Phase Ib trial of IRX-2 plus durvalumab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

OBJECTIVES: IRX-2 is a multi-cytokine immune-activating agent with anti-tumor activity in non-metastatic head and neck squamous cell carcinoma (HNSCC). Here, we evaluated combined IRX-2 and durvalumab in patients with recurrent and/or metastatic HNSCC. MATERIALS AND METHODS: This was a phase Ib trial consisting of dose escalation and expansion. Primary endpoints were safety and biomarkers to assess the immune response in the tumor microenvironment including significant increases in PD-L1 expression and CD8 + tumor infiltrating lymphocytes (TIL) comparing pre- and on-treatment tumor biopsies. Secondary endpoints were objective response rates (ORR) and survival outcomes. RESULTS: Sixteen patients were evaluable for response, and nine patients were evaluable for biomarkers. Thirteen patients (68 %) had exposure to prior anti-PD-1 therapy. No dose-limiting or grade ≥ 3 treatment-related adverse events were observed. On-treatment biopsies showed significantly increased PD-L1 (p = 0.005), CD3+ (p = 0.020), CD4+ (p = 0.022), and CD8 + T cells (p = 0.017) compared to pre-treatment. Median overall survival and progression-free survival (PFS) were 6.18 months (95 % CI, 2.66-8.61) and 2.53 months (95 % CI, 1.81-4.04), respectively. One patient had an objective response (ORR, 5.3 %) with an ongoing PFS of > 25 months. Disease control rate was 42 %. The responder harbored an ARID1A variant of unknown significance (VUS) that was predicted to bind her HLA-I alleles with a higher affinity than the reference peptide. CONCLUSIONS: IRX-2 and durvalumab were safe and elicited the evidence of immune activation in the tumor microenvironment determined by increased PD-L1 expression and CD8+ TILs. CLINICAL TRIAL REGISTRATION NUMBER: NCT03381183.

Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress. METHODS: We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT. RESULTS: We discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL. CONCLUSIONS: Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity.

Combination Nivolumab, CD137 Agonism, and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

PURPOSE: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically programmed cell death protein 1 (PD-1) blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TILs. PATIENTS AND METHODS: Patients with stage III/IV metastatic melanoma with unresectable disease who were anti-PD-1 treatment-naïve were enrolled. TILs were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in cohort 1 received TIL infusion followed by nivolumab. Patients in cohort 2 also received nivolumab prior to surgical harvest and during TIL production. RESULTS: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TILs were successfully expanded from all ACT-treated patients and were tumor reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36%, and median progression-free survival was 5 months. Two nonresponders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction. CONCLUSIONS: Combination therapy with TILs and nivolumab was safe and feasible for patients with metastatic melanoma and provides important insights for future therapeutic developments in ACT with TILs.

Laser wakefield acceleration based x ray source using 225-TW and 13-fs laser pulses produced by thin film compression.

We show that 13-fs laser pulses associated with 225 TW of peak power can be used to produce laser wakefield acceleration (LWFA) and generate synchrotron radiation. To achieve this, 130-TW high-power laser pulses (3.2 J, 24 fs) are efficiently compressed down to 13 fs with the thin film compression (TFC) technique using large chirped mirrors after propagation and spectral broadening through a 1-mm-thick fused silica plate. We show that the compressed 13-fs laser pulse can be properly focused even if it induces a 10% degradation of the Strehl ratio. We demonstrate the usability of such a laser beam. We observe both an increase of the electron energy and of the betatron radiation critical energy when the pulse duration is reduced to 13 fs compared with the 24-fs case.

Tackling gambling harm to bingo players at a time of commercial, regulatory and technological change - towards a public health approach.

