Mcphersonraynor9293
The complex, diverse ethical views and reasoning of donors and recipients expand a traditionally dichotomous discussion. Their perspectives challenge the transition towards non-anonymity and international guidelines, raising awareness to the need for their involvement in the design of policies to enable choice according to their values and preferences, and of psychosocial counselling responsive to their socioethical concerns and sensitive to their parental status. Empirical frameworks complement rights-based approaches to uphold justice, fairness and equal respect, and to incorporate utility, beneficence and non-maleficence in policymaking and healthcare in the transition towards non-anonymity.The concept of epistemic (specifically testimonial) injustice is the latest philosophical tool with which to try to theorise what goes wrong when mental health service users are not listened to by clinicians, and what goes right when they are. Is the tool adequate to the task? It is argued that, to be applicable at all, the concept needs some adjustment so that being disbelieved as a result of prejudice is one of a family of alternative necessary conditions for its application, rather than a necessary condition all on its own. It is then argued that even once adjusted in this way, the concept does not fit well in the area where the biggest efforts have been made to apply it so far, namely the highly sensitive case of adult patients suffering from delusions. Indeed it does not serve the interests of service users struggling for recognition to try to apply it in this context, because there is so much more to being listened to than simply being believed. However, the concept is found to apply smoothly in many cases where the service users are children, for example, in relation to children's testimony on the efficacy of treatment. It is suggested that further research would demonstrate the usefulness of the concept in adult cases of a similar kind.In a recent JME paper, Matthew John Minehan applies John Rawls' veil of ignorance against Judith Thomson's famous violinist argument for the permissibility of abortion. Minehan asks readers to 'imagine that one morning you are back to back in bed with another person. One of you is conscious and the other unconscious. You do not know which one you are'. Since from this position of ignorance, you have an equal chance of being the unconscious violinist and the conscious person attached to him, it would be rational to oppose a right for detachment. Likewise, behind the veil of ignorance, it is rational to oppose abortions since you could be the fetus, Minehan claims. This paper provides a plausible reply to this argument.
We examine the levels of post-trial responsibility ascribed to different stakeholders, following a community-based clinical trial and how the 'responsibility' is understood.
We employed photovoice, unstructured observations and key informant interviews to gain insights into contexts of access to care following transition to the public health system post trial. We used an inductive narrative analysis to explore experiences and understandings of post-trial access (PTA).
In their photovoice stories, many participants expressed a sense of abandonment after the trial. This was viewed as a contributing factor to failing to re-engage with care available in the public health system. This led to the experiences of loss as some trial participants defaulted and died. Research investigators, department of health participants and sponsor agreed that PTA was especially important for communities in resource-limited settings. The government has an obligation towards its citizens while researchers have a responsibility ated further.
Current clinical trials are using radiation therapy (RT) to enhance an antitumor response elicited by high-dose interleukin (IL)-2 therapy or immune checkpoint blockade (ICB). Bempegaldesleukin (BEMPEG) is an investigational CD122-preferential IL-2 pathway agonist with prolonged in vivo half-life and preferential intratumoral expansion of T effector cells over T regulatory cells. BEMPEG has shown encouraging safety and efficacy in clinical trials when used in combination with PD-1 checkpoint blockade. In this study, we investigated the antitumor effect of local RT combined with BEMPEG in multiple immunologically 'cold' tumor models. Additionally, we asked if ICB could further enhance the local and distant antitumor effect of RT+BEMPEG in the setting of advanced solid tumors or metastatic disease.
Mice bearing flank tumors (B78 melanoma, 4T1 breast cancer, or MOC2 head and neck squamous cell carcinoma) were treated with combinations of RT and immunotherapy (including BEMPEG, high-dose IL-2, anti(α)-CTLA-4,OC2), the triple combination of RT, BEMPEG, and ICB significantly improved primary tumor response and survival.
The combination of local RT, BEMPEG, and ICB cured mice with advanced, immunologically cold tumors and distant metastasis in a T cell-dependent manner, suggesting this triple combination warrants clinical testing.
The combination of local RT, BEMPEG, and ICB cured mice with advanced, immunologically cold tumors and distant metastasis in a T cell-dependent manner, suggesting this triple combination warrants clinical testing.
Therapeutic regimens designed to augment the immunological response of a patient with breast cancer (BC) to tumor tissue are critically informed by tumor mutational burden and the antigenicity of expressed neoepitopes. Herein we describe a neoepitope and cognate neoepitope-reactive T-cell identification and validation program that supports the development of next-generation immunotherapies.
Using GPS Cancer, NantOmics research, and The Cancer Genome Atlas databases, we developed a novel bioinformatic-based approach which assesses mutational load, neoepitope expression, human leukocyte antigen (HLA)-binding prediction, and in vitro confirmation of T-cell recognition to preferentially identify targetable neoepitopes. This program was validated by application to a BC cell line and confirmed using tumor biopsies from two patients with BC enrolled in the Tumor-Infiltrating Lymphocytes and Genomics (TILGen) study.
The antigenicity and HLA-A2 restriction of the BC cell line predicted neoepitopes were determinethe successful identification of neoepitopes targeted by TILs in patients with BC, providing a means to identify tumor-specific immunogenic targets for individualized treatment, including vaccines or adoptively transferred cellular therapies.Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.
There is intense interest in developing novel oncolytic viruses, which can be used in cancer therapies along with immune cells such as natural killer (NK) cells. We have previously developed a particle-based method for in vitro expansion of highly cytotoxic human NK cells (PM21-NK cells). Here, we have tested the hypothesis that oncolytic parainfluenza virus 5 (P/V virus) can combine with PM21-NK cells for targeted killing of lung cancer cells.
PM21-NK cells were assayed for killing of P/V virus-infected A549, H1299 and Calu-1 lung cancer cells in two-dimensional (2D) and three-dimensional (3D) cultures using flow cytometry, luminescence and kinetic imaging-based methods. Blocking antibodies were used to evaluate NK cell activating receptors involved in PM21-NK cell killing of infected target cells. Media transfer experiments tested soluble factors that increase PM21-NK cell killing of both P/V virus-infected and uninfected tumor cells.
In 2D cultures, PM21-NK cells efficiently killed P/V virus-infectedwith PM21-NK cell adoptive therapy against lung cancer.
The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%-30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003).
To determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003,
l unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1
. Antitumor activity with minimal toxicity was found
. Ubenimex Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.
A unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1 in vitro. Antitumor activity with minimal toxicity was found in vivo. Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.
Most dementia algorithms are unsuitable for population-level assessment and planning as they are designed for use in the clinical setting. A predictive risk algorithm to estimate 5-year dementia risk in the community setting was developed.
The Dementia Population Risk Tool (DemPoRT) was derived using Ontario respondents to the Canadian Community Health Survey (survey years 2001 to 2012). Five-year incidence of physician-diagnosed dementia was ascertained by individual linkage to administrative healthcare databases and using a validated case ascertainment definition with follow-up to March 2017. Sex-specific proportional hazards regression models considering competing risk of death were developed using self-reported risk factors including information on socio-demographic characteristics, general and chronic health conditions, health behaviours and physical function.
Among 75 460 respondents included in the combined derivation and validation cohorts, there were 8448 cases of incident dementia in 348 677 person-years of follow-up (5-year cumulative incidence, men 0.
