Significance Of Different Subtypes Research Articles

AMPK activation reduces cancer cell aggressiveness via inhibition of monoamine oxidase A (MAO-A) expression/activity

AimAMPK can be considered as an important target molecule for cancer for its unique ability to directly recognize cellular energy status. The main aim of this study is to explore the role of different AMPK activators in managing cancer cell aggressiveness and to understand the mechanistic details behind the process. Main methodsFirst, we explored the AMPK expression pattern and its significance in different subtypes of lung cancer by accessing the TCGA data sets for LUNG, LUAD and LUSC patients and then established the correlation between AMPK expression pattern and overall survival of lung cancer patients using Kaplan-Meire plot. We further carried out several cell-based assays by employing different wet lab techniques including RT-PCR, Western Blot, proliferation, migration and invasion assays to fulfil the aim of the study. Key findings•Expression of AMPK is correlated with survival and prognosis of lung cancer patients.•AMPK activators like Metformin and Phenformin downregulate A549 and HCT-116 cell proliferation and migration via repression of p38MAPK activity, subsequent augmentation of R1 repressor and corresponding downregulation of MAO-A expression/activity resulting reduction in the intracellular ROS.•SRT-1720 directly activates AMPK in LKB1 mutant A549 cells either alone or in combination with Metformin resulting regulation of cancer cell aggressiveness. SignificanceThis study identifies the importance of AMPK activators as a repurposing agent for combating lung and colon cancer cell aggressiveness. It also suggests SRT-1720 as a potent repurposing agent for cancer treatment especially in NSCLC patients where a point mutation is present in LKB1.

C-Kit and Flt3 mutation status in acute myeloid leukaemia with cytogenetic correlation and prognosis: A series of 75 cases

Recent WHO classification (5 edition) has included Acute Myeloid Leukaemia (AML) with mutations in NPM1, CEBPA as separate entities along with AML with cytogenetic abnormalities in AML with recurrent genetic abnormalities. Even though C-kit and FLT3 mutations in AML have no diagnostic importance, prognostic significance in different subtypes of AML for the presence of these mutations are not the same.To assess the correlation between French American British (FAB) AML classification, specific cytogenetic abnormalities with C-kit, and FLT3 mutation in AML and to evaluate the prognosis and survival of AML patients with respect to cytogenetic abnormalities and C-kit and FLT3 mutation status. Retrospectively all AML cases in which C-kit and FLT3 mutation status was assessed were retrieved; C-kit D816V mutation status had been assessed by Real time PCR; For FLT3 mutation, both Internal tandem duplication (ITD) and D835V mutation status had been assessed using PCR and gel electrophoresis; The data regarding morphological with immunophenotypic diagnosis, conventional karyotyping, FISH for translocation 8;21 (t (8;21)) and inversion16 / translocation16;16 (t (16;16) were also retrieved in all these cases along with follow-up from hospital records. Total 75 cases were included; Male/ Female ratio was 1.21:1 (41/34); Median age was 31 (Range: 2 - 64); 18 cases had translocation 8;21 (t (8;21)); 3 cases showed inversion16 / translocation16;16 (t (16;16); Out of the 18 cases which showed t (8;21), 10 cases had associated loss of sex chromosome. Eight cases had C-kit D816V mutation; three of which had t (8;21) while two had inversion 16. 12 cases had FLT3 mutations among which nine were ITD while three had D835V mutation. On karyotyping, one of these cases showed hyperdiploidy while the majority had normal karyotype. A single case had both C-kit D816V mutation and FLT3 D835V mutation with inversion 16 on karyotyping; Most common type of AML in both cases with FLT3 mutation and C-kit mutation was AML-M2 (FAB); Commonest karyotyping abnormality for cases with C-kit mutation was t(8;21); while for FLT3 mutation, the majority had normal karyotype; The single case which had both C-kit D816V mutation and FLT3 D835V mutation was alive event-free at three-year follow-up. Both FLT3 ITD and TKD mutations had a worse prognosis in our study. However, AML cases with C-kit mutation had a similar prognosis comparable to C kit negative cases. A large-scale study is required to elucidate the significance of this.

Multilocus Sequence Typing as a Useful Tool for the Study of the Genetic Diversity and Population Structure of Cryptosporidium Spp.

Abstract One of the most important aquatic parasites in industrialized countries, Cryptosporidium spp., is a major cause of diarrheal disease in humans and animals worldwide. The contingent evolution of cryptosporidia with hosts, host adaptation, and geographic variation contributed to the creation of species subtypes, thereby shaping their population genetic structures. Multilocus typing tools for population genetic characterizations of transmission dynamics and delineation of mechanisms for the emergence of virulent subtypes have played an important role in improving our understanding of the transmission of this parasite. However, to better understand the significance of different subtypes with clinical disease manifestations and transmission risks, a large number of samples and preferably from different geographical areas need to be analyzed. This review provides an analysis of genetic variation through multilocus sequence typing, provides an overview of subtypes, typing gene markers for Cryptosporidium parvum, Cryptosporidium hominis, Cryptosporidium muris and Cryptosporidium andersoni genotypes and an overview of the hosts of these parasites.

Identification and validation of a muscle failure index to predict prognosis and immunotherapy in lung adenocarcinoma through integrated analysis of bulk and single-cell RNA sequencing data.

