Human papilloma virus circulating tumor DNA assay predicts treatment response in recurrent/metastatic head and neck squamous cell carcinoma

Despite the rising incidence of human papillomavirus related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), treatment of metastatic disease remains palliative. Even with new treatments such as immunotherapy, response rates are low and can be delayed, while even mild tumor progression in the face of an ineffective therapy can lead to rapid death. Real-time biomarkers of response to therapy could improve outcomes by guiding early change of therapy in the metastatic setting. Herein, we developed and analytically validated a new droplet digital PCR (ddPCR)-based assay for HPV16 circulating tumor DNA (ctDNA) and evaluated plasma HPV16 ctDNA for predicting treatment response in metastatic HPV+ OPSCC. We found that longitudinal changes HPV16 ctDNA correlate with treatment response and that ctDNA responses are observed earlier than conventional imaging (average 70 days, range: 35–166). With additional validation in multi-site studies, this assay may enable early identification of treatment failure, allowing patients to be directed promptly toward clinical trials or alternative therapies.     

Sexuality and mental health: Issues and what next?

Abstract

Human sexuality plays a major role in an individual's existence and functioning. In addition, rightly or wrongly sexuality often defines people and also affects social attitudes. These attitudes, if negative, can contribute to stigma and prevent people from help seeking if they are suffering from mental health problems. Recent changes in policy towards same-sex relationships have been positive in many countries including the UK and the USA, whereas in others such as Russia and Uganda attitudes have become more negative and punitive. Sexual activity is seen as having both pleasurable and procreational functions which contribute to society's attitudes to homosexual behaviour. Inevitably, individual responses to their own sexuality and sexual behaviour will be influenced by social attitudes. To ensure that those with various sexual variations can access psychiatric services without discrimination, various levels of interventions are needed. Here we discuss different levels of intervention and organizational change that may make it possible. Social organization and institutional organization of services need to be sensitive, especially as rates of many mental disorders are high in individuals who may be sexually variant. Those providing services need to understand their own negative attitudes as well as prejudices to ensure that services are emotionally accessible.     

Refining Measurement of Social Cognitive Theory Factors Associated with Exercise Adherence in Head and Neck Cancer Patients

Social cognitive theory (SCT) measures related to exercise adherence in head and neck cancer (HNCa) patients were developed. Enrolling 101 HNCa patients, psychometric properties and associations with exercise behavior were examined for barriers self-efficacy, perceived barriers interference, outcome expectations, enjoyment, and goal setting. Cronbach's alpha ranged from.84 to.95; only enjoyment demonstrated limited test-retest reliability. Subscales for barriers self-efficacy (motivational, physical health) and barriers interference (motivational, physical health, time, environment) were identified. Multiple SCT constructs were cross-sectional correlates and prospective predictors of exercise behavior. These measures can improve the application of the SCT to exercise adherence in HNCa patients.     

Propagation of cutaneous thermal injury: a mathematical model

Cutaneous burn wounds represent a significant public health problem with 500,000 patients per year in the USA seeking medical attention. Immediately after skin burn injury, the volume of the wound burn expands due to a cascade of chemical reactions, including lipid peroxidation chain reactions. Such expansion threatens life and is therefore highly clinically significant. Based on these chemical reactions, the present paper develops for the first time a three-dimensional mathematical model to quantify the propagation of tissue damage within 12 hours post initial burn. We use the model to investigate the effect of supplemental antioxidant vitamin E for intercepting propagation. We show, for example, that if tissue levels of vitamin E tocotrienol are increased, postburn, by five times then this would slow down the lipid peroxide propagation by at least 50%. We chose the alpha-tocotrienol form of vitamin E as it is a potent inhibitor of 12-lipoxygenase, which is known to propagate oxidative lipid damage. Our model is formulated in terms of differential equations, and sensitivity analysis is performed on the parameters to ensure the robustness of the results.     

