Incorporating cancer risk information into general practice: a qualitative study using focus groups with health professionals.

BACKGROUND: It is estimated that approximately 40% of all cases of cancer are attributable to lifestyle factors. Providing people with personalised information about their future risk of cancer may help promote behaviour change. AIM: To explore the views of health professionals on incorporating personalised cancer risk information, based on lifestyle factors, into general practice. DESIGN AND SETTING: Qualitative study using data from six focus groups with a total of 24 general practice health professionals from the NHS Nene Clinical Commissioning Group in England. METHOD: The focus groups were guided by a schedule covering current provision of lifestyle advice relating to cancer and views on incorporating personalised cancer risk information. Data were audiotaped, transcribed verbatim, and then analysed using thematic analysis. RESULTS: Providing lifestyle advice was viewed as a core activity within general practice but the influence of lifestyle on cancer risk was rarely discussed. The word 'cancer' was seen as a potentially powerful motivator for lifestyle change but the fact that it could generate health anxiety was also recognised. Most focus group participants felt that a numerical risk estimate was more likely to influence behaviour than generic advice. All felt that general practice should provide this information, but there was a clear need for additional resources for it to be offered widely. CONCLUSION: Study participants were in support of providing personalised cancer risk information in general practice. The findings highlight a number of potential benefits and challenges that will inform the future development of interventions in general practice to promote behaviour change for cancer prevention.This study was funded by an innovation grant from the Cancer Research UK — BUPA Foundation Fund (ref: C55650/A20818). Juliet Usher-Smith is supported by a National Institute for Health Research Clinical Lectureship. Barbora Silarova was supported by the Medical Research Council [MC_UU_12015/4]

A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

43 p.-5 fig.Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.C.T. thanks the CMVM of the University of Edinburgh (Principal's scholarship). D.L. acknowledges support from the Spanish Ministry of Science, Innovation and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00, cofunded by the European Regional Development Fund (FEDER). E.R.W., J.C.D. and K.G.M. are funded by CRUK. J.R.L.O. acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T.V. is funded by H2020-MSCA-IF-2016-749299. RCM thanks the support from the Vice Rectorate for Research of the University of Granada. X.-F.L. and B.-Z.Q. are funded by a CRUK Career Development Fellowship (C49791/A17367). B.-Z.Q. also acknowledges support from an ERC Starting Grant (716379). C.S, M.C.F. and V.G.B are funded by CRUK Programme Grant C157/A15703. N.O.C. and A.U.B are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3).Peer reviewe

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy

Objective: The MAST family of microtubule-associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at \u3c2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274–284

Toll-like receptor orchestrates a tumor suppressor response in non-small cell lung cancer

Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after Tlr2 loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.F.R.M. is funded by a Wellcome Trust clinical research fellowship through the Edinburgh Clinical Academic Track (ECAT) program (203913/Z/16/Z), a Wellcome Trust-ISSF3 award (IS3-R1.07 20/21), and a Wellcome Trust iTPA award (209710/Z/17/Z). J.C.A. core lab funding was received from Cancer Research UK (C47559/A16243, Training and Career Development Board – Career Development Fellowship), the University of Edinburgh (Chancellor’s Fellowship), and the Ministry of Science and Innovation of the Government of Spain (Proyecto PID2020-117860GB-100 financiado por MCIN/AEI/10.13039/501100011033). S.W. is supported by a Cancer Research UK senior fellowship (A29576). J.C. is supported by a Wellcome Trust clinical lectureship through the ECAT program (203913/Z/16/Z). M.M. is supported by a CRUK Edinburgh Centre Award (C157/A25140). S.V. and J.F.P. are funded by National Institute on Aging (NIA) grants (R01AG 68048-1 and UG3CA 268103-1)

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids

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Management of cutaneous metastases using electrochemotherapy

Background. Cutaneous metastases may cause considerable discomfort as a consequence of ulceration, oozing, bleeding and pain. Electrochemotherapy has proven to be highly effective in the treatment of cutaneous metastases. Electrochemotherapy utilises pulses of electricity to increase the permeability of the cell membrane and thereby augment the effect of chemotherapy. For the drug bleomycin, the effect is enhanced several hundred-fold, enabling once-only treatment. The primary endpoint of this study is to evaluate the efficacy of electrochemotherapy as a palliative treatment. Methods. This phase II study is a collaboration between two centres, one in Denmark and the other in the UK. Patients with cutaneous metastases of any histology were included. Bleomycin was administered intratumourally or intravenously followed by application of electric pulses to the tumour site. Results. Fifty-two patients were included. Complete and partial response rate was 68% and 18%, respectively, for cutaneous metastases <3 cm and 8% and 23%, respectively, for cutaneous metastases >3 cm. Treatment was well-tolerated by patients, including the elderly, and no serious adverse events were observed. Conclusions. ECT is an efficient and safe treatment and clinicians should not hesitate to use it even in the elderly

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011