It was previously reported that the production of exerkines is positively associated with the beneficial effects of exercise in lung adenocarcinoma (LUAD) patients. This study proposes a novel scoring system based on muscle failure-related genes, to assist in clinical decision making. A comprehensive analysis of bulk and single cell RNA sequencing (scRNA-seq) of early, advanced and brain metastatic LUAD tissues and normal lung tissues was performed to identify muscle failure-related genes in LUAD and to determine the distribution of muscle failure-related genes in different cell populations. A novel scoring system, named MFI (Muscle failure index), was developed and validated. The differences in biological functions, immune infiltration, genomic alterations, and clinical significance of different subtypes were also investigated. First, we conducted single cell analysis on the dataset GSE131907 and identified eight cell subpopulations. We found that four muscle failure-related genes (BDNF, FNDC5, IL15, MSTN) were significantly increased in tumor cells. In addition, IL15 was widely distributed in the immune cell population. And we have validated it in our own clinical cohort. Then we created the MFI model based on 10 muscle failure-related genes using the LASSO algorithm, and MFI remained an independent prognostic factor of OS in both the training and validation cohorts. Moreover, we generated MFI in the single-cell dataset, in which cells with high MFI received and sent more signals compared to those with low MFI. Biological function analysis of both subtypes revealed stronger anti-tumor immune activity in the low MFI group, while tumor cells with high MFI had stronger metabolic and proliferative activity. Finally, we systematically assessed the immune cell activity and immunotherapy responses in LUAD patients, finding that the low MFI group was more sensitive to immunotherapy. Overall, our study can improve the understanding of the role of muscle failure-related genes in tumorigenesis and we constructed a reliable MFI model for predicting prognosis and guiding future clinical decision making.

Expression of leptin and its receptor in thyroid carcinoma: distinctive prognostic significance in different subtypes.

To investigate the potential prognostic significance of leptin and its receptor (Ob-R) in thyroid carcinoma. The study cohort consisted of 173 patients including 93 cases with papillary thyroid carcinoma (PTC), 41 cases with follicular thyroid carcinoma (FTC), 25 cases with medullary thyroid carcinoma (MTC) and 14 cases with anaplastic thyroid carcinoma (ATC). We investigated the correlation between clinicopathological features and leptin or Ob-R. The Kaplan-Meier method was used to analyse the survival rate. There was a strong correlation of leptin expression with Ob-R expression in PTC, FTC and ATC. For PTC, leptin expression was strongly correlated with older age, larger tumour size, nodal metastasis and advanced stage. Ob-R was significantly correlated with larger tumour size, nodal metastasis and advanced stage. The 5-year disease-free survival (DFS) rate in patients with positive leptin or its receptor expression was lower than that in patients without expression (with statistical difference). For FTC, patients with positive leptin or Ob-R expression developed no recurrence or metastasis during the follow-up. For MTC, Ob-R was significantly correlated with nodal metastasis and advanced stage (P<0·05). For ATC, patients with positive Ob-R expression had longer median DFS than those with negative expression (436±185 vs 57±71days), and the difference in the survival rate was statistically significant (P<0·05). There was a strong correlation of leptin expression with Ob-R expression in PTC, FTC and ATC. Leptin and Ob-R had negative prognostic significance in PTC, while Ob-R may play a protective role in ATC.

Does Androgen Receptor Have a Prognostic Role in Patients with Estrogen/Progesterone-Negative and c-erbB-2-Positive Breast Cancer?

Recently, it has been shown that androgen and androgen receptor (AR) also have an important role in the pathogenesis and outcome of breast cancer. However, their significance in different subtypes of breast cancer is still under investigation. The aim of this study was to study the effects of AR on clinicopathological features and prognosis in patients with estrogen and progesterone receptor (ER/PR)-negative, HER2-positive breast cancer. Tumor paraffin-embedded blocks from archives were used for AR study. Data of patients with ER/PR-negative and HER2-positive breast cancer diagnosed at our institute between 1999 and 2010 were recorded and analyzed retrospectively. We studied 36 patients with ER/PR-negative and HER2-positive breast cancer for AR status. Sixteen of them (44.4%) showed AR positivity. The median age was 47 and 56 years for AR-negative and -positive patients, respectively (P = 0.03). The number of postmenopausal patients was higher in the AR-positive than -negative group (56 vs 30%) (P = 0.01). Other demographic data were similar in both group. Histopathological parameters and tumor and nodal stages were similar in both groups. Trastuzumab treatment was more frequently given to AR-positive than -negative patients (94 vs 44%) (P = 0.01). Median follow-up was 47.1 and 34.7 months in AR-negative and -positive groups, respectively (P = 0.03). Relapse occurred in six and four patients in AR-negative and -positive groups. Median progression-free survival (PFS) was similar in both groups (15.7 and 19.6 months in AR-negative and -positive patients, respectively; P = 0.56). Two patients died at 23.4 and 46 months of follow-up in the AR-negative group. There were no deaths in the AR-positive group. Overall survival analyses were not done as a result of an unmet number of events. Median PFS was similar in AR-positive and -negative in that group of patients with ER/PR-negative and HER2-positive breast cancer. However AR-positive patients were more frequently postmenopausal, older, and positive for lymphovascular space invasion. More frequently applied trastuzumab in the AR-positive group might have an effect on the similarity of PFS between the two groups. Studies with higher numbers in this subset of patients with breast cancer will give more robust data.