Rapalogs induce non-apoptotic,autophagy-dependent cell death in HPV-negative TP53 mutant head and neck squamous cell carcinoma

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.     

Assessment of the knowledge,attitudes, and practices among UNRWA health staff in Jordan concerning mental health programme pre-implementation: a cross-sectional study

Background

Mental health is a major public health priority, particularly among refugees worldwide. The United Nations Relief and Works Agency for Palestine Refugees (UNRWA) started to integrate mental health and psychosocial support (MHPSS) into its primary health-care services in Jordan in late 2017. This baseline study aimed to assess the knowledge, attitudes, practices, and perceived barriers among UNRWA health staff regarding the implementation of the MHPSS programme.

Rapid behavioral assessment of barriers and opportunities to improve vaccination coverage among displaced Rohingyas in Bangladesh,January 2018

Background

In November 2017, the World Health Organization received initial reports of suspected diphtheria cases in camps established for displaced Rohingyas in Cox’s Bazar district, Bangladesh. By January 11, 2018, over 4,000 suspected cases of diphtheria and 30 deaths were reported. The Bangladesh government and partners implemented a diphtheria vaccination campaign in December 2017. Outbreak response staff reported anecdotal evidence of vaccine hesitancy. Our assessment aimed to understand vaccination barriers and opportunities to enhance vaccine demand among displaced Rohingyas in Bangladesh.

Depression and glioblastoma,complicated concomitant diseases: a systemic review of published literature

Glioblastoma multiforme (GBM) is the most common primary brain cancer. Depression is a common co-morbidity of this condition. Despite this common interaction, relatively little research has been performed on the development of GBM-associated depression. We performed a literary search of the PubMed database for articles published relating to GBM and depression. A total of 85 articles were identified with 46 meeting inclusion criteria. Depression significantly impacts care, decreasing medication compliance, and patient survival. Diagnostically, because depression and GBM share intricate neuro-connectivity in a way that effect functionality, these diseases can be mistaken for alternative psychological or pathological disorders, complicating care. Therapeutically, anti-depressants have anti-tumor properties; yet, some have been shown to interfere with GBM treatment. One reason for this is that the pathophysiological development of depression and GBM share several pathways including altered regulation of the 5-HT receptor, norepinephrine, and 3′:5′-cyclic monophosphate. Over time, depression can persist after GBM treatment, affecting patient quality of life. Together, depression and GBM are complicated concomitant diseases. Clinicians must be aware of their co-existence. Because of overlapping molecular pathways involved in both diseases, careful medication selection is imperative to avoid potential adverse interactions. Since GBMs are the most common primary brain cancer, physicians dealing with this disease should be prepared for the development of depression as a potential sequela of this condition, given the related pathophysiology and the known poor outcomes.     

Detectability and surgical outcomes in parathyroid surgery – a single-centre experience

The incidence of primary hyperparathyroidismand referrals for the removal of parathyroid adenomas are increasing. Factors that improve the detectability, and ultimately the surgical outcome, are the focus of this retrospective study. We included 117 patients who had parathyroid operations with intraoperative monitoring of parathyroid hormone (PTH). Sestamibi, ultrasound and, in selected cases, fusion with computed tomograms (CT), were done to locate the lesion preoperatively. Concentrations of calcium and PTH before and after operation, specimen weight, and preoperative vitamin D concentrations, were assessed. The sensitivity of sestamibi and ultrasound for the preoperative location of adenomas was 92% and 80%, respectively. Sestamibi located them more accurately in patients with low preoperative concentrations of vitamin D (p = 0.037) and with heavier adenomas (p < 0.001). We found no significant association between the preoperative concentrations of PTH and detectability on preoperative scans (p = 0.058). Postoperative follow up showed that 97% of the 117 patients were biochemically cured. Accurate location helps to lower morbidity as it facilitates a targeted approach. Further studies are needed to explore the role of vitamin D in the location of parathyroid adenomas before parathyroidectomy.