APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy.

Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression. Moreover, APOBEC-related mutagenesis correlated with immunotherapy response in a cohort of 99 patients with diverse cancers, and this correlation was independent of the tumor mutation burden (TMB). Combining APOBEC-related mutagenesis estimate and TMB resulted in greater predictive ability than either parameter alone. Based on these results, further investigation of APOBEC-related mutagenesis as a marker of response to anti-cancer checkpoint blockade is warranted

Construction of Non-Perturbative, Unitary Particle-Antiparticle Amplitudes for Finite Particle Number Scattering Formalisms

Starting from a unitary, Lorentz invariant two-particle scattering amplitude , we show how to use an identification and replacement process to construct a unique, unitary particle-antiparticle amplitude. This process differs from conventional on-shell Mandelstam s,t,u crossing in that the input and constructed amplitudes can be off-diagonal and off-energy shell. Further, amplitudes are constructed using the invariant parameters which are appropriate to use as driving terms in the multi-particle, multichannel non-perturbative, cluster decomposable, relativistic scattering equations of the Faddeev-type integral equations recently presented by Alfred, Kwizera, Lindesay and Noyes. It is therefore anticipated that when so employed, the resulting multi-channel solutions will also be unitary. The process preserves the usual particle-antiparticle symmetries. To illustrate this process, we construct a J=0 scattering length model chosen for simplicity. We also exhibit a class of physical models which contain a finite quantum mass parameter and are Lorentz invariant. These are constructed to reduce in the appropriate limits, and with the proper choice of value and sign of the interaction parameter, to the asymptotic solution of the non-relativistic Coulomb problem, including the forward scattering singularity, the essential singularity in the phase, and the Bohr bound-state spectrum

Space-Time Approach to Scattering from Many Body Systems

We present scattering from many body systems in a new light. In place of the usual van Hove treatment, (applicable to a wide range of scattering processes using both photons and massive particles) based on plane waves, we calculate the scattering amplitude as a space-time integral over the scattering sample for an incident wave characterized by its correlation function which results from the shaping of the wave field by the apparatus. Instrument resolution effects - seen as due to the loss of correlation caused by the path differences in the different arms of the instrument are automatically included and analytic forms of the resolution function for different instruments are obtained. The intersection of the moving correlation volumes (those regions where the correlation functions are significant) associated with the different elements of the apparatus determines the maximum correlation lengths (times) that can be observed in a sample, and hence, the momentum (energy) resolution of the measurement. This geometrical picture of moving correlation volumes derived by our technique shows how the interaction of the scatterer with the wave field shaped by the apparatus proceeds in space and time. Matching of the correlation volumes so as to maximize the intersection region yields a transparent, graphical method of instrument design. PACS: 03.65.Nk, 3.80 +r, 03.75, 61.12.BComment: Latex document with 6 fig

Dendritic Spine Shape Analysis: A Clustering Perspective

Functional properties of neurons are strongly coupled with their morphology. Changes in neuronal activity alter morphological characteristics of dendritic spines. First step towards understanding the structure-function relationship is to group spines into main spine classes reported in the literature. Shape analysis of dendritic spines can help neuroscientists understand the underlying relationships. Due to unavailability of reliable automated tools, this analysis is currently performed manually which is a time-intensive and subjective task. Several studies on spine shape classification have been reported in the literature, however, there is an on-going debate on whether distinct spine shape classes exist or whether spines should be modeled through a continuum of shape variations. Another challenge is the subjectivity and bias that is introduced due to the supervised nature of classification approaches. In this paper, we aim to address these issues by presenting a clustering perspective. In this context, clustering may serve both confirmation of known patterns and discovery of new ones. We perform cluster analysis on two-photon microscopic images of spines using morphological, shape, and appearance based features and gain insights into the spine shape analysis problem. We use histogram of oriented gradients (HOG), disjunctive normal shape models (DNSM), morphological features, and intensity profile based features for cluster analysis. We use x-means to perform cluster analysis that selects the number of clusters automatically using the Bayesian information criterion (BIC). For all features, this analysis produces 4 clusters and we observe the formation of at least one cluster consisting of spines which are difficult to be assigned to a known class. This observation supports the argument of intermediate shape types.Comment: Accepted for BioImageComputing workshop at ECCV 201

Health professionals, their medical interventions and uncertainty : a study focusing on women at midlife

