Due to the loss of DNA repair mechanisms in colorectal cancer (CRC) with microsatellite instability (MSI), somatic mutations accumulate within DNA; making them more prone to attack by tumor ...infiltrating lymphocytes (TIL) and macrophages. We hypothesize that MSI-High (MSI-H) patients have favorable survival due to increased tumor immunogenicity. The Cancer Genome Atlas (TCGA) was used to evaluate gene expression from 283 patients with CRC, comparing MSI-H and microsatellite stable (MSS) patients. CIBERSORT algorithm estimated the fraction of immune cell types. We found that low expression of DNA repair genes (MLH1, MLH3, PMS1, PMS2, ATR, PRKDC, ATM, BRCA2) associated with MSI-H. MSI-H was directly associated with Helper T-cells (p = 0.034) and M1 macrophages (p < 0.0001). MSI-H tumors associated with diminished intra-tumoral heterogeneity as well as higher expression of checkpoint molecules PD-1, PD-L1, CTLA4, LAG3 and TIM3 (p < 0.0001). Improved OS was seen in patients with low ATM, PMS2 and MLH3. In the TCGA CRC cohort, decreased expression of DNA repair genes associated with MSI-H. MSI-H patients had improved survival, likely due to higher TIL and M1 macrophage infiltration as well as lower intra-tumoral heterogeneity. MSI-H also associates with expression of immune checkpoint molecules with potential for development of therapeutic targets.
Leadership Training of Surgery in US Takabe, Kazuaki
Keio journal of medicine,
2017, 2017-00-00, 20170101, Letnik:
66, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Surgeons in the US are trained to be leaders during their surgical residencies as part of their postgraduate education. Leadership is considered to be essential, since the surgeon directs the medical ...team. Every surgeon is expected to gain leadership skills. I would like to introduce the leadership training that I received as an ASCO Leadership Development Program graduate and as a Scholarship recipient of Geisel Leadership Course at Dartmouth in addition to General Surgery Residency at University of California San Diego. I will also present our research on Precision Medicine.(Presented at the 1943rd Meeting, July 5, 2017)
APOBEC3 enzymes contribute significantly to DNA mutagenesis in cancer. These enzymes are also capable of converting C bases at specific positions of RNAs to U. However, the prevalence and ...significance of this C-to-U RNA editing in any cancer is currently unknown. We developed a bioinformatics workflow to determine RNA editing levels at known APOBEC3-mediated RNA editing sites using exome and mRNA sequencing data of 1040 breast cancer tumors. Although reliable editing determinations were limited due to sequencing depth, editing was observed in both tumor and adjacent normal tissues. For 440 sites (411 genes), editing was determinable for ≥5 tumors, with editing occurring in 0.6%-100% of tumors (mean 20%, SD 14%) at an average level of 0.6%-20% (mean 7%, SD 4%). Compared to tumors with low RNA editing, editing-high tumors had enriched expression of immune-related gene sets, and higher T cell and M1 macrophage infiltration, B and T cell receptor diversity, and immune cytolytic activity. Concordant with this, patients with increased RNA editing in tumors had better disease- and progression-free survivals (hazard ratio = 1.67-1.75,
< 0.05). Our study identifies that APOBEC3-mediated RNA editing occurs in breast cancer tumors and is positively associated with elevated immune activity and improved survival.
Rat sarcoma (RAS) is a well‐known oncogene that plays important roles in cancer proliferation, cell survival and cell invasion. RAS exists as three major isoforms, Kirsten rat sarcoma (KRAS), Harvey ...rat sarcoma (HRAS) and neuroblastoma rat sarcoma (NRAS). Mutations of these genes account for approximately 30% of all cancers. Among them, KRAS mutations are the most common, responsible for 85%, followed by NRAS (12%) and HRAS (3%). Although the development of RAS inhibitors has been explored for over the past decade, so far, no effective inhibitor has been found. MicroRNA (miRNA) are a class of small non–coding RNA that control the gene expression of pleural target genes at the post–transcriptional level. MiRNA play critical roles in the physiological and pathological processes at work in cancers, such as cell proliferation, cell death, cell invasion and metastasis. MicroRNA‐143 (MIR143) is known to function as a tumor suppressor in a variety of cancers. One of its known mechanisms is suppression of RAS expression and its effector signaling pathways, such as PI3K/AKT and MAPK/ERK. Within the last five years, we developed a potent chemically modified MIR143‐3p that enabled us to elucidate the details of the KRAS signaling networks at play in colon and other cancer cells. In this review, we will discuss the role of MIR143‐3p in those RAS signaling networks that are related to various biological processes of cancer cells. In addition, we will discuss the possibility of the use of MIR143 as a therapeutic drug for targeting RAS signaling networks.
