CD47 is a cell surface protein in the immunoglobulin superfamily which is normally expressed at low levels in every healthy cell. It´s main physiologic function is to act as an inhibitor of phagocytosis; this occurs throughout interaction with SIRPa expressed on macrophages. Interaction between CD47 and SIRPa leads to activation of tyrosine phosphatases that inhibit myosin accumulation at the submembrane assembly site of the phagocytic synapse, resulting in phagocytosis blockade. In this way CD47 acts as a “don´t eat me signal” for healthy self-cells; accordingly, loss of CD47 leads to phagocytosis of aged or damaged cells. Taking advantage of this anti-phagocytic signal provided by CD47, many types of tumors overexpress this protein, thereby avoiding phagocytosis by macrophages and aiding in the survival of cancer cells. The aim of this review is to describe the physiologic the pathophysiologic role of CD47; summarize the available high-quality information about this molecule as a potential biomarker and/or therapeutic target in cancer; finally, we present an in-depth analysis of the available information about CD47 in association with nonsmall cell lung cancer, EGFR mutations, and tumor microenvironment.
Taxane‐based chemotherapy regimens are used as first‐line treatment for breast cancer. Neurotoxicity, mainly taxane‐induced peripheral neuropathy (TIPN), remains the most important dose‐limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random‐effects gene meta‐analyses and examined interstudy heterogeneity with meta‐regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single‐nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta‐analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1‐rs2032582, ABCB1‐rs3213619, BCL6/‐rs1903216, /CAND1‐rs17781082, CYP1B1‐rs1056836, CYP2C8‐rs10509681, CYP2C8‐rs11572080, EPHA5‐rs7349683, EPHA6‐rs301927, FZD3‐rs7001034, GSTP1‐rs1138272, TUBB2A‐rs9501929, and XKR4‐rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta‐analysis. In conclusion, through systematic review and meta‐analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.
e15521 Background: In locoregional colon cancer, interindividual survival and recurrence rates following surgical resection are highly variable and not solely dependent on cancer anatomic extent. The HALP (hemoglobin, albumin, lymphocyte and platelet) index was recently developed to assess prognosis with greater accuracy. In the present work, we evaluate, for the first time, the prognostic value of the HALP index in Hispanic colon cancer patients. Methods: We conducted a retrospective cohort study in Mexican patients with histologically confirmed stage I–III primary colonic adenocarcinoma who underwent radical surgical resection at Mexico’s National Institute of Cancer, between 2008 and 2020. We collected clinical and pathological variables from electronic medical records for all included patients. We determined preoperative HALP score [hemoglobin level (g/L) × albumin level (g/L) × lymphocyte count (/L) / platelet count (/L)] optimal cut-off value by using the X-tile software. We plotted survival curves using the Kaplan-Meier method, and performed a multivariate Cox regression analysis to explore the association of the dichotomized preoperative HALP score with two primary endpoints: overall survival (OS) and disease-free survival (DFS). We also explored the association of all collected variables with both the dichotomized HALP score and our primary endpoints. Results: We included 640 patients (49.8% females). The most prevalent age group was 40-70 years and pathological TNM (pTNM) stages II and III represented most of our population (43.1% and 45.2% respectively). The optimal HALP cut-off value was 15.0, classifying patients into low or high HALP score. In the Kaplan-Meier analysis, low HALP score was significantly associated with shorter median OS (73.5 vs. 84.8 months; log-rank test p = 0.013). Multivariate Cox regression analysis established that a low HALP score is an independent factor associated with shorter OS (HR = 1.942, 95% CI = 1.647-2.875; p = 0.031). There was no significant association between HALP score and DFS. HALP index was statistically significantly associated with pTNM stage, tumor differentiation, colon cancer location and BMI. Surgical margin status and pTNM stage were significantly associated with OS. Cancer perforation was significantly associated with DFS. Conclusions: Our findings suggest that HALP index is a viable preoperative predictor of survival for Hispanic patients, despite recurrence. It seems to reflect both the anatomical extent of the disease, and traditionally unaccounted nutritional and inflammatory factors that are significant for prognosis. Since this index is computed through widely-available parameters, its adoption in clinical practice could significantly benefit developing countries, such as those in Latin America. We provide a cut-off value that can be used in Hispanic colon cancer patients to assess prognosis and guide management.
Histaminergic, orexinergic, and cannabinoid systems play a role in both physiologic and oncogenic mechanisms in digestive tissues. These three systems are important mediators of tumor transformation, as they are associated with redox alterations, which are key aspects in oncological disorders. The three systems are known to promote alterations in the gastric epithelium through intracellular signaling pathways, such as oxidative phosphorylation, mitochondrial dysfunction, and increased Akt, which might promote tumorigenesis. Histamine promotes cell transformation through redox-mediated alterations in the cell cycle, DNA repair, and immunological response. The increase in histamine and oxidative stress generates angiogenic and metastatic signals through the VEGF receptor and H2R-cAMP-PKA pathway. Immunosuppression in the presence of histamine and ROS is linked to a decrease in dendritic and myeloid cells in gastric tissue. These effects are counteracted by histamine receptor antagonists, such as cimetidine. Regarding orexins, overexpression of the Orexin 1 Receptor (OX1R) induces tumor regression through the activation of MAPK-dependent caspases and src-tyrosine. OX1R agonists are candidates for the treatment of gastric cancer by stimulating apoptosis and adhesive interactions. Lastly, cannabinoid type 2 (CB2) receptor agonists increase ROS, leading to the activation of apoptotic pathways. In contrast, cannabinoid type 1 (CB1) receptor agonists decrease ROS formation and inflammation in gastric tumors exposed to cisplatin. Overall, the repercussion of ROS modulation through these three systems on tumor activity in gastric cancer depends on intracellular and/or nuclear signals associated with proliferation, metastasis, angiogenesis, and cell death. Here, we review the role of these modulatory systems and redox alterations in gastric cancer.
Background. Survival and recurrence rates following locoregional colon cancer surgical resection are highly variable. Currently used tools to assess patient risk are still imperfect. In the present work, we evaluate, for the first time, the prognostic value of the recently developed HALP (hemoglobin, albumin, lymphocyte, and platelet) index in Hispanic colon cancer patients. Patients and Methods. We conducted a retrospective cohort study in Mexican patients with a nonmetastatic colon cancer diagnosis who underwent surgical resection. We determined the preoperative HALP score optimal cut-off value by using the X-tile software. We plotted survival curves using the Kaplan–Meier method and performed a multivariate Cox regression analysis to explore the association of preoperative HALP score with two primary endpoints: overall survival (OS) and disease-free survival (DFS). Results. We included 640 patients (49.8% female). The optimal HALP cut-off value was 15.0. A low HALP index was statistically significantly associated with a higher TNM stage. Low HALP score was statistically significantly associated with shorter median OS in the Kaplan–Meier analysis (73.5 vs. 84.8 months) and in the multivariate Cox regression analysis (HR = 1.942, 95% CI = 1.647–2.875). There was no significant association between the HALP score and DFS. Conclusions. Our findings show that the HALP index is an independent factor associated with survival in Hispanic patients, despite recurrence. It seems to reflect both the anatomical extent of the disease and traditionally unaccounted nutritional and inflammatory factors that are significant for prognosis.
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