OBJECTIVES: The aim of this paper is to identify possible regulatory, policy and program measures to address gambling harm to bingo players and their communities, and in doing so extend existing public health approaches to gambling to better include bingo. STUDY DESIGN: This was a qualitative case study of three populations in Victoria, Australia where bingo was popular and structural disadvantage common: Indigenous people in the state's east, Pacific people in the north and older people on low or fixed incomes in the capital, Melbourne. METHODS: Our study investigated experiences of bingo, including gambling harm and recommendations for change. Data were generated through interviews with 53 bingo players and 13 stakeholders as well as 12 participant observations of bingo sessions. RESULTS: Five broad drivers of and influences on harm to bingo players are identified: technological, regulatory and commercial changes eroding bingo's protective factors; bingo being used to bolster other forms of gambling; promotion of gambling interests over people's wellbeing; not recognising experiences of different communities and; external structural influences such as racialised poverty. We identify recommendations from bingo players and stakeholders to address harm arising from bingo involving wagering. Based on these recommendations and available evidence, we propose five sets of measures to mitigate against gambling harm to bingo players and their communities, and so extend existing public health approaches to gambling to better encompass bingo. These sets of measures are: safeguarding bingo's protective features; delinking bingo from the gambling eco-system; dismantling political protection of the gambling industry; tailoring strategies for sub-populations and preventing oppression and abuse. CONCLUSIONS: In the face of significant regulatory, commercial and technological changes to bingo that risk increasing and intensifying harm, a public health approach to bingo could help mitigate gambling harm.

The problem of over-medicalisation: How AOD disease models perpetuate inequity for young people with multiple disadvantage.

Young people who experience multiple disadvantage have been identified as some of the most marginalised and under-serviced people in the alcohol and other drug (AOD) system. In this paper, we draw on a range of research evidence to argue that one of the challenges in responding appropriately to the needs of these young people are models of care which seek to ameliorate 'illness' rather than promote wellness. While disease approaches have some important benefits, overly-medicalised AOD treatment responses also have negative impacts. We argue that disease models rest on understandings of substance use as an individual enterprise and thereby pay insufficient attention to the material disadvantage that shape young people's substance use, creating feelings of shame, failure and a reluctance to return to care if they continue to use. Additionally we draw on literature that shows how disease models construe young people's substance use as compulsive, perpetuating deficit views of them as irrational and failing to account for the specific meanings that young people themselves give to their substance use. By focusing on clinical solutions rather than material and relational ones, medicalised treatment responses perpetuate inequity: they benefit young people whose resources and normative values align with the treatments offered by disease models, but are much less helpful to those who are under-resourced,. We suggest that alternative approaches can be found in First Nations models of care and youth programs that attend to social, cultural, and material wellbeing, making living well the focus of treatment rather than illness amelioration.

Optimal Duration of Antibiotics Following Appendectomy for Patients With Complicated Appendicitis.

BACKGROUND: Complicated appendicitis patients typically undergo appendectomy followed by antibiotics. The optimal course of antibiotics for complicated appendicitis is poorly defined. METHODS: Data were collected from patients presenting with acute appendicitis and underwent appendectomy at the index hospitalization (2015-2017). Primary outcomes were readmission rate, superficial surgical site infection (SSI), deep space infection (DSI), which includes abscess. Length of post-operative antibiotic use was recorded and an average intent-to-treat (ITT) by operative grade was calculated. RESULTS: Two hundred seventy-two patients (23%) were diagnosed with complicated appendicitis. SSI occurred in 4% of patients (n = 11); SSI rates ranged from 0% to 14.6% by ITT group with 3-4 days being the lowest (0%) and <3 days the highest (14.6%) (P = .008). DSI including abscesses occurred in 27 (9.9%) patients; least frequently in the 5-6 day ITT group (7.4%). Length of stay (LOS) was significantly related to longer antibiotic use (P < .001) and increasing operative grade (P < .01). CONCLUSIONS: Given the lower incidence of postoperative complications between 3 and 6 days and no added benefit for ITT >6 days, we recommend limiting antibiotic treatment to 3-6 days for all complicated appendicitis cases with additional workup warranted if infectious symptoms persist.

Development of a recombinant murine tumour model using hepatoma cells expressing hepatitis C virus nonstructural antigens.

