Identification of Lethal Inhibitors and Inhibitor Combinations for Mono-Driver versus Multi-Driver Triple-Negative Breast Cancer Cells

There are no signaling-based targeted therapies for triple-negative breast cancer. The development of targeted cancer therapy relies on identifying oncogenic signaling drivers, understanding their contributions to oncogenesis and developing inhibitors to block such drivers. In this study, we determine that DU-4475 is a mono-driver cancer cell line relying on BRAF and the mitogen-activated protein kinase pathway for viability and proliferation. It is fully and lethally inhibited by BRAF or Mek inhibitors at low nM concentrations, but it is resistant to inhibitors targeting other signaling pathways. The inhibitory lethality caused by blocking Mek or BRAF is through apoptosis. In contrast, MDA-MB-231 is a multi-driver triple-negative breast cancer cell line dependent on both Src and the KRAS-activated mitogen-activated kinase pathway for proliferation and viability. Blocking each pathway alone only partially inhibits cell proliferation without killing them, but the combination of dasatinib, an Src inhibitor, and trametinib, a Mek inhibitor, achieves synthetic lethality. The combination is highly potent, with an IC50 of 8.2 nM each, and strikingly synergistic, with a combination index of less than 0.003 for 70% inhibition. The synthetic lethality of the drug combination is achieved by apoptosis. These results reveal a crucial difference between mono-driver and multi-driver cancer cells and suggest that pharmacological synthetic lethality may provide a basis for effectively inhibiting multi-driver cancers

Identification of Lethal Inhibitors and Inhibitor Combinations for Mono-Driver versus Multi-Driver Triple-Negative Breast Cancer Cells

There are no signaling-based targeted therapies for triple-negative breast cancer. The development of targeted cancer therapy relies on identifying oncogenic signaling drivers, understanding their contributions to oncogenesis and developing inhibitors to block such drivers. In this study, we determine that DU-4475 is a mono-driver cancer cell line relying on BRAF and the mitogen-activated protein kinase pathway for viability and proliferation. It is fully and lethally inhibited by BRAF or Mek inhibitors at low nM concentrations, but it is resistant to inhibitors targeting other signaling pathways. The inhibitory lethality caused by blocking Mek or BRAF is through apoptosis. In contrast, MDA-MB-231 is a multi-driver triple-negative breast cancer cell line dependent on both Src and the KRAS-activated mitogen-activated kinase pathway for proliferation and viability. Blocking each pathway alone only partially inhibits cell proliferation without killing them, but the combination of dasatinib, an Src inhibitor, and trametinib, a Mek inhibitor, achieves synthetic lethality. The combination is highly potent, with an IC50 of 8.2 nM each, and strikingly synergistic, with a combination index of less than 0.003 for 70% inhibition. The synthetic lethality of the drug combination is achieved by apoptosis. These results reveal a crucial difference between mono-driver and multi-driver cancer cells and suggest that pharmacological synthetic lethality may provide a basis for effectively inhibiting multi-driver cancers

Risk of sudden sensorineural hearing loss in patients with dysrhythmia: A nationwide population-based cohort study.

ObjectiveWhether dysrhythmia is a risk factor of sudden sensorineural hearing loss (SSNHL) remains unclear. In this study, we aimed to investigate the risk of developing SSNHL among patients with dysrhythmia in different age and gender groups by using population-based data in Taiwan.MethodsWe conducted a matched cohort study by analyzing data between January 2000 and December 2013 obtained from the Taiwan National Health Insurance Research Database. 41,842 newly diagnosed dysrhythmia patients and 83,684 comparison subjects without dysrhythmia were selected from claims. The incidence of sudden sensorineural hearing loss at the end of 2013 was determined in both groups. Univariate and multivariate logistic regression analyses were used to investigate the risk of SSNHL among patients with dysrhythmia.ResultsThe incidence of SSNHL was 1.30-fold higher in the dysrhythmia group compared with the control group (53.2 versus 40.9 per 100,000 person-years), and using Cox proportional hazard regressions, the adjusted hazard ratio (HR) was 1.40 (95% confidence interval [CI], 1.15-1.70). Gender-stratified analysis revealed a significantly higher risk of SSNHL in patients with dysrhythmia than in those without dysrhythmia for both men and women (HR = 1.34, 95% CI = 1.02-1.76, P = 0.039, HR = 1.35, 95% CI = 1.02-1.78, P = 0.035, respectively). Age-stratified analysis revealed remarkable associations between dysrhythmia and SSNHL among those aged less than 40 years and more than 65 years (HR = 2.18, 95% CI = 1.03-4.64, P = 0.043 and HR = 1.54, 95% CI = 1.14-2.09, P = 0.006, respectively).ConclusionsOur findings support dysrhythmia as an independent risk factor for SSNHL. Based on the study results, clinicians managing patients with dysrhythmia should be aware of the increased risk of developing SSNHL, especially among patients aged 65 years, and counsel patients to seek medical advice immediately if they experience any acute change in their hearing ability

