The unfolded protein response affects readthrough of premature termination codons

One-third of monogenic inherited diseases result from premature termination codons (PTCs). Readthrough of in-frame PTCs enables synthesis of full-length functional proteins. However, extended variability in the response to readthrough treatment is found among patients, which correlates with the level of nonsense transcripts. Here, we aimed to reveal cellular pathways affecting this inter-patient variability. We show that activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts carrying PTCs. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTCs, correlating with their response. We further found a significant inverse correlation between the UPR and nonsense-mediated mRNA decay (NMD), suggesting a feedback loop between these homeostatic pathways. We uncovered and characterized the mechanism underlying this NMD-UPR feedback loop, which augments both UPR activation and NMD attenuation. Importantly, this feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Altogether, our study demonstrates the importance of the UPR and its regulatory network for genetic diseases caused by PTCs and for cell homeostasis under normal conditions

Posttraumatic stress disorder predicts poor health-related quality of life in cardiac patients in Palestine

BACKGROUND: The longitudinal association of posttraumatic stress disorder (PTSD) with health-related quality of life (HRQL) in cardiac patients' remains poorly studied, particularly in conflict-affected settings. MATERIALS AND METHODS: For this cohort study, we used baseline and one-year follow-up data collected from patients 30 to 80 years old consecutively admitted with a cardiac diagnosis to four major hospitals in Nablus, Palestine. All subjects were screened for PTSD and HRQL using the PTSD Checklist Specific and the HeartQoL questionnaire. We used a generalized structural equation model (GSEM) to examine the independent predictive association of PTSD at baseline with HRQL at follow-up. We also examined the mediating roles of depression, anxiety, and stress at baseline. RESULTS: The prevalence of moderate-to-high PTSD symptoms among 1022 patients at baseline was 27∙0%. Patients with PTSD symptoms reported an approximate 20∙0% lower HRQL at follow-up. The PTSD and HRQL relationship was largely mediated by depressive and anxiety symptoms. It was not materially altered by adjustment for socio-demographic, clinical, and lifestyle factors. DISCUSSION: Our findings suggest that individuals with a combination of PTSD and depression, or anxiety are potentially faced with poor HRQL as a longer-term outcome of their cardiac disease. In Palestine, psychological disorders are often stigmatized; however, integration of mental health care with cardiac care may offer an entry door for addressing psychological problems in the population. Further studies need to assess the effective mental health interventions for improving quality of life in cardiac patients

A remarkable response to palliative treatment in metastatic breast cancer: A case report and comprehensive literature review

The case report describes a patient with stage IV breast cancer which metastasized to the lungs. The patient's initial computed tomography (CT) scan revealed a malignant lesion in the upper outer quadrant of the left breast and multiple pulmonary nodules, suggesting pulmonary metastasis. After starting palliative chemotherapy with intravenous paclitaxel and subcutaneous injections of Herceptin, a follow-up CT scan 3 months after the initiation of treatment showed the disappearance of metastasis, and her cancer regressed to stage II breast cancer that could be surgically resected. This case report highlights the importance of timely and appropriate palliative treatment measures, which can lead to unexpected outcomes, such as the regression of metastatic lesions and the possibility of curative treatment in such advanced cancer. © 202