Dual contribution of the gut microbiome to immunotherapy efficacy and toxicity: supportive care implications and recommendations.

The efficacy of immune checkpoint inhibitors (immunotherapy) is increasingly recognized to be linked to the composition the gut microbiome. Given the high rates of resistance, interventions targeting the gut microbiome are now being investigated for its ability to improve the efficacy of immunotherapy. In light of recently published data demonstrating a strong correlation between the efficacy and toxicity of immunotherapy, there is a risk that efforts to enhance immunotherapy efficacy may be undermined by increases in immune-related adverse events (IrAEs) This is particularly important for microbial interventions aimed at increasing immunotherapy efficacy, with many microbes implicated in tumour response also linked to IrAEs, especially colitis. IrAEs have a profound impact on patient quality of life, causing physical, psychosocial, and financial distress. Here, we outline strategies at the discovery, translational, and clinical research phases to ensure the impact of augmenting immunotherapy efficacy is approached in a manner that considers adverse implications. Adopting these strategies will ensure that our ongoing efforts to overcome immunotherapy resistance are not impacted by unacceptable toxicity

Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

Semi-analytic results for quasi-normal frequencies

The last decade has seen considerable interest in the quasi-normal frequencies [QNFs] of black holes (and even wormholes), both asymptotically flat and with cosmological horizons. There is wide agreement that the QNFs are often of the form omega_n = (offset) + i n (gap), though some authors have encountered situations where this behaviour seems to fail. To get a better understanding of the general situation we consider a semi-analytic model based on a piecewise Eckart (Poeschl-Teller) potential, allowing for different heights and different rates of exponential falloff in the two asymptotic directions. This model is sufficiently general to capture and display key features of the black hole QNFs while simultaneously being analytically tractable, at least for asymptotically large imaginary parts of the QNFs. We shall derive an appropriate "quantization condition" for the asymptotic QNFs, and extract as much analytic information as possible. In particular, we shall explicitly verify that the (offset)+ i n (gap) behaviour is common but not universal, with this behaviour failing unless the ratio of rates of exponential falloff on the two sides of the potential is a rational number. (This is "common but not universal" in the sense that the rational numbers are dense in the reals.) We argue that this behaviour is likely to persist for black holes with cosmological horizons.Comment: V1: 28 pages, no figures. V2: 3 references added, no physics changes. V3: 29 pages, 9 references added, no physics changes; V4: reformatted, now 27 pages. Some clarifications, comparison with results obtained by monodromy techniques. This version accepted for publication in JHEP. V5: Minor typos fixed. Compatible with published versio

In-lecture learning motivation predicts students’ motivation, intention, and behaviour for after-lecture learning: Examining the trans-contextual model across universities from UK, China, and Pakistan

This paper presents a cross-cultural examination of the trans-contextual model in University education setting. The purpose of the study was to test the effect of students’ perceived autonomy support and in-lecture learning motivation on motivation, intention, and behaviour with respect to after-lecture learning via the mediation of the social cognitive variables: attitude, subjective norm, and perceived behavioural control. University students from UK, China, and Pakistan completed the questionnaires of the study variables. Results revealed that in-lecture perceived autonomy support and autonomous motivation were positively associated with autonomous motivation and intention to engage in after-lecture learning activities via the mediation of the social cognitive variables in all samples. After controlling for the effect of past behaviour, relations between intention and behaviour were only observed in the Chinese sample. In conclusion, the trans-contextual model can be applied to University education, but cultural differences appear to moderate the predictive power of the model, particularly for the intention-behaviour relationship

Exploring local knowledge and perceptions on zoonoses among pastoralists in northern and eastern Tanzania

