miR-183 potentially inhibits NF-κB1 expression by directly targeting its 3'-untranslated region.

Nuclear factor-κB (NF-κB) is an important transcription factor. While the NF-κB signaling pathway is modulated by many microRNAs (miRNAs), very few have been reported to target NF-κB1 gene directly. In this study, we used multiple miRNA target prediction programs to predict miRNAs with putative NF-κB1 3'-untranslated region (UTR) binding sites. miR-183 was strongly implicated and experimentally validated by reporter assays. The results showed a reduced expression of the NF-κB1 3'UTR containing luciferase vector by ∼30%, which was comparable to the reduction by miR-9 (the only known miRNA targeting the NF-κB1 3'UTR). Mutagenesis of the miR-183 seed region binding sequence in the NF-κB1 3'UTR abolished the inhibitory effect of miR-183, as noted by the NF-κB1 3'UTR-containing reporter. Moreover, similar to miR-9, miR-183 could down-regulate the expression of the reporter driven by NF-κB promoter to some degree, suggesting that miR-183 might negatively regulate the endogenous NF-κB1. Overall, our data provide computational and experimental evidence that NF-κB1 is a potential target of miR-183.

Clinical outcomes with use of radiation therapy and risk of transformation in early-stage follicular lymphoma.

Between 1998 and 2009, a total of 295 patients (median age 58, 53% females) with newly diagnosed early-stage follicular lymphoma (FL) were managed at Memorial Sloan Kettering Cancer Center. Approximately half of patients (137, 46%) underwent initial observation and half (158, 54%) immediate treatment: radiation alone (n = 108), systemic treatment alone (n = 29), or combined modality treatment (n = 21). Median follow-up was 8.4 years (range 0.3-17.2), and 10-year overall survival (OS) was 87.2%. OS was similar between initially-observed and immediately-treated patients (hazard ratio [HR]: 1.25, 95% CI: 0.67-2.36, p = 0.49). For patients receiving radiation alone, 5-year OS was 98.0%. Patients selected for systemic therapy alone had high-risk baseline features and had shorter OS than patients treated with radiation alone (HR 3.38, 95% CI 1.29-8.86, p = 0.01). Combined modality treatment did not yield superior survival compared with radiation alone (P > 0.05) but was associated with better progression-free survival (HR 0.36, 95% CI 0.14-0.90, p = 0.03). The rate of transformation increased steadily over time and was 4.2% at 5 years and 10.8% at 10 years. This modern-era analysis rationalized the role of initial observation in patients with early-stage FL although patients receiving radiation therapy also demonstrate excellent outcome.

Clinical benefit of neoadjuvant anti-PD-1/PD-L1 utilization among different tumors.

PD-1/PD-L1 (programmed cell death-1 and programmed death-ligand 1) inhibitors utilization in neoadjuvant therapy has been assessed in tumors. This study focused on the clinical benefits of neoadjuvant anti-PD-1/PD-L1 therapy. A comprehensive search was conducted in electronic databases to identify eligible studies. Major response rate (MRR) and complete response rate (CRR) were pooled in this analysis to assess the efficacy of neoadjuvant anti-PD-1/PD-L1 utilization, all grades and high-grade adverse events (AEs) were pooled to evaluate its safety. Twenty studies were included in this meta-analysis, with 828 patients suffering from different tumors. The pooled CRR of triple-negative breast cancer was 0.569 (95% CI 0.514, 0.624, I 2 = 0%) and the pooled MRR of lung cancer was 0.471 (95% CI 0.267, 0.575, I 2 = 0%). The most frequent adverse event was fatigue (0.272 95% CI 0.171, 0.402, I 2 = 87%), and the most common high-grade adverse event was febrile neutropenia (0.084 95% CI 0.063, 0.112, I 2 = 85%). In conclusion, neoadjuvant anti-PD-1/PD-L1 therapy received satisfactory clinical results in these tumors included.

Update on treatment and preventive interventions against COVID-19: an overview of potential pharmacological agents and vaccines.

The outbreak of coronavirus disease 2019 (COVID-19) triggered by the new member of the coronaviridae family, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created an unprecedented challenge for global health. In addition to mild to moderate clinical manifestations such as fever, cough, and fatigue, severe cases often developed lethal complications including acute respiratory distress syndrome (ARDS) and acute lung injury. Given the alarming rate of infection and increasing trend of mortality, the development of underlying therapeutic and preventive treatment, as well as the verification of its effectiveness, are the top priorities. Current research mainly referred to and evaluated the application of the empirical treatment based on two precedents, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), including antiviral drugs targeting different stages of virus replication, immunotherapy modulating the overactivated inflammation response, and other therapies such as herbal medicine and mesenchymal stem cells. Besides, the ongoing development of inventing prophylactic interventions such as various vaccines by companies and institutions worldwide is crucial to decline morbidity and mortality. This review mainly focused on promising candidates for the treatment of COVID-19 and collected recently updated evidence relevant to its feasibility in clinical practice in the near future.

Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups.

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1-3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Positron-emission tomography-based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma.

BACKGROUND: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. METHODS: In this retrospective study, we identified 1088 patients with grade I-IIIA FL; of whom, 238 patients with stage II-IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. RESULTS: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. CONCLUSION: In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy.

Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: progressive shortening in response duration and survival after each relapse.

As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P < 0.01), with a trend toward longer OS (median OS: 165.0 versus 120.0 months; P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P < 0.01). Our study should facilitate establishing proper endpoints for future clinical trials using novel treatment approaches.