibiotics. For the treatment of neonatal sepsis in resource-poor, high-mortality settings in developing countries where most neonatal deaths occur, simplified treatment regimens are needed. Recommended therapy for neonatal sepsis includes gentamicin, a parenteral aminoglycoside antibiotic, which has excellent activity against gram-negative bacteria, in combination with an antimicrobial with potent gram-positive activity. Traditionally, gentamicin has been administered 2–3 times daily. However, recent evidence suggests that extended-interval (i.e. ≥24 hours) dosing may be applicable to neonates. This review examines the available data from randomized and non-randomized studies of extended-interval dosing of gentamicin in neonates from both developed and developing countries. Available data on the use of gentamicin among neonates suggest that extended dosing intervals and higher doses (>4 mg/kg) confer a favourable pharmacokinetic profile, the potential for enhanced clinical efficacy and decreased toxicity at reduced cost. In conclusion, the following simplified weight-based dosing regimen for the treatment of serious neonatal infections in developing countries is recommended: 13.5 mg (absolute dose) every 24 hours for neonates of ≥2,500 g, 10 mg every 24 hours for neonates of 2,000–2,499 g, and 10 mg every 48 hours for neonates of <2,000 g

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

Attitudes of Healthcare Providers towards Non-initiation and Withdrawal of Neonatal Resuscitation for Preterm Infants in Mongolia

Antenatal parental counselling by healthcare providers is recommended to inform parents and assist with decision-making before the birth of a child with anticipated poor prognosis. In the setting of a low-income country, like Mongolia, attitudes of healthcare providers towards resuscitation of high-risk newborns are unknown. The purpose of this study was to examine the attitudes of healthcare providers regarding ethical decisions pertaining to non-initiation and withdrawal of neonatal resuscitation in Mongolia. A questionnaire on attitudes towards decision-making for non-initiation and withdrawal of neonatal resuscitation was administered to 113 healthcare providers attending neonatal resuscitation training courses in 2009 in Ulaanbaatar, the capital and the largest city of Mongolia where ~40% of deliveries in the country occur. The questionnaire was developed in English and translated into Mongolian and included multiple choices and free-text responses. Participation was voluntary, and anonymity of the participants was strictly maintained. In total, 113 sets of questionnaire were completed by Mongolian healthcare providers, including neonatologists, paediatricians, neonatal and obstetrical nurses, and midwives, with 100% response rate. Ninety-six percent of respondents were women, with 73% of participants from Ulaanbaatar and 27% (all midwives) from the countryside. The majority (96%) of healthcare providers stated they attempt pre-delivery counselling to discuss potential poor outcomes when mothers present with preterm labour. However, most (90%) healthcare providers stated they feel uncomfortable discussing not initiating or withdrawing neonatal resuscitation for a baby born alive with little chance of survival. Religious beliefs and concerns about long-term pain for the baby were the most common reasons for not initiating neonatal resuscitation or withdrawing care for a baby born too premature or with congenital birth-defects. Most Mongolian healthcare providers provide antenatal counselling to parents regarding neonatal resuscitation. Additional research is needed to determine if the above-said difficulty with counselling stems from deficiencies in communication training and whether these same counselling-related issues exist in other countries. Future educational efforts in teaching neonatal resuscitation in Mongolia should incorporate culturally-sensitive training on antenatal counselling

Respiratory distress syndrome management in resource limited settings—Current evidence and opportunities in 2022

The complications of prematurity are the leading cause of neonatal mortality worldwide, with the highest burden in the low- and middle-income countries of South Asia and Sub-Saharan Africa. A major driver of this prematurity-related neonatal mortality is respiratory distress syndrome due to immature lungs and surfactant deficiency. The World Health Organization's Every Newborn Action Plan target is for 80% of districts to have resources available to care for small and sick newborns, including premature infants with respiratory distress syndrome. Evidence-based interventions for respiratory distress syndrome management exist for the peripartum, delivery and neonatal intensive care period- however, cost, resources, and infrastructure limit their availability in low- and middle-income countries. Existing research and implementation gaps include the safe use of antenatal corticosteroid in non-tertiary settings, establishing emergency transportation services from low to high level care facilities, optimized delivery room resuscitation, provision of affordable caffeine and surfactant as well as implementing non-traditional methods of surfactant administration. There is also a need to optimize affordable continuous positive airway pressure devices able to blend oxygen, provide humidity and deliver reliable pressure. If the high prematurity-related neonatal mortality experienced in low- and middle-income countries is to be mitigated, a concerted effort by researchers, implementers and policy developers is required to address these key modalities

Extended-interval Dosing of Gentamicin for Treatment of Neonatal Sepsis in Developed and Developing Countries

Serious bacterial infections are the single most important cause of neonatal mortality in developing countries. Case-fatality rates for neonatal sepsis in developing countries are high, partly because of inadequate administration of necessary antibiotics. For the treatment of neonatal sepsis in resource-poor, high-mortality settings in developing countries where most neonatal deaths occur, simplified treatment regimens are needed. Recommended therapy for neonatal sepsis includes gentamicin, a parenteral aminoglycoside antibiotic, which has excellent activity against gram-negative bacteria, in combination with an antimicrobial with potent gram-positive activity. Traditionally, gentamicin has been administered 2-3 times daily. However, recent evidence suggests that extended-interval (i.e. 65 24 hours) dosing may be applicable to neonates. This review examines the available data from randomized and non-randomized studies of extended-interval dosing of gentamicin in neonates from both developed and developing countries. Available data on the use of gentamicin among neonates suggest that extended dosing intervals and higher doses (&gt;4 mg/kg) confer a favourable pharmacokinetic profile, the potential for enhanced clinical efficacy and decreased toxicity at reduced cost. In conclusion, the following simplified weight-based dosing regimen for the treatment of serious neonatal infections in developing countries is recommended: 13.5 mg (absolute dose) every 24 hours for neonates of 65 2,500 g, 10 mg every 24 hours for neonates of 2,000-2,499 g, and 10 mg every 48 hours for neonates of &lt;2,000 g

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