The future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role?

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies

Mortality in Peripheral Arterial Disease: A Comparison of Patients Managed by Vascular Specialists and General Practitioners

BACKGROUND: Peripheral arterial disease (PAD) is undertreated by general practitioners (GPs). However, the impact of the suboptimal clinical management is unknown. OBJECTIVE: To assess the mortality rate of PAD patients in relation to the type of physician who provides their care (GP or vascular specialist). DESIGN: Prospective study. SETTING: Primary care practice and academic vascular laboratory. PARTICIPANTS: GP patients (n = 60) were those of the Peripheral Arteriopathy and Cardiovascular Events study (PACE). Patients managed by specialists (n = 82) were consecutive subjects with established PAD who were referred to our vascular laboratory during the enrolment period of the PACE study. MEASUREMENTS: All-cause and cardiovascular mortality. RESULTS: After 32 months of follow-up, specialist management was associated with a lower rate of all-cause mortality (RR = 0.04; 95% CI 0.01–0.34; p = .003) and cardiovascular mortality (RR = 0.07; 95% CI 0.01–0.65; p = .020), after adjustment for patients’ characteristics. Specialists were more likely to use antiplatelet agents (93% vs 73%, p < .001), statins (62% vs 25%, p < .001) and beta blockers (28% vs 3%, p < .001). Survival differences between specialists and GPs disappeared once the use of pharmacotherapies was added to the proportional hazard model. The fully adjusted model showed that the use of statins was significantly associated with a reduced risk of all-cause mortality (RR = 0.02; 95% CI 0.01–0.73, p = .034) and cardiovascular mortality (RR = 0.02; 95% CI 0.01–0.71, p = .033). CONCLUSIONS: Specialist management of patients with symptomatic PAD resulted in better survival than generalist management. This effect appears to be mainly caused by the more frequent use of effective medicines by specialists

Systematic Development of the YouRAction program, a computer-tailored Physical Activity promotion intervention for Dutch adolescents, targeting personal motivations and environmental opportunities

Background. Increasing physical activity (PA) among adolescents is an important health promotion goal. PA has numerous positive health effects, but the majority of Dutch adolescents do not meet PA requirements. The present paper describes the systematic development of a theory-based computer-tailored intervention, YouRAction, which targets individual and environmental factors determining PA among adolescents. Design. The intervention development was guided by the Intervention Mapping protocol, in order to define clear program objectives, theoretical methods and practical strategies, ensure systematic program planning and pilot-testing, and anticipate on implementation and evaluation. Two versions of YouRAction were developed: one that targets individual determinants and an extended version that also provides feedback on opportunities to be active in the neighbourhood. Key determinants that were targeted included: knowledge and awareness, attitudes, self-efficacy and subjective norms. The extended version also addressed perceived availability of neighbourhood PA facilities. Both versions aimed to increase levels of moderate-to-vigorous PA among adolescents. The intervention structure was based on self-regulation theory, comprising of five steps in the process of successful goal pursuit. Monitoring of PA behaviour and behavioural and normative feedback were used to increase awareness of PA behaviour; motivation was enhanced by targeting self-efficacy and attitudes, by means of various interactive strategies, such as web movies; the perceived environment was targeted by visualizing opportunities to be active in an interactive geographical map of the home environment; in the goal setting phase, the adolescents were guided in setting a goal and developing an action plan to achieve this goal; in the phase of active goal pursuit adolescents try to achieve their goal and in the evaluation phase the achievements are evaluated. Based on the results of the evaluation adolescents could revise their goal or choose another behaviour to focus on. The intervention is delivered in a classroom setting in three lessons. YouRAction will be evaluated in a cluster-randomized trial, with classes as unit of randomization. Evaluation will focus on PA outcomes, cognitive mediators/moderators and process measures. Discussion. The planned development of YouRAction resulted in two computer-tailored interventions aimed at the promotion of PA in a Dutch secondary school setting. Trial registration. NTR1923

Extracellular Hsp72, an endogenous DAMP, is released by virally infected airway epithelial cells and activates neutrophils via Toll-like receptor (TLR)-4

<p>Abstract</p> <p>Background</p> <p>Neutrophils play an important role in the pathophysiology of RSV, though RSV does not appear to directly activate neutrophils in the lower airways. Therefore locally produced cytokines or other molecules released by virally-infected airway epithelial cells are likely responsible for recruiting and activating neutrophils. Heat shock proteins (HSPs) are generally regarded as intracellular proteins acting as molecular chaperones; however, HSP72 can also be released from cells, and the implications of this release are not fully understood.</p> <p>Methods</p> <p>Human bronchial epithelial cells (16HBE14o-) were infected with RSV and Hsp72 levels were measured by Western blot and ELISA. Tracheal aspirates were obtained from critically ill children infected with RSV and analyzed for Hsp72 levels by ELISA. Primary human neutrophils and differentiated HL-60 cells were cultured with Hsp72 and supernatants analyzed for cytokine production. In some cases, cells were pretreated with polymyxin B prior to treatment with Hsp72. IκBα was assessed by Western blot and EMSA's were performed to determine NF-κB activation. HL-60 cells were pretreated with neutralizing antibody against TLR4 prior to Hsp72 treatment. Neutrophils were harvested from the bone marrow of wild type or TLR4-deficient mice prior to treatment with Hsp72.</p> <p>Results</p> <p>Infection of 16HBE14o- with RSV showed an induction of intracellular Hsp72 levels as well as extracellular release of Hsp72. Primary human neutrophils from normal donors and differentiated HL-60 cells treated with increasing concentrations of Hsp72 resulted in increased cytokine (IL-8 and TNFα) production. This effect was independent of the low levels of endotoxin in the Hsp72 preparation. Hsp72 mediated cytokine production via activation of NF-κB translocation and DNA binding. Using bone marrow-derived neutrophils from wild type and TLR4-mutant mice, we showed that Hsp72 directly activates neutrophil-derived cytokine production via the activation of TLR4.</p> <p>Conclusion</p> <p>Collectively these data suggest that extracellular Hsp72 is released from virally infected airway epithelial cells resulting in the recruitment and activation of neutrophils.</p

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

CXCR6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells

Background: A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+. Conclusions/Significance: The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT