Integrated multi-omics analysis and machine learning developed a prognostic model based on mitochondrial function in a large multicenter cohort for Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is a common and aggressive type of cancer worldwide. Despite recent advancements in its treatment, the prognosis for patients with GC remains poor. Understanding the mechanisms of cell death in GC, particularly those related to mitochondrial function, is crucial for its development and progression. However, more research is needed to investigate the significance of the interaction between mitochondrial function and GC cell death. METHODS: We employed a robust computational framework to investigate the role of mitochondria-associated proteins in the progression of GC in a cohort of 1,199 GC patients. Ten machine learning algorithms were utilized and combined into 101 unique combinations. Ultimately, we developed a Mitochondrial-related-Score (MitoScore) using the machine learning model that exhibited the best performance. We observed the upregulation of LEMT2 and further explored its function in tumor progression. Mitochondrial functions were assessed by measuring mitochondrial ATP, mitochondrial membrane potential, and levels of lactate, pyruvate, and glucose. RESULTS: MitoScore showed significant correlations with GC immune and metabolic functions. The higher MitoScore subgroup exhibited enriched metabolic pathways and higher immune activity. Overexpression of LETM2 (leucine zipper and EF-hand containing transmembrane protein 2) significantly enhanced tumor proliferation and metastasis. LETM2 plays a role in promoting GC cell proliferation by activating the mTOR pathway, maintaining mitochondrial homeostasis, and promoting glycolysis. CONCLUSION: The powerful machine learning framework highlights the significant potential of MitoScore in providing valuable insights and accurate assessments for individuals with GC. This study also enhances our understanding of LETM2 as an oncogene signature in GC. LETM2 may promote tumor progression by maintaining mitochondrial health and activating glycolysis, offering potential targets for diagnosis, treatment, and prognosis of GC.

Cognitive and neural mechanisms of voluntary versus forced language switching in Chinese-English bilinguals: an fMRI study.

The ecological validity of bilingual code-switching has garnered increasing attention in recent years. Contrary to traditional studies that have focused on forced language switching, emerging theories posit that voluntary switching may not incur such a cost. To test these claims and understand differences between forced and voluntary switching, the present study conducted a systematic comparison through both behavioral and neural perspectives. Utilizing fMRI alongside picture-naming tasks, our findings diverge from prior work. Voluntary language switching not only demonstrated switching costs at the behavioral level but also significantly activated brain regions associated with inhibitory control. Direct comparisons of voluntary and forced language switching revealed no significant behavioral differences in switching costs, and both shared several common brain regions that were activated. On the other hand, a nuanced difference between the two types of language switching was revealed by whole-brain analysis: voluntary switching engaged fewer language control regions than forced switching. These findings offer a comprehensive view of the neural and behavioral dynamics involved in bilingual language switching, challenging prior claims that voluntary switching imposes no behavioral or neural costs, and thus providing behavioral and neuroimaging evidence for the involvement of inhibitory control in voluntary language switching.

Primary mucinous adenocarcinoma of the urethra: A clinicopathological analysis of 35 cases.

AIM: Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. METHODS AND RESULTS: Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear ß-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. CONCLUSION: Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.

CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.

Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in patients with non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca2+ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation and, in turn, enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca2+-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.

Systemic lupus erythematosus and prostate cancer risk: a pool of cohort studies and Mendelian randomization analysis.

BACKGROUND: Current observational studies suggest that there may be a causal relationship between systemic lupus erythematosus (SLE) and prostate cancer (PC). However, there is contradictory evidence. This study aimed to investigate and clarify the association between SLE and PC. METHODS: We searched PubMed, Embase, Web of Science, and Scopus until May 2022. A meta-analysis was conducted on the standard incidence rate (SIR) and 95% CI. Subgroup analysis was performed based on the follow-up duration, study quality, and appropriate SLE diagnosis. Mendelian randomization (MR) of the two samples was used to determine whether genetically elevated SLE was causal for PC. Summary MR data were obtained from published GWASs, which included 1,959,032 individuals. The results were subjected to sensitivity analysis to verify their reliability. RESULTS: In a meta-analysis of 79,316 participants from 14 trials, we discovered that patients with SLE had decreased PC risk (SIR, 0.78; 95% CI, 0.70-0.87) significantly. The MR results showed that a one-SD increase in genetic susceptibility to SLE significantly reduced PC risk (OR, 0.9829; 95% CI, 0.9715-0.9943; P = 0.003). Additional MR analyses suggested that the use of immunosuppressants (ISs) (OR, 1.1073; 95% CI, 1.0538-1.1634; P < 0.001), but not glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs), which were associated with increased PC risk. The results of the sensitivity analyses were stable, and there was no evidence of directional pleiotropy. CONCLUSIONS: Our results suggest that patients with SLE have a lower risk of developing PC. Additional MR analyses indicated that genetic susceptibility to the use of ISs, but not GCs or NSAIDs, was associated with increased PC risk. This finding enriches our understanding of the potential risk factors for PC in patients with SLE. Further study is required to reach more definitive conclusions regarding these mechanisms.

A novel optical coherence tomography­based calcium scoring system can predict the stent expansion of moderate and severe calcified lesions.

Coronary calcified lesions can exert serious effects on stent expansion. A calcium scoring system, based on optical coherence tomography (OCT), has been previously developed to identify relatively mild calcified lesions that would benefit from plaque modification procedures. Therefore, the present study aimed to establish a novel OCT-based scoring system to predict the stent expansion of moderate and severe calcified lesions. A total of 33 patients who underwent percutaneous coronary intervention (PCI; 34 calcified lesions were observed using coronary angiography) were retrospectively included in the present study. Coronary angiography and OCT images were subsequently reviewed and analyzed. Furthermore, a calcium scoring system was developed based on the results of multivariate analysis before the optimal threshold for the prediction of stent underexpansion in patients with moderate and severe calcified lesions was determined. The mean age of the patients was 67±10 years. The present analysis demonstrated that the final post-PCI median stent expansion was 70.74%, where stent underexpansion (defined as stent expansion <80%) was observed in 23 lesions. The mean maximum calcium arc, length and thickness, which were assessed using OCT, were found to be 230˚, 25.10 mm and 1.18 mm, respectively. A multivariate logistic regression model demonstrated that age and the maximum calcium arc were independent predictors of stent underexpansion. A novel calcium scoring system was thereafter established using the following formula: (0.16 x age) + (0.03 x maximum calcium arc) according to the ß-coefficients in the multivariate analysis, with the optimal cut-off value for the prediction of stent underexpansion being 16.87. Receiver operating characteristic curve analysis demonstrated that this novel scoring system yielded a larger area under the curve value compared with that from a previous study's scoring system. Therefore, in conclusion, since the calcium scoring system of the present study based on age and the maximum calcium arc obtained from OCT was specifically developed in the subjects with moderate and severe calcified lesions, it may be more accurate in predicting the risk of stent underexpansion in these patients.