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.     

Anaerobes in cardiac infections: A decade experience from the tertiary care center

PurposeAnaerobic infections are common yet life-threatening. They are being recovered from all sites of the body, including the cardiovascular system. This study was aimed to determine the retrospective analysis on the isolation of anaerobes in cardiovascular samples received for a decade-long duration. It helps in knowing the frequency of isolation of anaerobic causes of cardiovascular infection.MethodsAll cardiovascular samples from the department of Cardio-thoracic vascular surgery from January 2010 to December 2020 were studied.ResultsOf 601 samples received, predominant samples were vegetations and valvular tissues of 258, followed by 98 samples of pericardial tissues, 92 samples of embolus, 90 samples of blood and post-operative collections, and 63 excised aneurysms and vascular grafts. Of the total, 15 samples grew anaerobes where Clostridium species were the predominant isolates. Clostridioides difficile was isolated in 2 samples.ConclusionsAnaerobes in cardiovascular samples are uncommon yet form a significant cause of morbidity and mortality. Most infections are from the contiguous spread, penetrating trauma, and hematogenous causing endocarditis or valvular infections. These conditions and samples form the seat of infectious focus and clinical suspicion towards the anaerobic cause of these conditions, especially in conventional routine culture-negative samples. Timely diagnosis of anaerobic infections plays a vital role in the good prognostic outcome of patients undergoing cardiothoracic and vascular surgery.     

A Device for Warming Solutions in Transfusion–Infusion Therapy

Biomedical Engineering - The possible use of the vortex effect in medical transfusion–infusion solution heaters was studied. A design for a device is presented, along with the trial results....     

Correction to: The protean world of non-coding RNAs in glioblastoma

Journal of Molecular Medicine -     

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Bioimpedance as a measure of fluids in patients with septic shock. A prospective observational study

Background

Septic shock is often treated with aggressive fluid resuscitation leading to profound fluid overload. The assessment of fluid status relies on suboptimal measures making treatment difficult. Bioelectrical impedance analysis is an alternative but the validity is unclear. The aim of this study was to determine the validity of bioelectrical impedance analysis for fluid measures in patients with septic shock.

Methods

Single-center, prospective observational cohort study. We included adult ICU patients with septic shock. We evaluated the agreement between measures on the left and right side of the patient and measures 1 h apart by two bioelectrical impedance devices. Results are presented as Bland Altman plots with 95% Limits of Agreements (LoA) and as correlations between bioelectrical impedance analysis results and clinical markers of fluids.

Results

Forty-nine patients were included. The agreement between measures on the left and the right side of the patient and after 1 h was overall without bias, but with wide LoA's. Fluid overload 1 h apart showed the most narrow 95% LoA (−2.4–2.9 L). The same wide limits of agreements were observed when comparing devices. For example, total body water with 95% LoA of −14.8 –16.7 L. Correlations between bioelectrical impedance analysis and clinical measures were low but statistically significant.

Conclusions

In patients with septic shock bioelectrical impedance analysis had no systematic errors or bias, but wide limits of agreement, indicating that the devices have a large and uncorrectable random error. Fluid status by bioelectrical impedance analysis is not sufficiently accurate to guide treatment in this group of patients.     

Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure

Heart Failure Reviews - The nitric oxide (NO)–guanylate cyclase (GC)–cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal...     

Psychosocial outcomes of group prenatal care

Journal of Public Health - Group prenatal care provides an alternative model of prenatal care that allows for collaboration with peers, education, discussion, and self-management training in...