A Nomogram Incorporating Neutrophil-to-Lymphocyte Ratio and Squamous Cell Carcinoma Antigen Predicts the Prognosis of Oral Cancers

We introduced a novel squamous cell carcinoma inflammatory index (SCI) and explored its prognostic utility for individuals with operable oral cavity squamous cell carcinomas (OSCCs). We retrospectively analyzed data from 288 patients who were given a diagnosis of primary OSCC from January 2008 to December 2017. The SCI value was derived by multiplying the serum squamous cell carcinoma antigen and neutrophil-to-lymphocyte ratio values. We appraised the associations of the SCI with survival outcomes by performing Cox proportional hazards and Kaplan–Meier analyses. We constructed a nomogram for survival predictions by incorporating independent prognostic factors in a multivariable analysis. By executing a receiver operating characteristic curve analysis, we identified the SCI cutoff to be 3.45, and 188 and 100 patients had SCI values of p p < 0.001). The SCI-based nomogram accurately predicted overall survival (concordance index: 0.779). Our findings indicate that SCI is a valuable biomarker that is highly associated with patient survival outcomes in OSCC

Mortality in tongue cancer patients treated by curative surgery: a retrospective cohort study from CGRD

Background Our study aimed to compare the outcomes of surgical treatment of tongue cancer patients in three different age groups. Methods From 2004 to 2013, we retrospectively analyzed the clinical data of 1,712 patients who were treated in the four institutions constituting the Chang Gung Memorial Hospitals (CGMH). We divided and studied the patients in three age groups: Group 1, younger (<65 years); Group 2, young old (65 to <75); and Group 3, older old patients (≥75 years). Results Multivariate analyses determined the unfavorable, independent prognostic factors of overall survival to be male sex, older age, advanced stage, advanced T, N classifications, and surgery plus chemotherapy. No significant differences were found in adjusted hazard ratios (HR) of death in early-stage disease (stage I–II) among Group 1 (HR 1.0), Group 2 (HR 1.43, 95% confidence interval (CI) [0.87–2.34], p = 0.158), and Group 3 (HR 1.22, 95% CI [0.49–3.03], p = 0.664) patients. However, amongst advanced-stage patients (stage (III–IV)), Group 3 (HR 2.53, 95% CI [1.46–4.38], p  = 0.001) showed significantly worse survival than the other two groups after other variables were adjusted for. Fourteen out of 21 older old, advanced-staged patients finally died, and most of the mortalities were non-cancerogenic (9/14, 64.3%), and mostly occurred within one year (12/14, 85%) after cancer diagnosis. These non-cancer cause of death included underlying diseases in combination with infection, pneumonia, poor nutrition status, and trauma. Conclusions Our study showed that advanced T classification (T3–4), positive nodal metastasis (N1–3) and poorly differentiated tumor predicted poor survival for all patients. Outcome of early-stage patients (stage I–II) among three age groups were not significantly different. However, for advanced-stage patients (stage III–IV), the older old patients (≥75) had significantly worse survival than the other two patient groups. Therefore, for early-stage patients, age should not deny them to receive optimal treatments. However, older old patients (≥75) with advanced cancer should be comprehensively assessed by geriatric tools before surgical treatment and combined with intensive postoperative care to improve outcome, especially the unfavorable non-cancerogenic mortalities within one year after cancer diagnosis