ResearchPad - research-perspective https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections]]> https://www.researchpad.co/article/elastic_article_10789 The recently identified SARS-CoV-2 betacoronavirus responsible for the COVID-19 pandemic has uncovered the age-associated vulnerability in the burden of disease and put aging research in the spotlight. The limited data available indicates that COVID-19 should be referred to as a gerolavic (from Greek, géros “old man” and epilavís, “harmful”) infection because the infection rates, severity, and lethality are substantially higher in the population aged 60 and older. This is primarily due to comorbidity but may be partially due to immunosenescence, decreased immune function in the elderly, and general loss of function, fitness, and increased frailty associated with aging. Immunosenescence is a major factor affecting vaccination response, as well as the severity and lethality of infectious diseases. While vaccination reduces infection rates, and therapeutic interventions reduce the severity and lethality of infections, these interventions have limitations. Previous studies showed that postulated geroprotectors, such as sirolimus (rapamycin) and its close derivative rapalog everolimus (RAD001), decreased infection rates in a small sample of elderly patients. This article presents a review of the limited literature available on geroprotective and senoremediative interventions that may be investigated to decrease the disease burden of gerolavic infections. This article also highlights a need for rigorous clinical validation of deep aging clocks as surrogate markers of biological age. These could be used to assess the need for, and efficacy of, geroprotective and senoremediative interventions and provide better protection for elderly populations from gerolavic infections. This article does not represent medical advice and the medications described are not yet licensed or recommended as immune system boosters, as they have not undergone clinical evaluation for this purpose.

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<![CDATA[COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?]]> https://www.researchpad.co/article/N7da57d83-9e01-4062-b16c-de93123b2f1c COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.

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<![CDATA[Cytochrome P450 monooxygenase/soluble epoxide hydrolase-mediated eicosanoid pathway in colorectal cancer and obesity-associated colorectal cancer]]> https://www.researchpad.co/article/Nbbf91823-5a78-4b8a-8eb4-22fab5e12dc2

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Furthermore, it is well established that obese individuals have high risks of developing CRC, and obesity-associated CRC represents an unmet medical problem in the United States. Using a metabolomics approach, our recent research supports that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH)-mediated eicosanoid pathway could play critical roles in the pathogenesis of CRC and obesity-associated CRC. Here in this review, we discuss recent studies about the roles of the CYP/sEH eicosanoid pathway in the pathogenesis of these diseases.

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<![CDATA[Tissue-agnostic cancer drugs in the fight against molecular subsets of metastases of unknown origin]]> https://www.researchpad.co/article/Na113f81c-80b4-47c8-a5f9-72d3fce22be2 ]]> <![CDATA[Inside a mystery of oncoscience: The cancer-sniffing pets]]> https://www.researchpad.co/article/N86bf5f99-e492-4794-bb03-54c652f6e221 ]]> <![CDATA[Cracking the riddle of dedifferentiated liposarcoma: is EV-MDM2 a key?]]> https://www.researchpad.co/article/Neb1477ce-fb9a-48d9-b1a1-bb73bc727f52

Dedifferentiated liposarcoma (DDLPS) is molecularly characterized by wt p53 and MDM2 gene amplification causing MDM2 protein over-production, the key oncogenic process in DDLPS. Commonly located in fat-bearing retroperitoneal areas, almost 60% of DDLPS patients undergo multifocal recurrence, typically amenable to palliative treatment only, and occasionally develop distant metastasis. These factors lead to an abysmal 10% 10 year overall survival rate. Tumor cell-derived extracellular vesicles (EVs) can facilitate loco-regional malignancy dissemination by depositing molecular factors that participate in the development of pre-metastatic niches for tumor cell implantation and growth. High number of MDM2 DNA molecules was identified within EVs from DDLPS patient serum (ROC vs normal; 0.95) as well as from DDLPS cell lines. This MDM2 DNA could be transferred to preadipocytes (P-a), a major and ubiquitous cellular component of the DDLPS tumor microenvironment (TME), with subsequent P-a production of matrix metalloproteinase 2 (MMP2), a critical component in the metastatic cascade. From here the hypothesis that the DDLPS microenvironment (specifically P-a cells) may participate in DDLPS recurrence events. Since multifocal loco-regional DDLPS spreading is the main cause of the remarkably high lethality of this disease, a better understanding of the underlying oncogenic processes and their regulatory mechanisms is essential to improve the outcome of this devastating disease.

