MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma, namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies, may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.

Treatment of Cardiovascular Disease in Rheumatoid Arthritis: A Complex Challenge with Increased Atherosclerotic Risk

Rheumatoid arthritis (RA) carries significant risk for atherosclerotic cardiovascular disease (ASCVD). Traditional ASCVD risk factors fail to account for this accelerated atherosclerosis. Shared inflammatory pathways are fundamental in the pathogenesis of both diseases. Considering the impact of RA in increasing cardiovascular morbidity and mortality, the characterization of therapies encompassing both RA and ASCVD management merit high priority. Despite little progress, several drugs discussed here promote remission and or lower rheumatoid disease activity while simultaneously conferring some level of atheroprotection. Methotrexate, a widely used disease-modifying drug used in RA, is associated with significant reduction in cardiovascular adverse events. MTX promotes cholesterol efflux from macrophages, upregulates free radical scavenging and improves endothelial function. Likewise, the sulfonamide drug sulfasalazine positively impacts the lipid profile by increasing HDL-C, and its use in RA has been correlated with reduced risk of myocardial infraction. In the biologic class, inhibitors of TNF-α and IL-6 contribute to improvements in endothelial function and promote anti-atherogenic properties of HDL-C, respectively. The immunosuppressant hydroxychloroquine positively affects insulin sensitization and the lipid profile. While no individual therapy has elicited optimal atheroprotection, further investigation of combination therapies are ongoing.

An Immune-Related Prognostic Signature for Predicting Clinical Outcomes and Immune Landscape in IDH-Mutant Lower-Grade Gliomas

Background. IDH mutation is the most common in diffuse LGGs, correlated with a favorable prognosis. However, the IDH-mutant LGGs patients with poor prognoses need to be identified, and the potential mechanism leading to a worse outcome and treatment options needs to be investigated. Methods. A six-gene immune-related prognostic signature in IDH-mutant LGGs was constructed based on two public datasets and univariate, multivariate, and LASSO Cox regression analysis. Patients were divided into low- and high-risk groups based on the median risk score in the training and validation sets. We analyzed enriched pathways and immune cell infiltration, applying the GSEA and the immune evaluation algorithms. Results. Stratification and multivariate Cox analysis unveiled that the six-gene signature was an independent prognostic factor. The signature (0.806/0.795/0.822) showed a remarkable prognostic performance, with 1-, 3-, and 5-year time-dependent AUC, higher than for grade (0.612/0.638/0.649) and 1p19q codeletion status (0.606/0.658/0.676). High-risk patients had higher infiltrating immune cells. However, the specific immune escape was observed in the high-risk group after immune activation, owing to increasing immunosuppressive cells, inhibitory cytokines, and immune checkpoint molecules. Moreover, a novel nomogram model was developed to evaluate the survival in IDH-mutant LGGs patients. Conclusion. The six-gene signature could be a promising prognostic biomarker, which is promising to promote individual therapy and improve the clinical outcomes of IDH-mutant gliomas. The study also refined the current classification system of IDH-mutant gliomas, classifying patients into two subtypes with distinct immunophenotypes and overall survival.

Cranial and Spinal Metastasis of a Nonfunctioning Pituitary Adenoma: Report of a Case

Pituitary carcinoma is a rare disease with surgical, radiotherapeutic, and chemotherapeutic treatment options. We present the case of a female patient diagnosed with a nonfunctioning pituitary adenoma who underwent several surgical procedures, radiations, and chemotherapeutic treatments with various substances. Sixteen years after the first diagnosis, a cranial and spinal metastatic spread of the tumor occurred. We opted for an individual therapy based on anecdotal evidence. Unfortunately, the recommended off-label treatment with a somatostatin analog substance was never given due to bureaucratic delays. This case report is about the challenging aspects of individual decision-making in rare neurosurgical diseases.

Inpatient Mental Healthcare before and during the COVID-19 Pandemic

Prior studies have demonstrated disruption to outpatient mental health services after the onset of the COVID-19 pandemic. Inpatient mental health services have received less attention. The current study utilized an existing cohort of 33 Veterans Health Affairs (VHA) acute inpatient mental health units to examine disruptions to inpatient services. It further explored the association between patient demographic, clinical, and services variables on relapse rates. Inpatient admissions and therapeutic services (group and individual therapy and peer support) were lower amongst the COVID-19 sample than prior to the onset of COVID-19 while lengths of stay were longer. Relapse rates did not differ between cohorts. Patients with prior emergent services use as well as substance abuse or personality disorder diagnoses were at higher risk for relapse. Receiving group therapy while admitted was associated with lower risk of relapse. Inpatient mental health services saw substantial disruptions across the cohort. Inpatient mental health services, including group therapy, may be an important tool to prevent subsequent relapse.

