An m1A/m6A/m5C-associated long non-coding RNA signature: Prognostic and immunotherapeutic insights into cervical cancer.

BACKGROUND: Cervical cancer (CC) remains a significant clinical challenge, even though its fatality rate has been declining in recent years. Particularly in developing countries, the prognosis for CC patients continues to be suboptimal despite numerous therapeutic advances. METHODS: Using The Cancer Genome Atlas database, we extracted CC-related data. From this, 52 methylation-related genes (MRGs) were identified, leading to the selection of a 10 long non-coding RNA (lncRNA) signature co-expressed with these MRGs. R programming was employed to filter out the methylation-associated lncRNAs. Through univariate, least absolute shrinkage and selection operator (i.e. LASSO) and multivariate Cox regression analysis, an MRG-associated lncRNA model was constructed. The established risk model was further assessed via the Kaplan-Meier method, principal component analysis, functional enrichment annotation and a nomogram. Furthermore, we explored the potential of this model with respect to guiding immune therapeutic interventions and predicting drug sensitivities. RESULTS: The derived 10-lncRNA signature, linked with MRGs, emerged as an independent prognostic factor. Segmenting patients based on their immunotherapy responses allowed for enhanced differentiation between patient subsets. Lastly, we highlighted potential compounds for distinguishing CC subtypes. CONCLUSIONS: The risk model, associated with MRG-linked lncRNA, holds promise in forecasting clinical outcomes and gauging the efficacy of immunotherapies for CC patients.

Prognostic impact of lactylation-associated gene modifications in clear cell renal cell carcinoma: Insights into molecular landscape and therapeutic opportunities.

Clear cell renal cell carcinoma (ccRCC) stands as a challenging subtype of kidney cancer, frequently complicating patient prognosis due to factors like postsurgical recurrences or late-stage diagnoses. In this study, we employed bioinformatics to investigate lactylation modifications in ccRCC, focusing on the TCGA-KIRC cohort. Out of 328 lactylation-associated genes, 31 emerged as differentially expressed, with 16 showing a marked correlation with overall survival. These genes exhibited strong protein-protein interactions and significant expression correlations. Intriguingly, a notable loss of gene copy numbers suggests potential implications in tumor progression. Utilizing unsupervised clustering, KIRC samples were grouped into two distinct subcategories, each showcasing different survival outcomes. While pathway enrichment highlighted an aggressive, inflammation-driven profile for subgroup 2, subgroup 1 was characterized by metabolic prominence. Furthermore, subgroup 2 presented an intensified inflammatory response, hinting at potential immune exhaustion. Capitalizing on machine learning, we developed a risk model using the TCGA-KIRC dataset, efficiently categorizing ccRCC patients into high- and low-risk clusters. Notably, those in the low-risk group indicated a more favorable survival trajectory. Clinical evaluations further corroborated these findings, linking better outcomes with reduced risk scores. Additionally, observed mutation patterns allude to a potential association between elevated risk scores and cytokine storms. TIDE analysis illuminated possible immunotherapeutic benefits for the low-risk group, underscored by an evident rise in microsatellite instability. Finally, our drug sensitivity evaluations revealed distinct therapeutic responses between the groups. In summary, this research underscores the pivotal role of lactylation modifications in ccRCC and introduces a promising prognostic model. These revelations pave the way for enhanced prognostic precision, presenting a promising path toward personalized treatment strategies and enriching our comprehension of the multifaceted molecular landscape of the disease.

Therapeutic Advances in Oncology.

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.

Peptides to combat viral infectious diseases.

Viral infectious diseases have resulted in millions of deaths throughout history and have created a significant public healthcare burden. Tremendous efforts have been placed by the scientific communities, health officials and government organizations to detect, treat, and prevent viral infection. However, the complicated life cycle and rapid genetic mutations of viruses demand continuous development of novel medicines with high efficacy and safety profiles. Peptides provide a promising outlook as a tool to combat the spread and re-emergence of viral infection. This article provides an overview of five viral infectious diseases with high global prevalence: influenza, chronic hepatitis B, acquired immunodeficiency syndrome, severe acute respiratory syndrome, and coronavirus disease 2019. The current and potential peptide-based therapies, vaccines, and diagnostics for each disease are discussed.

Identification of benign and malignant pulmonary nodules on chest CT using improved 3D U-Net deep learning framework.

