Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a ...tolerable safety profile.
We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity.
The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively.
The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.
The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we ...analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival.
Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.
During underground longwall coal extraction, overburden strata deformation may result in vertical goaf drainage holes, which are drilled in advance of mining for tail gate gas management, to fail. ...The performance of these vertical goaf drainage holes is controlled by mine design parameters and local geomechanical properties. This paper investigates the use of advanced 3D finite element modelling and 2D discrete element modelling simulation techniques to understand the fundamentals of vertical goaf drainage hole failure mechanism due to strata shear at a currently operating gassy Australian mine site. Finite element modelling is used to investigate the location of high shear in the overburden strata at the vertical goaf gas drainage hole region during longwall mining and the discrete element modelling is used to examine connectivity from the goaf region to the goaf-gas drainage system.
•Cheapest electric cooking technology: Solar panel directly powers resistive heater.•Phase Change Thermal Storage (PCTS): power & versatility improves cooking.•More broadly, PTCS may provide solution ...to solar energy intermittency.•Erythritol: inexpensive, nontoxic, high specific & latent heat. Melts @ 118° C.•Cooking is great application of PCTS, but erythritol degrades after months above 180 °C.
A 100 W solar panel directly powering an Insulated Solar Electric Cooker (ISEC) can slowly cook 5 kg of food over the course of a day. However, 0.4 kWh of the day’s energy can be stored in 2.5 kg of erythritol phase change material, allowing ISEC to cook more rapidly, as well as cook after sunset. We control supercooling by forcing crystallization, making erythritol an ideal thermal storage material for cooking and other thermal-storage processes, but the erythritol degrades in quality when cycled for several months over 180 °C. The efficiency of thermal storage is comparable to that of more expensive systems using battery storage and induction cooktops. ISECs can be built in low-income communities, and the best design varies depending on availability of materials, access to building technologies, and local preferences. A Global Learning Community of researchers, funding agencies, nonprofits, student groups, and local enterprises is collaboratively developing the open source technology with partners in low income communities to optimize designs, construction, and dissemination.
Small businesses are seen as vital to the Australian economy. However one particular issue of concern is the stability of their cash flow which can be exacerbated by the unpredictability of the ...markets, management practices, availability of financing and taxes, such as the goods and services tax (GST). This article reports a multiple case study of small (including micro) businesses which explored how the interaction with the GST affected small businesses' cash flow stability. Findings suggest that the cash flow stability of small businesses may be adversely affected when trading with retail consumers due to an inability to pass on the GST. Also, businesses trading with other businesses appear to face problems due to late payment by debtors. A common issue in supporting cash flow stability appears to be a lack of sophisticated cash management practices.
This study developed a screening tool for use by family physicians to identify and assess women patients experiencing emotional and/or physical abuse by their partner.
An initial set of eight ...questions developed for the Woman Abuse Screening Tool (WAST) was completed by both abused and non-abused women. Participants were also asked to indicate their comfort in answering the questions in both research and family practice contexts. They also completed the Abuse Risk Inventory and a demographic questionnaire. Analysis of the WAST included 1) standard assessment of the validity and reliability of the measure and 2) examination of the efficacy of further reducing the number of questions on the WAST for screening purposes.
The final samples of abused (n = 24) and non-abused women (n = 24) differed significantly on a number of demographic and abuse variables. After eliminating one of the original items, a strong single factor structure was identified for the WAST that accounted for 85% of the total variance in responses to the WAST items. The WAST was found to be a highly reliable measure; coefficient alpha was estimated at.95. The scale also demonstrated construct and discriminant validity. The abused women reported being less comfortable responding to the WAST questions, in both the research and family practice contexts, than the non-abused women. The two WAST questions the abused women reported being most comfortable with were used to construct the WAST-Short for initial screening purposes. The WAST-Short correctly classified 100% of the non-abused women and 91.7% of the abused women.
The WAST demonstrated good reliability and validity and discriminated between abused and non-abused women. Development of the WAST-Short provides physicians with a relatively unobtrusive screening tool for assessing abuse. The use of additional WAST questions can be used to further explore the possibility that a woman patient is experiencing abuse by her partner. Further study includes field testing the WAST in the family practice setting.
To determine the proportion of patients who are accompanied by another person (ie, partner, child, relative, friend) during visits to their doctors; to describe the demographic characteristics and ...role(s) assumed by the main accompanying person and the nature of the presenting dyads; and to describe the influence of the main accompanying person on the patient-doctor interaction.
Prospective observational survey.
Family practices in London, Ont, and surrounding area.
Eight family physicians completed surveys on 100 consecutive patients attending for both regularly scheduled and emergency visits.
Roles and influence of the main accompanying person.
Approximately one third (30.4%) of patients were accompanied during visits to their doctors. Children and patients older than 75 years most frequently had another person with them. Most patients (74.1%) were accompanied by one person who most often was female (72.6%) and between the ages of 21 and 40 years (53.6%). The accompanying person's role was most frequently described by doctors as an advocate for the patient (n = 235, 68.5%). If the accompanying person was a child, however, the role was most often described as a silent observer (n = 36, 68.6%). The influence of the main accompanying person on the patient-doctor encounter was usually described as positive (95.1%).
Physicians report that people accompanying patients usually have a positive influence on medical encounters. Future studies need to include patients' and accompanying persons' perspectives.
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