Construction of a single nucleotide variant score-related gene-based prognostic model in hepatocellular carcinoma: analysis of multi-independent databases and validation in vitro

Background The accumulation of single nucleotide variants (SNVs) and the emergence of neoantigens can affect tumour proliferation and the immune microenvironment. However, the SNV-related immune microenvironment characteristics and key genes involved in hepatocellular carcinoma (HCC) are still unclear. We aimed to evaluate differences in the SNV-related immune microenvironment, construct a prognostic model and validate the key genes in vitro. Methods The categories of samples were defined by the expression of SNV score-related genes to evaluate the differences in mutational features, immune environment and prognosis. The survival model was constructed with survival-associated genes and verified in two independent test datasets. RCAN2, the key gene screened out for biofunction, was validated in vitro. Results IC2, among the three integrated clusters (IC1, IC2, IC3) classified by the 82 SNV score-related genes, was distinct from the rest in SNV score and immune cell infiltration, showing a better prognosis. Seven prognostic markers, HTRA3, GGT5, RCAN2, LGALS3, CXCL1, CLEC3B, and CTHRC1, were screened to construct a prognostic model. The survival model distinguished high-risk patients with poor prognoses in three independent datasets (log-rank P < 0.0001, 0.011, and 0.0068, respectively) with acceptable sensitivity and specificity. RCAN2 was inversely correlated with NK cell infiltration, and knockdown of RCAN2 promoted proliferation in HCC. Conclusions This study revealed the characteristics of the HCC SNV-associated subgroup and screened seven latent markers for their accuracy of prognosis. Additionally, RCAN2 was preliminarily proven to influence proliferation in HCC and it had a close relationship with NK cell infiltration in vitro. With the capability to predict HCC outcomes, the model constructed with seven key differentially expressed genes offers new insights into individual therapy.

Cardiac Magnetic Resonance in the assessment of pericardial abnormalities: a case series

Background Cardiac Magnetic Resonance (CMR) has a unique role in evaluating pericardial disease, permitting non-invasive tissue analysis and hemodynamic assessment. Case Summary In Case 1 of recurrent pericarditis, CMR confirmed reactivation of inflammation with late gadolinium enhancement (LGE) and native T1/T2 mapping techniques, prompting therapeutic changes. In constrictive pericarditis, CMR is the only modality capable of differentiating a subacute potentially reversible form (Case 2), from a chronic, burnt out irreversible phase characterized by constrictive physiology (Case 3). Discussion CMR is an effective tool to tailor individual therapy, particularly in cases of recurrent and constrictive pericarditis. LGE provides diagnostic and prognostic information, and multiparametric mapping has emerged as a promising tool with incremental diagnostic value.

Necroptosis-Related lncRNAs: Predicting Prognosis and the Distinction between the Cold and Hot Tumors in Gastric Cancer

Background. In the face of poor prognosis and immunotherapy failure of gastric cancer (GC), this project tried to find new potential biomarkers for predicting prognosis and precision medication to ameliorate the situation. Methods. To form synthetic matrices, we retrieved stomach adenocarcinoma transcriptome data from Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA). Necroptosis-related prognostic lncRNA was identified by coexpression analysis and univariate Cox regression. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the necroptosis-related lncRNA model. Next, the Kaplan–Meier analysis, time-dependent receiver operating characteristics (ROC), univariate Cox (uni-Cox) regression, multivariate Cox (multi-Cox) regression, nomogram, and calibration curves were made to verify and evaluate the model. Gene set enrichment analyses (GSEA), principal component analysis (PCA), immune analysis, and prediction of the half-maximal inhibitory concentration (IC50) in risk groups were also analyzed. For further discussing immunotherapy between the cold and hot tumors, we divided the entire set into two clusters based on necroptosis-related lncRNAs. Results. We constructed a model with 16 necroptosis-related lncRNAs. In the model, we found the calibration plots showed a good concordance with the prognosis prediction. The area’s 1-, 2-, and 3-year OS under the ROC curve (AUC) were 0.726, 0.763, and 0.770, respectively. Risk groups could be a guide of systemic treatment because of significantly different IC50 between risk groups. Above all, clusters could help distinguish between the cold and hot tumors effectively and contribute to precise mediation. Cluster 2 was identified as the hot tumor and more susceptible to immunotherapeutic drugs. Conclusion. The results of this project supported that necroptosis-related lncRNAs could predict prognosis and help make a distinction between the cold and hot tumors for improving individual therapy in GC.

Treatment of acromegaly has substantial effects on body composition. A long-term follow-up study.

Background: Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated. Methods: We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). To investigate specific effects of treatment vs ageing, changes in body composition were compared in a group of patients evaluated both at the time of active and controlled disease (A>C; n=31) and in another group of patients evaluated two times while the disease was controlled (C>C; n=32). Results: In the whole cohort, IGF-I correlated with fat (r=-0.369;p<0.001) and lean mass (r=0.383;p<0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (p=n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39±34 vs +10±15%, p<0.001; lean mass: -8±8 vs -0.2±6%, p<0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r=-0.450; p=0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r=0.421;p=0.002) and insulin sensitivity index (r=-0.466;p<0.001). Conclusions: Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with ageing.