Identification of novel signal of Raynaud's phenomenon with Calcitonin Gene-Related Peptide(CGRP) antagonists using data mining algorithms and network pharmacological approaches.

BACKGROUND: Calcitonin gene-related peptide (CGRP) antagonists are recently approved for the treatment of migraine. AIM: The main aim of the current study was to find out the association of CGRP antagonists with RP using data mining algorithms integrated with network pharmacological approaches. RESEARCH DESIGN AND METHODS: The individual case safety reports were extracted using OpenVigil2.1-MedDRA-V17 (2004Q1-2022Q3), the United States Adverse Event Reporting System (US FAERS). The data mining algorithms i.e. reporting odds ratio (ROR) with 95% confidence and proportionality reporting ratio (PRR) with associated chi-square value were calculated along with a minimum of three ICSRs to identify the signal. Further, the network was constructed using Cytoscape 3.7.2. Finally, molecular docking was performed using Glide, Schrodinger Inc. RESULTS: The PRR ≥2 with a linked chi-square value ≥4, add up of co-occurrence ≥3, and a lower limit of 95% confidence interval of ROR exceeding 2 indicates a positive signal of RP. Further, the network pharmacological and molecular docking results have shown the involvement of insulin-like growth factor 1-receptor (IGF1R) pathways. CONCLUSION: The RP is recognized as a novel signal with all CGRP antagonists.

Understanding zebrafish sleep and wakefulness physiology as an experimental model for biomedical research.

Sleep is a globally observable fact, or period of reversible distracted rest, that can be distinguished from arousal by various behavioral criteria. Although the function of sleep is an evolutionarily conserved behavior, its mechanism is not yet clear. The zebrafish (Danio rerio) has become a valuable model for neurobehavioral studies such as studying learning, memory, anxiety, and depression. It is characterized by a sleep-like state and circadian rhythm, making it comparable to mammals. Zebrafish are a good model for behavioral studies because they share genetic similarities with humans. A number of neurotransmitters are involved in sleep and wakefulness. There is a binding between melatonin and the hypocretin system present in zebrafish. The full understanding of sleep and wakefulness physiology in zebrafish is still unclear among researchers. Therefore, to make a clear understanding of the sleep/wake cycle in zebrafish, this article covers the mechanism involved behind it, and the role of the neuromodulator system followed by the mechanism of the HPA axis.

Interruption of the Intratumor CD8:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy.

PD-1 blockade unleashes the potent antitumor activity of CD8 cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen response to immunotherapy. Tumor Treg inhibition is a promising strategy to overcome therapeutic resistance; however, the mechanisms supporting tumor Tregs during PD-1 immunotherapy are largely unexplored. Here, we report that PD-1 blockade increases tumor Tregs in mouse models of immunogenic tumors, including melanoma, and metastatic melanoma patients. Unexpectedly, Treg accumulation was not caused by Treg-intrinsic inhibition of PD-1 signaling but instead depended on an indirect effect of activated CD8 cells. CD8 cells colocalized with Tregs within tumors and produced IL-2, especially after PD-1 immunotherapy. IL-2 upregulated the anti-apoptotic protein ICOS on tumor Tregs, causing their accumulation. ICOS signaling inhibition before PD-1 immunotherapy resulted in increased control of immunogenic melanoma. Thus, interrupting the intratumor CD8:Treg crosstalk is a novel strategy that may enhance the efficacy of immunotherapy in patients.

Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.

The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEMs) in vitro and performed detailed, multiomic characterization (i.e., transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single-cell RNA sequencing dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.

Importance of Zebrafish as an Efficient Research Model for the Screening of Novel Therapeutics in Neurological Disorders.

Over the previous years, the use of an animal model has become very common for the screening of novel drugs. Animal model represents the complex problems of humans into the simplest forms, so these can be extended further to be included in the experimental procedure. The most successful models in neuroscience, rats and mice, are undoubtedly considered as one of the best models to understand the psychology of the mammalian brain and its associated functions involved in behavioral repertoire. Moreover, recently researchers in behavioral neuroscience are focusing more on the use of aquatic animals, especially fish, as model species due to their simplicity and cost-effectiveness. Zebrafish (Danio rerio) is a tropical fish from the minnow family, a genetic structure surprisingly 84% similar to humans. It is gaining popularity as a model to study the mechanism in behavioral neuropharmacology. Moreover, zebrafish has numerous advantages over other rodent models like the ease in maintenance due to their small size, more breeding power, transparency of embryos, overall reduced cost of experimentation, and many more. Nowadays, it is considered an ideal model to study the neurobehavioral aspects with relevance to humans. It is also used in a variety of scientific studies like genetics, neuroscience, pharmacology, and toxicology. In this manuscript, we have described the feasibility and importance of zebrafish as a model for the screening of novel drugs for different neurological disorders.

CpG-creating mutations are costly in many human viruses.

Mutations can occur throughout the virus genome and may be beneficial, neutral or deleterious. We are interested in mutations that yield a C next to a G, producing CpG sites. CpG sites are rare in eukaryotic and viral genomes. For the eukaryotes, it is thought that CpG sites are rare because they are prone to mutation when methylated. In viruses, we know less about why CpG sites are rare. A previous study in HIV suggested that CpG-creating transition mutations are more costly than similar non-CpG-creating mutations. To determine if this is the case in other viruses, we analyzed the allele frequencies of CpG-creating and non-CpG-creating mutations across various strains, subtypes, and genes of viruses using existing data obtained from Genbank, HIV Databases, and Virus Pathogen Resource. Our results suggest that CpG sites are indeed costly for most viruses. By understanding the cost of CpG sites, we can obtain further insights into the evolution and adaptation of viruses.

Adenoid cystic carcinoma of the hard palate presenting as ipsilateral sixth nerve palsy.

Adenoid cystic carcinoma (ACC) is an uncommon malignant neoplasm composed of basaloid epithelial and myoepithelial cells. The palate is the most commonly involved intraoral site for ACC. Here, we document the case of an advanced ACC arising from the hard palate that presented with right-sided sixth nerve palsy in a 75-year-old male with no other systemic illnesses. ACC of the head and neck involving the cavernous sinus and presenting as isolated sixth nerve palsy is exceedingly rare. In the absence of vasculopathic or ischemic risk factors, regardless of the age of the patient; neuroimaging should be performed in cases of isolated nontraumatic sixth nerve palsy.