PURPOSE: To accurately distinguish benign from malignant pulmonary nodules with CT based on partial structures of 3D U-Net integrated with Capsule Networks (CapNets) and provide a reference for the early diagnosis of lung cancer. METHOD: The dataset consisted of 1177 samples (benign/malignant: 414/763) from 997 patients provided by collaborating hospital. All nodules were biopsy or surgery proven, and pathologic results were regarded as the "golden standard". This study utilized partial U-Net to capture the low-level (edge, corner, etc.) information and CapNets to preserve high-level (semantic information) information of nodules. For CapNets, each capsule had a 4 × 4 matrix representing the pose and an activation probability representing the presence of an object. Furthermore, we chose accuracy (ACC), area under the curve (AUC), sensitivity (SE) and specificity (SP) to evaluate the generalization of the proposed architecture and compared its identification performance with 3D U-Net and experienced radiologists. RESULTS: The AUC of our architecture (0.84) was superior to that (0.81) of the original 3D U-Net (p = 0.04, DeLong's test). Moreover, ACC (84.5 %) and SE (92.9 %) of our model were clearly higher than radiologists' ACC (81.0 %) and SE (84.3 %) at the optimal operating point. However, SP (70 %) of our model was slightly lower than radiologists' SP (75 %), which might be the result of class imbalance with limited benign samples involved for algorithm training. CONCLUSIONS: Our architecture showed a high performance for identifying benign and malignant pulmonary nodules, indicating the improved model has a promising application in clinic.

Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling.

The progressive loss of cardiomyocytes caused by cell death leads to cardiac dysfunction and heart failure (HF). Rapamycin has been shown to be cardioprotective in pressure­overloaded and ischemic heart diseases by regulating the mechanistic target of rapamycin (mTOR) signaling network. However, the impact of rapamycin on cardiomyocyte death in chronic HF remains undetermined. Therefore, in the current study we addressed this issue using a rat myocardial infarction (MI)­induced chronic HF model induced by ligating the coronary artery. Following surgery, rats were randomly divided into six groups, including the sham­, vehicle­ and rapamycin­operated groups, at 8 or 12 weeks post­MI. A period of 4 weeks after MI induction, the rats were treated with rapamycin (1.4 mg­kg­day) or vehicle for 4 weeks. Cardiac function was determined using echocardiography, the rats were subsequently euthanized and myocardial tissues were harvested for histological and biochemical analyses. In the cell culture experiments with H9c2 rat cardiomyocytes, apoptosis was induced using angiotensin II (100 nM; 24 h). Cardiomyocyte apoptosis and autophagy were assessed via measuring apoptosis­ and autophagy­associated proteins. The activities of mTOR complex 1 (mTORC1) and mTORC2 were evaluated using the phosphorylation states of ribosomal S6 protein and Akt, respectively. The activity of the endoplasmic reticulum (ER) stress pathway was determined using the levels of GRP78, caspase­12, phospho­JNK and DDIT3. Echocardiographic and histological measurements indicated that rapamycin treatment improved cardiac function and inhibited cardiac remodeling at 8 weeks post­MI. Additionally, rapamycin prevented cardiomyocyte apoptosis and promoted autophagy at 8 weeks post­MI. Rapamycin treatment for 4 weeks inhibited the mTOR and ER stress pathways. Furthermore, rapamycin prevented angiotensin II­induced H9c2 cell apoptosis and promoted autophagy by inhibiting the mTORC1 and ER stress pathways. These results demonstrated that rapamycin reduced cardiomyocyte apoptosis and promoted cardiomyocyte autophagy, by regulating the crosstalk between the mTOR and ER stress pathways in chronic HF.

Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance.