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<![CDATA[Metabolic Reprogramming by c-MET Inhibition as a Targetable Vulnerability in Glioblastoma]]> https://www.researchpad.co/article/N1c378990-6c8d-4cfd-86b3-20fe74c5f736

The elucidation of better treatments for solid tumors and especially malignant glial tumors is a priority. Better understanding of the molecular underpinnings of treatment response and resistance are critical determinants in the success for this endeavor. Recently, a battery of novel tools have surfaced that allow to interrogate tumor cell metabolism to more precise extent than this was possible in the earlier days. At the forefront of these developments are the extracellular flux and carbon tracing analyses. Through utilization of these techniques our group made the recent observation that acute and chronic c-MET inhibition drives fatty acid oxidation that in turn can be therapeutically targeted for drug combination therapies. Herein, we summarize and comment on some of our key findings related to this study.

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<![CDATA[The flip side of sirtuins: the emerging roles of protein acetyltransferases in aging]]> https://www.researchpad.co/article/Nae9eb667-3984-4e09-b905-9f1146a882c8

Protein N-ε-lysine acetylation is is an important post-translational modification that plays critical roles in the regulation of many cellular processes. A role for this modification in the process of aging goes back two decades to the discovery that the yeast NAD+-dependent histone deacetylase Sir2 regulates lifespan in yeast. While the Sirtuin family of protein deacetylases has been intensively studied in many model systems and is definitively linked to aging, the enzymes responsible for protein acetylation, protein acetyltransferases (KATs), have not received a similar level of attention. However, a series of recent studies have directly explored the role of specific KATs in aging. These studies have shown that modulation of KAT activity can influence cellular pathways important for aging and directly effect organismal lifespan.

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<![CDATA[Precision health for breast cancer metastasis: biomaterial scaffolds as an engineered metastatic niche to define, study, and monitor metastatic progression]]> https://www.researchpad.co/article/N41396101-9c1a-4abe-93a0-f951edb08a3d

Metastasis represents the greatest challenge to treatment of cancer patients. Biomaterial scaffolds that recruit tumor cells to a defined site in vivo are an emerging platform for the diagnosis, treatment, and study of metastasis. Recruitment of immune cells and metastatic tumor cells to a defined location provides a precision health platform to assess current clinical cancer biomarkers in a metastatic setting, and to define the next generation of biomarkers. These platforms represent an opportunity to create a molecular staging of metastasis that could aid in both the early diagnosis and treatment of metastasis.

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<![CDATA[Improving patient classification and biomarker assessment using Gaussian Mixture Models and Bayes’ rule]]> https://www.researchpad.co/article/Nc7a5a135-2449-4e3f-bbdc-f5396fa0ecdf

In clinical research, determining cutoff values for continuous variables in test results remains challenging, particularly when considering candidate biomarkers or therapeutic targets for disease. Distribution of a continuous variable into two populations is known as dichotomization and has been commonly used in clinical studies. We recently reported a new method for determining multiple cutoffs for continuous variables. The development of this original approach was based on fitting Gaussian Mixture Models (GMM) onto real-world clinical data. We also explored how to leverage Bayesian probability to minimize uncertainty while classifying individual patients into respective subpopulations. In addition, we investigated the performance of the proposed method for the distribution of classical prognostic markers in breast cancer. Finally, we applied the proposed method to analyze a candidate marker and a target for cancer therapy. Here, we present an overview of this method and our prospects for its implementation in biomedical and clinical research.

