Dynamic MAIT cell response with progressively enhanced innateness during acute HIV-1 infection.

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer

Introduction: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. Materials and Methods: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). Results: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. Conclusion: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.</p

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer

Introduction: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients’ outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors.// Materials and Methods: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket).// Results: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response.// Conclusion: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients

Discovery and Evaluation of Protein Biomarkers as a Signature of Wellness in Late-Stage Cancer Patients in Early Phase Clinical Trials

From MDPI via Jisc Publications RouterHistory: accepted 2021-05-12, pub-electronic 2021-05-18Publication status: PublishedFunder: Bloodwise; Grant(s): 19007Funder: Medical Research Council; Grant(s): MR/M008959/1Funder: Cancer Research UK; Grant(s): C5759/A25254, A20465TARGET (tumour characterisation to guide experimental targeted therapy) is a cancer precision medicine programme focused on molecular characterisation of patients entering early phase clinical trials. Performance status (PS) measures a patient’s ability to perform a variety of activities. However, the quality of present algorithms to assess PS is limited and based on qualitative clinician assessment. Plasma samples from patients enrolled into TARGET were analysed using the mass spectrometry (MS) technique: sequential window acquisition of all theoretical fragment ion spectra (SWATH)-MS. SWATH-MS was used on a discovery cohort of 55 patients to differentiate patients into either a good or poor prognosis by creation of a Wellness Score (WS) that showed stronger prediction of overall survival (p = 0.000551) compared to PS (p = 0.001). WS was then tested against a validation cohort of 77 patients showing significant (p = 0.000451) prediction of overall survival. WS in both sets had receiver operating characteristic curve area under the curve (AUC) values of 0.76 (p = 0.002) and 0.67 (p = 0.011): AUC of PS was 0.70 (p = 0.117) and 0.55 (p = 0.548). These signatures can now be evaluated further in larger patient populations to assess their utility in a clinical setting

Coupling models of cattle and farms with models of badgers for predicting the dynamics of bovine tuberculosis (TB)

Bovine TB is a major problem for the agricultural industry in several countries. TB can be contracted and spread by species other than cattle and this can cause a problem for disease control. In the UK and Ireland, badgers are a recognised reservoir of infection and there has been substantial discussion about potential control strategies. We present a coupling of individual based models of bovine TB in badgers and cattle, which aims to capture the key details of the natural history of the disease and of both species at approximately county scale. The model is spatially explicit it follows a very large number of cattle and badgers on a different grid size for each species and includes also winter housing. We show that the model can replicate the reported dynamics of both cattle and badger populations as well as the increasing prevalence of the disease in cattle. Parameter space used as input in simulations was swept out using Latin hypercube sampling and sensitivity analysis to model outputs was conducted using mixed effect models. By exploring a large and computationally intensive parameter space we show that of the available control strategies it is the frequency of TB testing and whether or not winter housing is practised that have the most significant effects on the number of infected cattle, with the effect of winter housing becoming stronger as farm size increases. Whether badgers were culled or not explained about 5%, while the accuracy of the test employed to detect infected cattle explained less than 3% of the variance in the number of infected cattle

Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2

Background Entrectinib is a potent inhibitor of ROS1 (in addition to TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumor activity in multiple intracranial tumor models. We present an updated integrated safety and efficacy analysis from three Phase I/II studies of entrectinib (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in patients with locally advanced or metastatic ROS1 fusion-positive NSCLCs. Methods The analysis included patients with ROS1 inhibitor-naive NSCLC harboring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included patients with ROS1 fusion-positive NSCLC who received ≥1 dose of entrectinib; the integrated efficacy analysis included patients with at least 6 months of follow-up. Tumor assessments were done at week 4 and every 8 weeks thereafter. Blinded independent central review (BICR), RECIST v1.1 was performed. Primary endpoints by BICR: overall response rate (ORR) and duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial responses), DOR in patients with an intracranial response, PFS in patients with baseline CNS disease. Results In the ROS1 safety-evaluable population (n=134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of patients. Patients with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of patients, respectively. In the efficacy-evaluable population (n=53 patients with treatment-naive, ROS1 fusion-positive NSCLC; median age 53 years, 64% female, 59% never smokers), BICR-assessed ORR was 77% (95% CI 64-88), complete responses n=3 (6%). Median BICR-assessed DOR: 25 mo (95% CI 11-35). Median BICR-assessed PFS: 26 mo (95% CI 16-37) and 14 mo (95% CI 5-NR) for patients without (n=30) and with CNS disease (n=23) at baseline, respectively. In patients with baseline CNS disease (per BICR assessment, n=20), intracranial ORR was 55% (95% CI 32-77) and median intracranial DOR in patients with an intracranial response (n=11) was 13 mo (95% CI 6-not reached). Conclusion Entrectinib is highly active in patients with ROS1 fusion-positive NSCLC, including those with CNS disease. Entrectinib is well tolerated and has a manageable safety profile. Citation Format: Alexander Drilon, Fabrice Barlesi, Filippo De Braud, Byoung Chul Cho, Myung-Ju Ahn, Salvatore Siena, Matthew G. Krebs, Chia-Chi Lin, Tom John, Daniel SW Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Christian Rolfo, Jurgen Wolf, Chenglin Ye, Todd Riehl, Susan Eng, Robert C. Doebele. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT192