Ghrelin, a growth hormone-releasing peptide, potentially improves cardiac function, but the mechanisms remain unclear. In the study, the rat heart failure (HF) model was established by ligating the left anterior descending coronary artery (LAD) and treated with ghrelin (100µg/kg, subcutaneous injection, bid); neonatal rat cardiomyocytes were cultured and stimulated with Ang II (0.1µM) and ghrelin(0.1µM) to explore the underlying mechanism of ghrelin in myocardial remodeling. Hemodynamic changes and serum brain natriuretic peptide (BNP) concentrations were measured to assess cardiac function. Left ventricular mass index (LVMI), hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were performed to evaluate myocardial fibrosis. Interestingly, ghrelin significantly improved cardiac function by inhibiting fibrous tissue proliferation. To further explore the mechanisms by which ghrelin interferes with myocardial fibrosis, the levels of activin A (Act A) and its blocker-follistatin (FS) were examined by immunohistochemistry; Act A levels were significantly increased in the myocardial infarction (MI), and ghrelin administeration downregulated Act A expression. In contrast, FS expression showed no significant change in all experimental groups. Furthermore, ghrelin decreased Ang II-induced Act A expression with no effect on FS expression in primary rat cardiomyocytes in vitro (real-time quantitative PCR and ELISA). Thus, ghrelin corrected the Act A/FS imbalance. Finally, Act A treated cultured primary rat cardiac fibroblasts (CFs) showed increased proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay] and enhanced expressions of type I and type III collagen (Col I and Col III) (real-time quantitative PCR). These data suggest that ghrelin inhibits myocardial fibrosis, attenuates left ventricular remodeling, and eventually improves cardiac function by adjusting Act A/FS imbalance.

Sulforaphane protection against the development of doxorubicin-induced chronic heart failure is associated with Nrf2 Upregulation.

BACKGROUND: Doxorubicin (DOX) is an anthracycline antitumor drug. However, its clinical use is limited by dose-dependent cardiotoxicity and even progresses to chronic heart failure (CHF). OBJECTIVE: This study aims to investigate whether the Nrf2 activator, sulforaphane (SFN), can prevent DOX-induced CHF. METHODS: Male Sprague-Dawley rats which received treatment for 6 weeks were divided into four groups (n=30 per group): control, SFN, DOX and DOX plus SFN group. RESULTS: Results revealed that DOX induced progressive cardiac damage as indicated by increased cardiac injury markers, cardiac inflammation, fibrosis and oxidative stress. SFN significantly prevented DOX-induced progressive cardiac dysfunction between 2-6 weeks and prevented DOX-induced cardiac function deterioration. Furthermore, it significantly decreased ejection fraction and increased the expression of brain natriuretic peptide. SFN also almost completely prevented DOX-induced cardiac oxidative stress, inflammation and fibrosis. SFN upregulated NF-E2-related factor 2 (Nrf2) expression and transcription activity, which was reflected by the increased mRNA expression of Nrf2 and its downstream genes. Furthermore, in cultured H9c2 cardiomyocytes, the protective effect of SFN against DOX-induced fibrotic and inflammatory responses was abolished by Nrf2 silencing. CONCLUSION: We arrived at the conclusion that DOX-induced CHF can be prevented by SFN through the upregulation of Nrf2 expression and transcriptional function.

Inhibition of prostate cancer RM1 cell growth in vitro by hydroxyapatite nanoparticle­delivered short hairpin RNAs against Stat3.

The present study investigated the effect of signal transducer and activator of transcription 3 (Stat3) interference on RM1 prostate cancer cell viability in vitro, using plasmid­based Stat3 specific short hairpin RNA (sh­Stat3) delivered by hydroxyapatite nanoparticles (HAP). HAP carrying sh­Stat3 plasmids were transfected into tumor cells. MTT assays were used to measure RM1 cell viability 24 and 48 h following transfection, and the apoptosis rate and cell cycle phase distribution were determined by flow cytometry. Stat3 mRNA expression levels were measured by reverse transcription­quantitative polymerase chain reaction and Stat3, Cyclin D1, B cell lymphoma 2 apoptosis regulator (Bcl­2), vascular endothelial growth factor (VEGF), Bcl­2 associated X apoptosis regulator (Bax) and cleaved­caspase­3 protein expression levels were detected using western blot analysis. The results demonstrated that HAP­delivered sh­Stat3 significantly decreased RM1 cell viability through the promotion of cell cycle arrest and apoptosis. Stat3 mRNA and protein expression levels were significantly downregulated in RM1 cells. Bcl­2, VEGF and Cyclin D1 were also significantly downregulated, but cleaved­caspase­3 and Bax mRNA and protein expression levels were significantly upregulated. HAP­delivered sh­Stat3 decreased RM1 cell viability in vitro, and HAP assisted plasmid­based delivery of shRNA into tumor cells. The present results suggest that HAP may be a useful method for successful shRNA delivery into tumors.