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<![CDATA[SOCS1: phosphorylation, dimerization and tumor suppression]]> https://www.researchpad.co/article/N5f7482da-3c2c-403e-ab79-809e5255afc9

Suppressor of cytokine signaling (SOCS) family members are upregulated following JAK-STAT pathway activation by cytokines. SOCS proteins are recognized inhibitors of cytokine signaling playing roles in cell growth and differentiation. Moreover, SOCS1 and SOCS3 have been shown to be involved in tumor suppression through their ability to interact with p53 leading to the activation of its transcriptional program and showing the implication of SOCS family members in the regulation of apoptosis, ferroptosis and senescence. More recently, we demonstrated that the SRC family of non-receptor tyrosine kinases (SFK) can phosphorylate SOCS1 leading to its homodimerization and inhibiting its interaction with p53. Then, we reactivated the SOCS1-p53 tumor suppressor axis with the SFK inhibitor dasatinib in combination with the p53 activating compound PRIMA. This work suggests new avenues for cancer treatment and leaves open several new questions that deserve to be addressed.

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<![CDATA[Aging and cancer: Is glucose a mediator between them?]]> https://www.researchpad.co/article/Na2a9a629-54d0-4733-90c8-ec63e121b1d1

Aging can increase cancer incidence because of accumulated mutations that initiate cancer and via compromised body control of premalignant lesions development into cancer. Relative contributions of these two factors are debated. Recent evidence suggests that the latter is rate limiting. In particular, hyperglycemia caused by compromised body control of blood glucose may be a factor of selection of somatic mutation-bearing cells for the ability to use glucose for proliferation. High glucose utilization in aerobic glycolysis is a long known characteristic of cancer. The new evidence adds to the concepts that have been being developed starting from mid-1970ies to suggest that age-related shifts in glucose and lipid metabolism increase the risk of cancer and compromise prognoses for cancer patients and to propose antidiabetic biguanides, including metformin, for cancer prevention and as an adjuvant means of cancer treatment aimed at the metabolic rehabilitation of patients. The new evidence is consistent with several effects of glucose contributing to aging and acting synergistically to enhance carcinogenesis. Glucose can affect (i) separate cells (via promoting somatic mutagenesis and epigenetic instability), (ii) cell populations (via being a factor of selection of phenotypic variants in cell populations for higher glucose consumption and, ultimately, for high aerobic glycolysis); (iii) cell microenvironment (via modification of extracellular matrix proteins), and (iv) the systemic levels (via shifting the endocrine regulation of metabolism toward increasing blood lipids and body fat, which compromise immunological surveillance and promote inflammation). Thus, maintenance of youthful metabolic characteristics must be important for cancer prevention and treatment.

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<![CDATA[Translating the role of PARP inhibitors in triple-negative breast cancer]]> https://www.researchpad.co/article/5c853ff8d5eed0c484228317 ]]> <![CDATA[Direct Inhibition of ?-catenin: A new strategy for colorectal cancer]]> https://www.researchpad.co/article/5c853ff7d5eed0c4842282c9 ]]> <![CDATA[]]> https://www.researchpad.co/article/5c853ffcd5eed0c484228352 ]]> <![CDATA[Still a hopeless case for personalized oncology? Pancreatic cancer revisited]]> https://www.researchpad.co/article/5c853ffad5eed0c48422832f ]]> <![CDATA[EPAC mediates the dual role of cAMP signaling in melanoma]]> https://www.researchpad.co/article/5c853ffed5eed0c48422835f ]]> <![CDATA[DNA methylation in senescence, aging and cancer]]> https://www.researchpad.co/article/5c854000d5eed0c48422838b ]]> <![CDATA[Gestational tumors as a model to probe reticulate evolution in human neoplasia]]> https://www.researchpad.co/article/5c671938d5eed0c484f1f08d

Reticulate evolution, which involves the transfer of genes and other inheritable information between organisms, is of interest to a cancer researcher if only because “pirating” a trait can help a cell and its progeny adapt, survive, or take over much faster than by accumulating random mutations. However, despite being observed repeatedly in experimental models of neoplasia, reticulate evolution is assumed to be negligible in human cancer primarily because detecting gene transfer between the cells of the same genetic background can be difficult or impossible. This commentary suggests that gestational tumors, which are genetically distinct from the women who carry them, provide an opportunity to test whether reticulate evolution affects the development of human neoplasia.

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<![CDATA[RBL2/p130: a direct AKT substrate and mediator of AKT inhibition-induced apoptosis]]> https://www.researchpad.co/article/5c48facfd5eed0c4841fb8a8 ]]>