Background: Zoonoses account for the most commonly reported emerging and re-emerging infectious diseases in Sub-Saharan Africa. However, there is limited knowledge on how pastoral communities perceive zoonoses in relation to their livelihoods, culture and their wider ecology. This study was carried out to explore local knowledge and perceptions on zoonoses among pastoralists in Tanzania. Methodology and principal findings: This study involved pastoralists in Ngorongoro district in northern Tanzania and Kibaha and Bagamoyo districts in eastern Tanzania. Qualitative methods of focus group discussions, participatory epidemiology and interviews were used. A total of 223 people were involved in the study. Among the pastoralists, there was no specific term in their local language that describes zoonosis. Pastoralists from northern Tanzania possessed a higher understanding on the existence of a number of zoonoses than their eastern districts' counterparts. Understanding of zoonoses could be categorized into two broad groups: a local syndromic framework, whereby specific symptoms of a particular illness in humans concurred with symptoms in animals, and the biomedical framework, where a case definition is supported by diagnostic tests. Some pastoralists understand the possibility of some infections that could cross over to humans from animals but harm from these are generally tolerated and are not considered as threats. A number of social and cultural practices aimed at maintaining specific cultural functions including social cohesion and rites of passage involve animal products, which present zoonotic risk. Conclusions: These findings show how zoonoses are locally understood, and how epidemiology and biomedicine are shaping pastoralists perceptions to zoonoses. Evidence is needed to understand better the true burden and impact of zoonoses in these communities. More studies are needed that seek to clarify the common understanding of zoonoses that could be used to guide effective and locally relevant interventions. Such studies should consider in their approaches the pastoralists' wider social, cultural and economic set up

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors

Structure of hadron resonances with a nearby zero of the amplitude

We discuss the relation between the analytic structure of the scattering amplitude and the origin of an eigenstate represented by a pole of the amplitude.If the eigenstate is not dynamically generated by the interaction in the channel of interest, the residue of the pole vanishes in the zero coupling limit. Based on the topological nature of the phase of the scattering amplitude, we show that the pole must encounter with the Castillejo-Dalitz-Dyson (CDD) zero in this limit. It is concluded that the dynamical component of the eigenstate is small if a CDD zero exists near the eigenstate pole. We show that the line shape of the resonance is distorted from the Breit-Wigner form as an observable consequence of the nearby CDD zero. Finally, studying the positions of poles and CDD zeros of the KbarN-piSigma amplitude, we discuss the origin of the eigenstates in the Lambda(1405) region.Comment: 7 pages, 3 figures, v2: published versio

Comparison of pharmacist managed anticoagulation with usual medical care in a family medicine clinic

Background The beneficial outcomes of oral anticoagulation therapy are dependent upon achieving and maintaining an optimal INR therapeutic range. There is growing evidence that better outcomes are achieved when anticoagulation is managed by a pharmacist with expertise in anticoagulation management rather than usual care by family physicians. This study compared a pharmacist managed anticoagulation program (PC) to usual physician care (UC) in a family medicine clinic. Methods A retrospective cohort study was carried out in a family medicine clinic which included a clinical pharmacist. In 2006, the pharmacist assumed anticoagulation management. For a 17-month period, the PC group (n = 112) of patients on warfarin were compared to the UC patients (n = 81) for a similar period prior to 2006. The primary outcome was the percentage of time patients' INR was in the therapeutic range (TTR). Secondary outcomes were the percentage of time in therapeutic range within ± 0.3 units of the recommended range (expanded TTR) and percentage of time the INR was >5.0 or <1.5. Results The baseline characteristics were similar between the groups. Fifty-five percent of the PC group was male with a mean age of 67 years; 51% of the UC group was male with a mean age of 71 years. The most common indications for warfarin in both groups were atrial fibrillation, mechanical heart valves and deep vein thrombosis. The TTR was 73% for PC and 65% for UC (p 5 were 0.3% for PC patients and 0.1% for UC (p < 0.0001). Conclusion The pharmacist-managed anticoagulation program within a family practice clinic compared to usual care by the physicians achieved significantly better INR control as measured by the percentage of time patients' INR values were kept in both the therapeutic and expanded range. Based on the results of this study, a collaborative family practice clinic using pharmacists and physicians may be an effective model for anticoagulation management with these results verified in future prospective randomized studies