First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma

BACKGROUND: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab. METHODS: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1-4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated. RESULTS: At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug-drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges. CONCLUSIONS: M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2

Concealment, communication and stigma: The perspectives of HIV-positive immigrant Black African men and their partners living in the United Kingdom

This study explored the perspectives of Black men, originally from East Africa, living in the United Kingdom and their families on what it means to live with diagnosed HIV. This article reports on concealment of HIV-positive status as a strategy adopted by the affected participants to manage the flow of information about their HIV-positive status. Analysis of the data, collected using in-depth interviews involving 23 participants, found widespread selective concealment of HIV-positive status. However, a few respondents had ‘come out’ publicly about their condition. HIV prevention initiatives should recognise concealment as a vital strategy in managing communication about one’s HIV-positive status

Help or hindrance : young people's experiences of predictive testing for Huntington's disease

Funded by Scottish GovernmentPeer reviewedPublisher PD

Why business angels reject investment opportunities: Is it personal?

A major focus of research on business angels has examined their decision-making processes and investment criteria. As business angels reject most of the opportunities that they receive, this article explores the reasons informing such decisions. In view of angel heterogeneity, investment opportunities might be expected to be rejected for differing reasons. Two sources of data are used to examine this issue. Face-to-face interviews with 30 business angels in Scotland and Northern Ireland provided information on typical ‘deal killers’. This was complemented by an Internet survey of United Kingdom that attracted responses from 238 UK business angels. The findings confirm that the main reason for rejection relates to the entrepreneur/management team. However, angel characteristics do not explain the number of reasons given for opportunity rejection nor do they predict the reasons for rejecting investment opportunities. This could be related to the increasing trend for business angels to join organised groups which, in turn, leads to the development of a shared repertoire of investment approaches. We suggest the concept of ‘communities-of-practice’ as an explanation for this finding

Biola Hour Highlights, 1976 - 04

Old Age by Al Sanders Lessons from the Word by Charles Swindoll Will We Know Our Loved Ones in Heaven? by Lehman Strauss Revelation by Lloyd Anderson Panel Discussion with Richard Chase, Charles Feinberg, and Samuel Sutherlandhttps://digitalcommons.biola.edu/bhhs/1026/thumbnail.jp

Perceptions of rewards among volunteer caregivers of people living with AIDS working in faith-based organizations in South Africa: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Volunteer caregivers are a critical source of support for the majority of people living with HIV and AIDS in southern Africa, which has extremely high HIV/AIDS prevalence rates. While studies have shown that volunteer caregiving is associated with negative health and socio-economic outcomes, little is known about the positive experiences of volunteers in the home-based care context in South Africa. The purpose of this study is to explore the perception of rewards among volunteers working in home-based care settings.</p> <p>Methods</p> <p>This study uses a qualitative design. Qualitative interviews were conducted with a purposively selected sample of 55 volunteer caregivers using an interview schedule containing open-ended questions.</p> <p>Results</p> <p>Volunteer caregivers derived intrinsic rewards related to self-growth and personal (emotional and psychological) development on the job; they also derived satisfaction from community members taking a liking for them and expressing a need for their services. Volunteers felt gratified by the improvements in their health behaviours, which were a direct consequence of the experiences of caring for terminally ill patients with AIDS. Extrinsic rewards came from appreciation and recognition shown by patients and community members. Extrinsic rewards also accrued to volunteers when the services they rendered made their patients happy. Perhaps the greatest sources of extrinsic rewards are skills and competencies acquired from training and experience while caring for their patients, and volunteers' ability to make a difference in the community.</p> <p>Conclusions</p> <p>Insights into volunteer caregiver rewards provide opportunities for policy makers and programme managers to develop a model of home-based care that facilitates the accrual of rewards to volunteers alongside volunteers' traditional duties of patient care. Programme managers could employ these insights in recruiting and assisting volunteers to identify and reflect on rewards in the caregiving situation as a means of reducing the burden of care and sustaining volunteer interest in caregiving.</p

Barriers to the development of palliative care in Western Europe

The Eurobarometer Survey of the &lt;i&gt;EAPC Task Force on the Development of Palliative Care in Europe&lt;/i&gt; is part of a programme of work to produce comprehensive information on the provision of palliative care across Europe. Aim: To identify barriers to the development of palliative care in Western Europe. Method: A qualitative survey was undertaken amongst boards of national associations, eliciting opinions on opportunities for, and barriers to, palliative care development. By July 2006, 44/52 (85%) European countries had responded to the survey; we report here on the results from 22/25 (88%) countries in Western Europe. Analysis: Data from the Eurobarometer survey were analysed thematically by geographical region and by the degree of development of palliative care in each country. Results: From the data contained within the Eurobarometer, we identified six significant barriers to the development of palliative care in Western Europe: (i) Lack of palliative care education and training programmes (ii) Lack of awareness and recognition of palliative care (iii) Limited availability of/knowledge about opioid analgesics (iv) Limited funding (v) Lack of coordination amongst services (vi) Uneven palliative care coverage. Conclusion: Findings from the EAPC Eurobarometer survey suggest that barriers to the development of palliative care in Western Europe may differ substantially from each other in both their scope and context and that some may be considered to be of greater significance than others. A number of common barriers to the development of the discipline do exist and much work still remains to be done in the identified areas. This paper provides a road map of which barriers need to be addressed

The liminality of trajectory shifts in institutional entrepreneurship

In this paper, we develop a process model of trajectory shifts in institutional entrepreneurship. We focus on the liminal periods experienced by institutional entrepreneurs when they, unlike the rest of the organization, recognize limits in the present and seek to shift a familiar past into an unfamiliar and uncertain future. Such periods involve a situation where the new possible future, not yet fully formed, exists side-by-side with established innovation trajectories. Trajectory shifts are moments of truth for institutional entrepreneurs, but little is known about the underlying mechanisms of how entrepreneurs reflectively deal with liminality to conceive and bring forth new innovation trajectories. Our in-depth case study research at CarCorp traces three such mechanisms (reflective dissension, imaginative projection, and eliminatory exploration) and builds the basis for understanding the liminality of trajectory shifts. The paper offers theoretical implications for the institutional entrepreneurship literature

Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pAR ser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy

Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-AR ser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-AR ser81 , PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation

Fake people, real effects : the presence of virtual onlookers can impair performance and learning

Can effects of social influence be elicited in virtual contexts, and if so, under which conditions can they be observed? Answering these questions has theoretical merit, as the answers can help broaden our understanding of the interaction mechanisms described by social psychology. The increasing popularity of immersive media in training applications, however, has made these questions of practical significance. Virtual reality (VR), in particular, is a weapon of choice in designing training and education simulations, as it can be used to generate highly realistic characters and environments. As a consequence, it is key to understand under which circumstances virtual ‘others’ can facilitate or impede performance and – especially – learning. In this study, we investigated the impact of virtual onlookers on an adapted Serial Reaction Time (SRT) task that was presented in VR. In each trial, participants responded to a series of spherical stimuli by tapping them with handheld controllers when they lit up. Depending on the experiment block, the sequence order was either the permutation of a fixed order (and therefore predictable given the first stimulus), or fully random (and therefore unpredictable). Participants were divided into three groups (audience variable), depending on the environment in which the task was set: a group without onlookers (none condition), a group with a computer-generated audience (CGI condition), and a group being watched by a prerecorded audience (filmed condition). Results showed that the presence of a virtual audience can hamper both overall performance and learning, particularly when the audience appears more realistic. This study further reinforces the notion that the effects of social influence transcend the physical presence of others, but rather extend to virtual audiences