Hepatitis C virus (HCV) chronically infects 2%-3% of the world's population, causing liver disease and cancer with prolonged infection. The narrow host range of the virus, being restricted largely to human hepatocytes, has made the development of relevant models to evaluate the efficacy of vaccines a challenge. We have developed a novel approach to accomplish this by generating a murine hepatoma cell line stably expressing nonstructural HCV antigens which can be used in vitro or in vivo to test HCV vaccine efficacies. These HCV-recombinant hepatoma cells formed large solid-mass tumours when implanted into syngeneic mice, allowing us to test candidate HCV vaccines to demonstrate the development of an HCV-specific immune response that limited tumour growth. Using this model, we tested the therapeutic potential of recombinant anti-HCV-specific vaccines based on two fundamentally different attenuated pathogen vaccine systems-attenuated Salmonella and recombinant adenoviral vector based vaccine. While attenuated Salmonella that secreted HCV antigens limited growth of the HCV-recombinant tumours when used in a therapeutic vaccination trial, replication-competent but noninfectious adenovirus expressing nonstructural HCV antigens showed overall greater survival and reduced weight loss compared to non-replicating nondisseminating adenovirus. Our results demonstrate a model with anti-tumour responses to HCV nonstructural (NS) protein antigens and suggest that recombinant vaccine vectors should be explored as a therapeutic strategy for controlling HCV and HCV-associated cancers.

Sheep from low-methane-yield selection lines created on alfalfa pellets also have lower methane yield under pastoral farming conditions.

Selection lines of sheep with low and high CH yield (g/kg DMI; CH/DMI) are being developed on the basis of feeding pelleted alfalfa hay at 2.0 times maintenance ME requirements in respiration chambers, but their divergence under predominant grazing conditions, as in New Zealand, is not known. The objectives of this study were to determine CH emissions and rumen fermentation characteristics in sheep from low and high CH/DMI selection lines while grazing pasture. Two grazing experiments were conducted with 42 selection line ewes in March 2013 (Exp. 1) and 98 selection line progeny ewe hoggets in October/November 2014 (Exp. 2), with CH emissions estimated by the SF tracer technique and DMI estimated by titanium oxide in combination with natural long-chain -alkanes. Total daily CH production (g/d) was similar between high and low CH/DMI selection line sheep in Exp. 1 and lower for low CH/DMI progeny compared with high CH/DMI progeny in Exp. 2 ( < 0.05). The CH/DMI tended to be 20% lower for low CH/DMI line sheep compared with high CH/DMI selection line sheep in Exp. 1 ( < 0.10) and was 15% lower for the low CH/DMI line in Exp. 2 ( < 0.01). Total VFA concentration and concentrations (m) of acetate, butyrate, and isobutyrate plus isovalerate were lower ( < 0.05) for low CH/DMI line sheep compared with high CH/DMI selection line sheep in both experiments. The current study indicates that differences in CH/DMI and VFA concentrations in selection line sheep, previously established on alfalfa pellets, are also present to a similar magnitude when grazing pasture.

Event-related brain potentials during the visuomotor mental rotation task: The contingent negative variation scales to angle of rotation.

Perceptual judgments about the angular disparity of a character from its standard upright (i.e., mental rotation task) result in a concurrent increase in reaction time (RT) and modulation of the amplitude of the P300 event-related brain potential (ERP). It has therefore been proposed that the P300 represents the neural processes associated with a visual rotation. In turn, the visuomotor mental rotation (VMR) task requires reaching to a location that deviates from a target by a predetermined angle. Although the VMR task exhibits a linear increase in RT with increasing oblique angles of rotation, work has not examined whether the task is supported via a visual rotation analogous to its mental rotation task counterpart. This represents a notable issue because seminal work involving non-human primates has ascribed VMR performance to the motor-related rotation of directionally tuned neurons in the primary motor cortex. Here we examined the concurrent behavioral and ERP characteristics of a standard reaching task and VMR tasks of 35°, 70°, and 105° of rotation. Results showed that the P300 amplitude was larger for the standard compared to each VMR task--an effect independent of the angle of rotation. In turn, the amplitude of the contingent negative variation (CNV)--an ERP related to cognitive and visuomotor integration for movement preparation--was systematically modulated with angle of rotation. Thus, we propose that the CNV represents an ERP correlate related to the cognitive and/or visuomotor transformation demands of increasing the angular separation between a stimulus and a movement goal.

Heritability estimates of methane emissions from sheep.