Investigating the changes in heart rate asymmetry (HRA) with perturbation of parasympathetic nervous system

The heart rate asymmetry (HRA) is a disproportionate distribution of heart rate signal. The current study was designed to assess the changes in HRA in experimental conditions using Poincaré plot during parasympathetic blockade (atropine infusion) and parasympathetic enhancement (scopolamine administration). After atropine infusion, the heart rate variability in 5 out of 8 subjects was found asymmetric. In contrast, all 8 subjects were found to be asymmetric during scopolamine administration. The physiological relevance of HRA was demonstrated by showing correlation with standard frequency domain parameters during all phases of the experiment. The deviation of asymmetry index (GI _p ) from symmetric range was further analyzed, which was maximum during scopolamine administration and minimum during atropine infusion. These findings suggest that parasympathetic block reduces the prevalence of HRA, and has significant correlation of GI _p with frequency domain features of HRV analysis.     

Design and immunological properties of Helicobacter pylori glycoconjugates based on a truncated lipopolysaccharide lacking Lewis antigen and comprising an α-1,6-glucan chain

To investigate the vaccine potential of H. pylori lipopolysaccharide (LPS), truncated LPS of H. pylori strain 26695 HP0826::Kan lacking O-chain polysaccharide and comprising an extended α-1,6-linked glucan chain was conjugated to tetanus toxoid (TT) or bovine serum albumin (BSA). Two approaches were used for delipidation or partial delipidation of H. pylori LPS: (1) mild hydrolysis resulting in delipidated LPS (dLPS) and (2) treatment with anhydrous hydrazine resulting in removal of O-linked fatty acids (LPS-OH). Both LPS-OH and dLPS were covalently linked through a 2-keto-3-deoxy-octulosonic acid (Kdo) residue to a diamino group-containing spacer, followed by conjugation to thiolated TT or BSA to give conjugates LPS-OH-TT, dLPS-BSA and dLPS-TT, respectively. The LPS-OH-TT, dLPS-BSA and dLPS-TT conjugates were immunogenic in both rabbits and mice, inducing strong and specific IgG responses against homologous and heterologous strains of H. pylori. Moreover, the rabbit post-immune sera showed cross-reactivity against clinical isolates of H. pylori in a whole-cell indirect ELISA, which was further confirmed by indirect immunofluorescent microscopy. A tenfold stronger IgG immune response to the immunizing antigen was generated in mice and rabbits that received dLPS-containing conjugate. The post-immune sera of rabbits immunized with LPS-OH-TT, dLPS-BSA or dLPS-TT displayed significant bactericidal activity against mutant and wild-type α-1,6-glucan-expressing strains and selected clinical isolates of H. pylori. Finally, partial protection against H. pylori challenge was demonstrated in mice vaccinated with dLPS-TT conjugate adjuvanted with cholera toxin. In summary, this study shows that glycoconjugates based on delipidated or partially delipidated LPS from H. pylori 26695 HP0826::Kan mutant induce broadly cross-reactive functional antibodies in immunized animals and should be considered for further vaccine development and testing.     

Specificity of the J-protein Sis1 in the propagation of 3 yeast prions

Yeast prions, such as [PSI(+)], [RNQ(+)], and [URE3], are heritable elements formed by proteins capable of acquiring self-perpetuating conformations. Their propagation is dependent on fragmentation of the amyloid protein complexes formed to generate the additional seeds necessary for conversion of nascent soluble protein to the prion conformation. We report that, in addition to its known role in [RNQ(+)] propagation, Sis1, a J-protein cochaperone of Hsp70 Ssa, is also specifically required for propagation of [PSI(+)] and [URE3]. Whereas both [RNQ(+)] and [URE3] are cured rapidly upon SIS1 repression, [PSI(+)] loss is markedly slower. This disparity cannot be explained simply by differences in seed number, as [RNQ(+)] and [PSI(+)] are lost with similar kinetics upon inhibition of Hsp104, a remodeling protein required for propagation of all yeast prions. Rather, in the case of [PSI(+)], our results are consistent with the partial impairment, rather than the complete abolition, of fragmentation of prion complexes upon Sis1 depletion. We suggest that a common set of molecular chaperones, the J-protein Sis1, the Hsp70 Ssa, and the AAA+ ATPase Hsp104, act sequentially in the fragmentation of all yeast prions, but that the threshold of Sis1 activity required for each prion varies.