Health professionals face a tension between focusing on the individual and attending to health issues for the population as a whole. This tension is intrinsic to medicine and gives rise to medical uncertainty, which here is explored through accounts of three medical interventions focused on women at midlife: breast screening, hormone replacement therapy and bone densitometry. The accounts come from interviews with UK health professionals using these medical interventions in their daily work. Drawing on the analysis of Fox [(2002). Health and Healing: The public/private divide (pp. 236–253). London: Routledge] we distinguish three aspects of medical uncertainty and explore each one of them in relation to one of the interventions. First is uncertainty about the balance between the individual and distributive ethic of medicine, explored in relation to breast screening. Second is the dilemma faced by health professionals when using medicial evidence generated through studies of populations and applying this to individuals. We explore this dilemma for hormone replacement therapy. Thirdly there is uncertainty because of the lack of a conceptual framework for understanding how new micro knowledge, such as human genetic information, can be combined with knowledge of other biological and social dimensions of health. The accounts from the bone denistometry clinic indicate the beginnings of an understanding of the need for such a framework, which would acknowledge complexity, recognising that factors from many different levels of analysis, from heredity through to social factors, interact with each other and influence the individual and their health. However, our analysis suggests biomedicine continues to be dominated by an individualised, context free, concept of health and health risk with individuals alone responsible for their own health and for the health of the population. This may continue to dominate how we perceive responsibilities for health until we establish a conceptual framework that recognises the complex interaction of many factors at macro and micro level affecting health

On structural properties of the value function for an unbounded jump Markov process with an application to a processor sharing retrial queue

The derivation of structural properties for unbounded jump Markov processes cannot be done using standard mathematical tools, since the analysis is hindered due to the fact that the system is not uniformizable. We present a promising technique, a smoothed rate truncation method, to overcome the limitations of standard techniques and allow for the derivation of structural properties. We introduce this technique by application to a processor sharing queue with impatient customers that can retry if they renege. We are interested in structural properties of the value function of the system as a function of the arrival rate

AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis

<p>Abstract</p> <p>Background</p> <p>Gossypol, a naturally occurring polyphenolic compound has been identified as a small molecule inhibitor of anti-apoptotic Bcl-2 family proteins. It induces apoptosis in a wide range of tumor cell lines and enhances chemotherapy- and radiation-induced cytotoxicity both <it>in vitro </it>and <it>in vivo</it>. Bcl-2 and related proteins are important inhibitors of apoptosis and frequently overexpressed in human tumors. Increased levels of these proteins confer radio- and chemoresistance and may be associated with poor prognosis. Consequently, inhibition of the anti-apoptotic functions of Bcl-2 family members represents a promising strategy to overcome resistance to anticancer therapies.</p> <p>Methods</p> <p>We tested the effect of (-)-gossypol, also denominated as AT-101, radiation and the combination of both on apoptosis induction in human leukemic cells, Jurkat T and U937. Because activation of the SAPK/JNK pathway is important for apoptosis induction by many different stress stimuli, and Bcl-X_Lis known to inhibit activation of SAPK/JNK, we also investigated the role of this signaling cascade in AT-101-induced apoptosis using a pharmacologic and genetic approach.</p> <p>Results</p> <p>AT-101 induced apoptosis in a time- and dose-dependent fashion, with ED₅₀values of 1.9 and 2.4 μM in Jurkat T and U937 cells, respectively. Isobolographic analysis revealed a synergistic interaction between AT-101 and radiation, which also appeared to be sequence-dependent. Like radiation, AT-101 activated SAPK/JNK which was blocked by the kinase inhibitor SP600125. In cells overexpressing a dominant-negative mutant of c-Jun, AT-101-induced apoptosis was significantly reduced.</p> <p>Conclusion</p> <p>Our data show that AT-101 strongly enhances radiation-induced apoptosis in human leukemic cells and indicate a requirement for the SAPK/JNK pathway in AT-101-induced apoptosis. This type of apoptosis modulation may overcome treatment resistance and lead to the development of new effective combination therapies.</p

Synthetic Retinoid Interventions and Outcomes in People with Cancer or Potentially Malignant Disorders of the Upper Aerodigestive Tract: A Systematic Review and Meta-analysis

Background & Aims: Retinoids may have a role in the chemoprevention of potentially malignant disorders of the upper aerodigestive tract. Therefore, we conducted a systematic review of randomised controlled trials to examine the effect of synthetic retinoid interventions in people with cancer or potentially malignant disorders of the upper digestive tract. Methods: We searched five electronic databases and reference lists to locate all eligible trials and analysed trial quality. Outcome measures were all-cause and cancer mortality, disease-free survival, second primary cancer, cancer and potentially malignant disorder recurrence and progression to cancer. Results of individual trials were combined by use of random-effects meta-analyses. Results & Conclusions: We identified 17 15 trials, eightnine in people with upper aerodigestive tract cancer and seven eight in people with potentially malignant disorders, respectively. The results provide little evidence that retinoids have a beneficial effect on disease-free survival (OR=0.74, 95% CI =0.51, 1.09), all cause mortality (OR = 1.28, 95% confidence interval [CI] =1.00 to 1.65), disease-free survival (OR=0.74, 95% CI =0.51, 1.09), recurrence of cancer (OR = 1.47, 95% CI = 0.95, 2.26), development of second primary cancers (OR = 0.96, 95% CI = 0.76, 1.20) or the progression to malignancy (OR = 0.69, 95% CIs = 0.22, 2.15). There was even a suggestion of harm for some outcomes. There was also a suggestion that retinoids may decrease the recurrence of potentially malignant disorders (OR = 0.22, 95% CIs = 0.03, 1.34). For now there is no evidence to support the use of retinoids in people with upper aerodigestive tract cancer