The objective of this study was to determine the genetic parameters of methane (CH4) emissions and their genetic correlations with key production traits. The trial measured the CH4 emissions, at 5-min intervals, from 1225 sheep placed in respiration chambers for 2 days, with repeat measurements 2 weeks later for another 2 days. They were fed in the chambers, based on live weight, a pelleted lucerne ration at 2.0 times estimated maintenance requirements. Methane outputs were calculated for g CH4/day and g CH4/kg dry matter intake (DMI) for each of the 4 days. Single trait models were used to obtain estimates of heritability and repeatability. Heritability of g CH4/day was 0.29 ± 0.05, and for g CH4/kg DMI 0.13 ± 0.03. Repeatability between measurements 14 days apart were 0.55 ± 0.02 and 0.26 ± 0.02, for the two traits. The genetic and phenotypic correlations of CH4 outputs with various production traits (weaning weight, live weight at 8 months of age, dag score, muscle depth and fleece weight at 12 months of age) measured in the first year of life, were estimated using bivariate models. With the exception of fleece weight, correlations were weak and not significantly different from zero for the g CH4/kg DMI trait. For fleece weight the phenotypic and genetic correlation estimates were -0.08 ± 0.03 and -0.32 ± 0.11 suggesting a low economically favourable relationship. These results indicate that there is genetic variation between animals for CH4 emission traits even after adjustment for feed intake and that these traits are repeatable. Current work includes the establishment of selection lines from these animals to investigate the physiological, microbial and anatomical changes, coupled with investigations into shorter and alternative CH4 emission measurement and breeding value estimation techniques; including genomic selection.

Tuberculosis of the patella masquerading as prepatellar bursitis.

Tuberculosis of bone is an uncommon entity in the western world. We present a case of tuberculosis of the patella mimicking prepatellar bursitis in an otherwise fit and well woman of Bangladeshi origin. We believe tuberculosis of bone should form a differential diagnosis of the swollen knee in high-risk patients.

The potential of stem cells in the treatment of skeletal muscle injury and disease.

Tissue engineering is a pioneering field with huge advances in recent times. These advances are not only in the understanding of how cells can be manipulated but also in potential clinical applications. Thus, tissue engineering, when applied to skeletal muscle cells, is an area of huge prospective benefit to patients with muscle disease/damage. This could include damage to muscle from trauma and include genetic abnormalities, for example, muscular dystrophies. Much of this research thus far has been focused on satellite cells, however, mesenchymal stem cells have more recently come to the fore. In particular, results of trials and further research into their use in heart failure, stress incontinence, and muscular dystrophies are eagerly awaited. Although no doubt, stem cells will have much to offer in the future, the results of further research still limit their use.

Tendon regeneration and repair with stem cells.

The use of stems cells in tendon repair is of particular interest given the frequency of tendon injuries worldwide together with the technical difficulty often encountered when repairing or augmenting tendons. Stems cells have the capability to differentiate into a variety of different cell types including osteocytes and tenocytes, and if normal architecture of damaged tendon (either macroscopic or microscopic) could be restored, this would significantly improve the management of patients with these injuries. There is already encouraging research on the use of stems cells clinically although considerable further work is required to improve knowledge and clinical applications of stem cells in tissue engineering.

Comparison of lethal versus non-lethal sample sources for the detection of infectious salmon anemia virus (ISAV).

The emergence of infectious salmon anemia virus (ISAV) in Canada and the USA has led to the establishment of ISAV surveillance programs for cultured Atlantic salmon (Salmo salar L.) and wild fish species, including Atlantic salmon. Current testing procedures for ISAV consist of viral culture, reverse-transcription polymerase chain reaction (RT-PCR) and indirect fluorescent antibody testing (IFAT), and require lethal sampling. As the focus of this study, blood was evaluated as a possible non-lethal sample source for ISAV diagnostic screening by viral culture and RT-PCR. Tissue samples (consisting of kidney/spleen for viral culture or kidney only for RT-PCR), blood and, to a lesser extent, mucus were tested from Atlantic salmon survivors of laboratory ISAV infection trials and moribund fish from marine salmon grow-out facilities participating in a USDA-sponsored surveillance program. The trial fish represented a potential carrier population, while the surveillance fish were composed of moribund individuals from ISA clinical sites. Sample sources and diagnostic techniques were compared. Blood compared well to tissue samples for viral culture and produced a greater number of positives than did kidney samples for ISAV detection by RT-PCR. RT-PCR using both kidney and blood samples was determined to be a more sensitive assay than viral isolation. Mucus did not perform well in either assay compared to the other sample sources. Blood appears to be a reliable non-lethal sample source for the detection of ISAV by viral culture and RT-PCR in both moribund and asymptomatic fish.