In this review, we will discuss the role of MIR143 in those Rat sarcoma (RAS) signaling networks that are related to various biological processes of cancer cells. In addition, we will discuss the possibility of the use of MIR143 as a therapeutic drug for targeting RAS signaling networks.
Abstract Malignant phyllodes tumors of the breast are a rare entity. They occur infrequently but most often in younger women in comparison to typical epithelial-based breast cancers. Treatment of ...these tumors is not without controversy and in this review we will present an update on the diagnosis and management of malignant phyllodes tumors of the breast.
Achievement of microscopic tumor clearance (R0) after pancreatic ductal adenocarcinoma (PDAC) surgery is determined by cancer biology rather than operative technique. Fibroblasts are known to play ...pro-cancer roles; however, a small subset was recently found to play anti-cancer roles. Therefore, we hypothesized that intratumor fibroblasts contribute to curative resection and a better survival of PDAC. Utilizing a large, publicly available PDAC cohort, we found that fibroblast composition was associated with R0 curative resection. A high amount of fibroblasts in PDACs was significantly associated with a higher amount of mature vessels, but not with blood angiogenesis. A high amount of fibroblasts was also associated with a higher infiltration of anti-cancer immune cells, such as CD8+ T-cells and dendritic cells, together with higher inflammatory signaling, including IL2/STAT5 and IL6/JAK/STAT3 signaling. Further, the fibroblast composition was inversely associated with cancer cell composition in the bulk tumor, along with an inverse association with proliferative characteristics, such as MYC signaling and glycolysis. The patients with high-fibroblast PDACs showed an improved prognosis. In conclusion, we found that PDACs with high fibroblasts were associated with a higher R0 resection rate, resulting in a better prognosis. These findings may be due to less aggressive biology with a higher vascularity and anti-cancer immunity, and a low cancer cell component.
Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the protein ...kinase B (AKT) and extracellular signal‐regulated kinase 1 and 2 (ERK1/2) signaling pathways through sphingosine 1‐phosphate receptor (S1PR) 2 in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)‐induced apoptosis. However, the role of S1PR2 in bile‐acid–mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here, we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA‐ and sphingosine‐1‐phosphate (S1P)‐induced activation of ERK1/2 and AKT were inhibited by JTE‐013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA‐ and S1P‐induced cell proliferation and migration were inhibited by JTE‐013 and a specific short hairpin RNA of S1PR2, as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, expression of S1PR2 was up‐regulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL‐induced cholangiocyte proliferation and cholestatic injury, as indicated by significant reductions in inflammation and liver fibrosis in S1PR2 knockout mice. Treatment of BDL mice with JTE‐013 significantly reduced total bile acid levels in serum and cholestatic liver injury. Conclusion: This study suggests that CBA‐induced activation of S1PR2‐mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases. (Hepatology 2017;65:2005‐2018).
Cancer cachexia, mechanism and treatment Aoyagi, Tomoyoshi; Terracina, Krista P; Raza, Ali ...
World journal of gastrointestinal oncology,
04/2015, Letnik:
7, Številka:
4
Journal Article
Odprti dostop
It is estimated that half of all patients with cancereventually develop a syndrome of cachexia, with anorexiaand a progressive loss of adipose tissue and skeletalmuscle mass. Cancer cachexia is ...characterized by systemicinflammation, negative protein and energy balance, andan involuntary loss of lean body mass. It is an insidioussyndrome that not only has a dramatic impact on patientquality of life, but also is associated with poor responsesto chemotherapy and decreased survival. Cachexia isstill largely an underestimated and untreated condition,despite the fact that multiple mechanisms are reported tobe involved in its development, with a number of cytokinespostulated to play a role in the etiology of the persistentcatabolic state. Existing therapies for cachexia, includingorexigenic appetite stimulants, focus on palliation ofsymptoms and reduction of the distress of patients andfamilies rather than prolongation of life. Recent therapiesfor the cachectic syndrome involve a multidisciplinaryapproach. Combination therapy with diet modificationand/or exercise has been added to novel pharmaceuticalagents, such as Megestrol acetate, medroxyprogesterone,ghrelin, omega-3-fatty acid among others. These agentsare reported to have improved survival rates as well asquality of life. In this review, we will discuss the emergingunderstanding of the mechanisms of cancer cachexia,the current treatment options including multidisciplinarycombination therapies, as well an update on new andongoing clinical trials.
PDF
