Background
Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T ...cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity.
Methods
Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA). CYT was defined by GZMA and PRF1 expression, and CIBERSORT was used to evaluate intratumoral immune cell composition.
Results
High CYT was associated with high microsatellite instability (MSI-H), as well as high levels of activated memory CD4+T cells, gamma-delta T cells, and M1 macrophages. CYT-high CRC patients had improved overall survival (
p
= 0.019) and disease-free survival (
p
= 0.016) compared with CYT-low CRC patients, especially in TIL-positive tumors. Multivariate analysis demonstrated that CYT- high associates with improved survival independently after controlling for age, lymphovascular invasion, colonic location, microsatellite instability, and TIL positivity. The levels of immune checkpoint molecules (ICMs)—programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), and indoleamine 2,3-dioxygenase 1 (IDO1)—correlated significantly with CYT (
p
< 0.0001); with improved survival in CYT-high and ICM-low patients, and poorer survival in ICM-high patients.
Conclusions
High CYT within CRC is associated with improved survival, likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CYT is also associated with high expression of ICMs; thus, further studies to elucidate the role of CYT as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.
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.
Pedestrian safety in Chennai Narayanan, Sumana
Journal of Road Safety (Australasian College of Road Safety. Online),
01/2020, Letnik:
31, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Pedestrian and cyclist safety are not considered by urban planners or road users in India. Data on road crashes tend to underreport crashes involving this group. In spite of adopting a ...Non-Motorised-Transport (NMT) friendly policy in 2014, Chennai city in Tamil Nadu continues to prioritise motorised transport. Five years after the NMT Policy adoption, pedestrian infrastructure was assessed in 11 locations. A perception survey of 37 road users was also conducted as the Policy calls for changing the mindset of motorists towards pedestrians. The pedestrian infrastructure assessment found that footpath and pedestrian crossings are inadequate with only six locations having contiguous, wide, walkable footpaths for some distance. Even in these locations, the footpath is encroached upon by parked vehicles, garbage, utilities, and shops. Even roads which have seen pedestrian-focussed interventions fall short. Pedestrian infrastructure, what little exists, is not friendly towards the elderly and people with disabilities. The perception survey suggests that pedestrians are not safe on the roads and that motorists do not slow down or stop for pedestrians. Some motorists (autorickshaw drivers and bus drivers) felt that pedestrians put themselves at risk by walking on the road and crossing the road as they please. Pedestrians interviewed, however, pointed out that footpaths are few, and those that exist are encroached upon, forcing pedestrians to walk on the road. In spite of being the first city in India to adopt an NMT Policy, many pedestrians continues to be precarious.
microRNA-143(miR-143) is a well-known tumor suppressive microRNA that exhibits anti-tumoral function by targeting KRAS signaling pathways in various malignancies. We hypothesized that miR-143 ...suppresses breast cancer progression by targeting KRAS and its effector molecules. We further hypothesized that high expression of miR-143 is associated with a favorable tumor immune microenvironment of estrogen receptor (ER)-positive breast cancer patients which result in improved survival. Two major publicly available breast cancer cohorts; The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. The miR-143 high expression group was associated with increased infiltration of anti-cancer immune cells and decreased pro-cancer immune cells, as well as enrichment of the genes relating to T helper (Th1) cells resulting in improved overall survival (OS) in ER-positive breast cancer patients. To the best of our knowledge, this is the first study to demonstrate that high expression of miR-143 in cancer cells associates with a favorable tumor immune microenvironment, upregulation of anti-cancer immune cells, and suppression of the pro-cancer immune cells, associating with better survival of the breast cancer patients.
Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer ...development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.
Laparoscopic and robotic hernia surgery offers advantages over open herniorrhaphy including faster recover and lower wound infection but is associated with rare but serious complications such as ...visceral injury and intestinal obstruction. We describe two cases of small bowel obstruction with strangulation that occurred shortly after routine robotic hernia surgery. We define this rare type of strangulating internal hernia as a peritoneal pocket hernia and call attention to its diagnosis and management.
Background
Concern for postoperative complications causing airway compromise has limited widespread acceptance of ambulatory thyroid surgery. We evaluated differences in outcomes and hospital costs ...in those monitored for a short stay of 6 h (SS), inpatient observation of 6–23 h (IO), or inpatient admission of >23 h (IA).
Methods
We retrospectively reviewed all patients undergoing thyroidectomy from 2006 to 2012. The incidence of postoperative hemorrhage, nerve dysfunction, and hypocalcemia were evaluated, as well as cost data comparing the SS and IO groups.
Results
Of 1447 thyroidectomies, 880 (60.8 %) were performed as SS, 401 (27.7 %) as IO, and 166 (11.5 %) as IA. Fewer patients in the SS group (59 %) underwent total thyroidectomy than IO (73 %) and IA (71 %;
p
< 0.01), and SS patients had smaller thyroid weights (27.9 g) compared with IO and IA (47.2 and 98.9 g, respectively;
p
< 0.01). Ten (0.69 %) patients developed hematomas requiring reoperation, five of the ten patients received antiplatelet or anticoagulant therapy perioperatively. Only one patient in the IA group bled within the 6- to 23-h period, and no patients with bleeding who were discharged at 6 h would have benefitted from 23-h observation. Twenty-four (1.66 %) recurrent laryngeal nerve injuries were identified, 16 with temporary neuropraxias. In addition, 24 (1.66 %) patients had symptomatic hypocalcemia, which was transient in 17 individuals. Financial data showed higher payments and lower costs associated with SS compared with IO.
Conclusions
Selective SS thyroidectomy can be safe and cost effective, with few overall complications in patients undergoing more complex operations involving larger thyroids who were admitted to hospital.
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, idiopathic, repeated inflammatory disease. Colorectal cancer (CRC) that develops in ...patients with IBD is known as colitis-associated colorectal cancer (CAC), but the underlying carcinogenic mechanism remains unclear. Genomic analysis of sporadic CRC has been well described based on next-generation sequencing (NGS) data. Using NGS, we compared all exons of 415 cancer-associated genes in patients in Japan and the USA who had CRC and found similar genomic alteration patterns among the two populations. However, genomic analysis of CAC has not been thoroughly investigated.
The molecular pathogenesis of CAC shares many features with sporadic CRC, but there are distinct variations in the time and frequency of some alterations. Gene alterations in CAC are gradually being elucidated using genomic sequencing analyses. Some studies have shown that gene alteration patterns differ between UC and CD. The carcinogenesis of CAC depends on unique environmental, genetic, and immunological factors.
In this review, we have discussed the differences in genomic alterations between sporadic CRC and CAC. NGS in patients with IBD has the potential to detect early CAC and to suggest therapeutic targets.
PDF