Sheep Updates 2003 - Posters

This session covers eleven papers from different authors:1 Sheep production on annual stubbles/pastures vs lucerne Maxine Brown Gaye Krebs Muresk Institute, Curtin University Diana Fedorenko Kathryn Egerton-Warburton Centre for Cropping Systems, Department of Agriculture Western Australia 2. The value chain of the Lake Grace livestock industry Evan Burt Nazrul Islam Department of Agriculture Western Australia 3. Native pastures, Dorper sheep and the 2002 drought Roy Butler Department of Agriculture Western Australia 4. Commercial sheep breeders can improve their sheep breeding program using wether trials L.G. Butler, S.R. Brown, M.F. D’Antuono, J.C. Greeff Department of Agriculture 5. Western Australia Linked ewe trials to benchmark wool traits and reproductive performance of Western Australian sheep flocks Ken Hart Department of Agriculture Western Australia 6. Damara sheep - what is their potential? A case study from the North-eastern wheatbelt Tanya Kilminster Evan Burt Department of Agriculture Western Australia 7, Australian Sheep Industry CRC - nutrition sub-program Rachel Kirby Sheep CRC Research Fellow 8. Dust penetration is not genetically and phenotypically the same trait as dust content M.E. Ladyman J.C. Greeff Department of Agriculture Western Australia A.C. Schlink CSIRO Livestock Industries, Private Bag 5, Wembley WA I.H. Williams P.E. Vercoe University of Western Australia, Crawley WA 9.Developing sustainable fodder crop systems with new annual pasture legumes Anyou Lui Department of Agriculture Western Australia 10. Seasonal pricing and seasonality of supply of prime lambs in the western wheatbelt Karen Smith Martin Bent Muresk Institute, Curtin University 11. The role of alternative and exotic sheep breeds in the Western Australian sheep industry Matthew Young Department of Agriculture Western Australi

PCM4EU and PRIME-ROSE:Collaboration for implementation of precision cancer medicine in Europe

Background: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. Patients and methods: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. Results: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu. eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. Conclusion: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.</p

Operative Environment

Postoperative SSIs are believed to occur via bacterial inoculation at the time of surgery or as a result of bacterial contamination of the wound via open pathways to the deep tissue layers.1–3 The probability of SSI is reflected by interaction of parameters that can be categorized into three major groups.2 The first group consists of factors related to the ability of bacteria to cause infection and include initial inoculation load and genetically determined virulence factors that are required for adherence, reproduction, toxin production, and bypassing host defense mechanisms. The second group involves those factors related to the defense capacity of the host including local and systemic defense mechanisms. The last group contains environmental determinants of exposure such as size, time, and location of the surgical wound that can provide an opportunity for the bacteria to enter the surgical wound, overcome the local defense system, sustain their presence, and replicate and initiate local as well as systemic inflammatory reactions of the host. The use of iodine impregnated skin incise drapes shows decreased skin bacterial counts but no correlation has been established with SSI. However, no recommendations regarding the use of skin barriers can be made (see this Workgroup, Question 27)

An Observational Cohort Comparison of Facilitators of Retention in Care and Adherence to Anti-Eetroviral Therapy at an HIV Treatment Center in Kenya

BACKGROUND: Most HIV treatment programs in resource-limited settings utilize multiple facilitators of adherence and retention in care but there is little data on the efficacy of these methods. We performed an observational cohort analysis of a treatment program in Kenya to assess which program components promote adherence and retention in HIV care in East Africa. METHODS: Patients initiating ART at A.I.C. Kijabe Hospital were prospectively enrolled in an observational study. Kijabe has an intensive program to promote adherence and retention in care during the first 6 months of ART that incorporates the following facilitators: home visits by community health workers, community based support groups, pharmacy counseling, and unannounced pill counts by clinicians. The primary endpoint was time to treatment failure, defined as a detectable HIV-1 viral load; discontinuation of ART; death; or loss to follow-up. Time to treatment failure for each facilitator was calculated using Kaplan-Meier analysis. The relative effects of the facilitators were determined by the Cox Proportional Hazards Model. RESULTS: 301 patients were enrolled. Time to treatment failure was longer in patients participating in support groups (448 days vs. 337 days, P<0.001), pharmacy counseling (480 days vs. 386 days, P = 0.002), pill counts (482 days vs. 189 days, P<0.001) and home visits (485 days vs. 426 days, P = 0.024). Better adherence was seen with support groups (89% vs. 82%, P = 0.05) and pill counts (89% vs. 75%, P = 0.02). Multivariate analysis using the Cox Model found significant reductions in risk of treatment failure associated with pill counts (HR = 0.19, P<0.001) and support groups (HR = 0.43, P = 0.003). CONCLUSION: Unannounced pill counts by the clinician and community based support groups were associated with better long term treatment success and with better adherence