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Human papilloma viruses (HPV) are the main culprit in cervical and oropharyngeal cancers. HPV positive (+) cancers are regarded as 'oncogene addicted', displaying an absolute requirement for the continued expression of the oncogenes for their viability owing their survival, and thus making these genes salient targets for developing specific therapeutic agents. There is a strong association between HPV and oropharyngeal squamous cell carcinomas (OPSCC), a subset of head and neck cancers (HNCs). Alarmingly, HPV-associated OPSCC are on the rise globally, and the number of cases of HPV + OPSCCs surpasses that of cervical cancer in the USA. Here, we show that major HPV oncogenes, E6 and E7, are essential for the survival of HPV positive (+) OPSCCs, making these oncogenes salient targets for HPV-driven OPSCCs. HPV E7 is known to interact with STING, a component of the viral DNA-sensing cGAS-STING machinery which activates a pro-typical anti-viral type I interferon (IFN) response. Our recent work showed that E7 from HPV type 16 is responsible for the blockade of cGAS-STING responses in HPV + OPSCC cells. In this study, we show that CRISPR/Cas9-mediated loss of E7 from HPV + OPSCC cells, SCC2 and SCC104, restored cGAS-STING responses. Future work could involve HPV oncogene targeting leading to HPV + OPSCC tumour regression and that the combined use of STING agonists would induce favourable tumour clearance by activating appropriate anti-tumour responses., Competing Interests: Declaration of competing interest Authors have no conflict of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Head and neck cancers (HNCs) are a major health problem and a leading cause of morbidity and mortality worldwide. More than 90% of these tumours are head and neck squamous cell carcinomas (HNSCCs). Amongst the common risk factors for HNCs (tobacco and alcohol use), there is a strong association of human papillomavirus (HPV) with HNSCCs. HPV type 16 (HPV 16), the major high-risk HPV type, is most commonly associated with HPV-driven HNSCCs. The promiscuous nature of the major HPV oncogene, E7, allows its interaction with a myriad of host proteins including STING, a component of the viral DNA-sensing cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) machinery. Sensing of viral DNA by the cGAS-STING machinery results in a type I interferon (IFN)-mediated anti-viral response. Amelioration of IFN responses resulting from the direct blockade of STING by E7 was first demonstrated in high-risk HPV type 18 (HPV 18) positive (+) cervical squamous cell carcinoma (CESC) cells. However, the role of E7 from HPV 16 (HPV 16E7) in antagonising cGAS-STING responses have not been investigated, let alone in the context of HNSCCs. Here, we show that HPV 16E7+, but not HPV 16E7 negative (-), HNSCC cells respond poorly to cGAS-STING activation stimulus. We further confirm that this inhibition occurred via the highly conserved LXCXE motif in 16E7. This finding contributes to the better understanding of role of high-risk HPV E7 in blocking cGAS-STING pathway, especially in the context of HNSCCs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Capecitabine induced toxicities such as hand-foot syndrome (HFS) and progression of metastatic cancer are both treatable with concurrent celecoxib as shown in the ADAPT (Activating Cancer Stem Cells from Dormancy And Potentiate for Targeting) trial. In the present study, five commonly used NSAIDs, including celecoxib were compared for their pro-oxidative capacities as cytotoxic drugs against human and mouse metastatic melanoma or breast cancer cells in vitroand the source of cellular ROS production induced by celecoxib was examined in greater detail., Results: Celecoxib was unique among the NSAIDs in that it showed particular potency as a cytotoxic drug against the metastatic cancer cells with IC 50 values in the low micromolar range. Celecoxib rapidly enhanced mitochondrial superoxide production in situ from cancer cells within minutes, leading to a decrease in cellular respiration and dissipation of the mitochondrial transmembrane potential (Δψ m ), followed by extensive ROS-dependent apoptosis of the metastatic cancer cells. Celecoxib also showed rapid and direct effects on isolated mitochondria, inducing extensive ROS production in a dose-dependent manner, whilst it inhibited respiration via Complex I or Complex II when tested in whole cells. Mitochondrial ROS production was necessary for the celecoxib induced cell death., Innovation and Conclusion: These novel findings for direct effects of celecoxib on mitochondria to induce metastatic cancer cell death via a ROS-dependent pro-oxidative mechanism provide supportive evidence for its combinatorial use as a chemosensitizing agent complementing chemotherapies to improve response rates in patients with advanced metastatic cancers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

An analysis was made of some immunological indices in patients with podagra. It was established that women showed a more pronounced reduction of T-lymphocytes in the peripheral blood and their functional activity in tests with phytohemagglutinin and concanavalin as well as a deficit of B-lymphocytes, hyperproduction of C-immunoglobulin and antibodies to DNA in the blood serum. Males showed an increased level of B-lymphocytes. M-immunoglobulin and antirenal antibody titers. The concentration of circulating immune complexes in the blood rose equally independent of age.

The authors studied the immunity indices in patients with gout against the background of a long-term (one year) therapy with allopurinol, and in animals with experimental hyperuricemia. During treatment the authors observed normalization of blood immunoglobulin M level, a considerable decrease in circulating immune complexes and anti-renal antibodies, a tendency to a rise in the function of T-lymphocytes, great enhancement of the activity of polymorphonuclear phagocytes in tests with Staphylococci and nitro-blue tetrazolium. Mechanisms of action of the given drug are discussed.

Patients with different types of podagric nephropathy were examined for 21 indicators of the functional activity of T and B lymphocytes and neutrophils. The data obtained were compared to the degree of impairment of the basic renal structures. Among the study immunologic indicators to estimate the gravity of morphological alterations in the glomeruli, the decrease of the titers of antibodies to DNA is of definite specificity, whereas the fall of the concentration of circulating immune complexes is of definite specificity in the assessment of alteration in the stroma.

Clinical studies in an acute medical unit were aimed at the analysis of the onset and clinical appearance of masked acute pneumonia. Such acute pneumonia masks as pulmonary edema, paroxysmal tachycardia, infective toxic shock, acute surgical conditions, hepatitis, pneumothorax considerably complicate the diagnosis of the underlying disease. However, some manifestations typical for acute pneumonia are recognizable. These, in combination with the above misleading symptoms, can be managed properly only provided close comprehensive examination of the patients is carried out.