Meaningful Response Research Articles

Adoptive cell therapy for high grade gliomas using simultaneous temozolomide and intracranial mgmt-modified γδ t cells following standard post-resection chemotherapy and radiotherapy: current strategy and future directions.

Cellular therapies, including chimeric antigen receptor T cell therapies (CAR-T), while generally successful in hematologic malignancies, face substantial challenges against solid tumors such as glioblastoma (GBM) due to rapid growth, antigen heterogeneity, and inadequate depth of response to cytoreductive and immune therapies, We have previously shown that GBM constitutively express stress associated NKG2D ligands (NKG2DL) recognized by gamma delta (γδ) T cells, a minor lymphocyte subset that innately recognize target molecules via the γδ T cell receptor (TCR), NKG2D, and multiple other mechanisms. Given that NKG2DL expression is often insufficient on GBM cells to elicit a meaningful response to γδ T cell immunotherapy, we then demonstrated that NKG2DL expression can be transiently upregulated by activation of the DNA damage response (DDR) pathway using alkylating agents such as Temozolomide (TMZ). TMZ, however, is also toxic to γδ T cells. Using a p140K/MGMT lentivector, which confers resistance to TMZ by expression of O(6)-methylguanine-DNA-methyltransferase (MGMT), we genetically engineered γδ T cells that maintain full effector function in the presence of therapeutic doses of TMZ. We then validated a therapeutic system that we termed Drug Resistance Immunotherapy (DRI) that combines a standard regimen of TMZ concomitantly with simultaneous intracranial infusion of TMZ-resistant γδ T cells in a first-in-human Phase I clinical trial (NCT04165941). This manuscript will discuss DRI as a rational therapeutic approach to newly diagnosed GBM and the importance of repeated administration of DRI in combination with the standard-of-care Stupp regimen in patients with stable minimal residual disease.

Artificial Intelligence and the Silent Pandemic of Antimicrobial Resistance: A Comprehensive Exploration

The rise of antimicrobial resistance (AMR) in the 21st century has made it a worldwide disaster. Due to the fast spread of AMR illnesses and the lack of novel antimicrobials, the silent pandemic is well known. This issue requires a fast and meaningful response, not just speculation. To address this dilemma, deep learning (DL) and machine learning (ML) have become essential in many sectors. As a cornerstone of modern research, machine learning helps handle the many aspects of AMR. AI helps researchers construct clinical decision-support systems by collecting clinical data. These methods enable antimicrobial resistance monitoring and wise use. Additionally, AI applications help research new drugs. AI also excels at synergistic medicine combinations, providing new treatment methods. This paper summarizes our extensive study of AI and the silent epidemic of antibiotic resistance. Through deep learning and machine learning applications across multiple dimensions, we hope to contribute to the proactive management of AMR, moving away from its presentation as a future problem to present-day solutions.

Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study.

Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab. This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV1 to Week 12. At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P<0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥5%. Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12. NCT02948959.

A phase 1 trial of combined MEK, STAT3 and PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC).

TPS713 Background: PDAC is characterized by its innate and acquired resistance to both MAPK pathway inhibition and immune checkpoint (e.g. PD-1/PD-L1) inhibition (ICI) via multiple mechanisms. In preclinical models of PDAC, combined MEK and STAT3 inhibition (MEKi+STAT3i) uncovers stromal plasticity by attenuating cancer-associated fibroblasts (CAF) with IL-6/CXCL1-secretory phenotypes while enriching for Ly6a/CD34-expressing CAF phenotypes with mesenchymal stem cell-like features. This remodeling of CAF heterogeneity is associated with a striking attenuation in and reprogramming of tumor-associated macrophages (TAMs) as well as enhanced trafficking of CD8 T cells, which exhibit a distinct effector and anti-apoptotic transcriptional program. The addition of MEKi+STAT3i to PD-1 blockade overcomes ICI resistance by significantly enhancing the recruitment, degranulating capacity, and functional cytotoxicity of CD8+ T-cells, thereby augmenting antitumor responses and dramatically improving survival in these models. Furthermore, a patient with refractory PDAC treated off-label with this combination achieved a meaningful response. Based on this strong rationale, a phase 1 trial was initiated to test the combination of MEKi+STAT3 and PD1 inhibition in patients with metastatic PDAC. Methods: NCT05440942 is an open-label, prospective, single-institution phase 1 trial testing the safety, preliminary efficacy, and biomarkers of response to the combination of trametinib (MEKi), ruxolitinib (JAK2/STAT3 inhibitor) and retifanlimab (PD-1 inhibitor) in patients with metastatic PDAC. Patients with metastatic PDAC who have had disease progression on at least one line of prior therapy, with good organ function, preserved performance status, and without major intercurrent illness are eligible. Patients must have an accessible lesion for biopsy and must be willing to undergo this research biopsy at baseline and on treatment. Part 1 of the study is a dose-escalation phase with 3 dose levels and a target dose of trametinib 2mg orally daily, ruxolitinib 15mg orally twice daily, and retifanlimab 500mg intravenously every 28 days. The dose escalation is being done using the novel Bayesian keyboard design and 9-15 patients will be treated to get to the potential maximum tolerated dose (MTD). Dose level 1 has been completed without any dose-limiting toxicities seen. Part 2 is an expansion phase which will accrue an additional 20 patients. All patients in part 1 and 2 will have core-needle biopsies pre-treatment and after 4 weeks. Serial blood samples will be collected at baseline and on treatment. Biopsies are being analyzed by multiparameter immune profiling using mass cytometry and bulk RNA sequencing; blood is being analyzed for circulating tumor DNA and immune profiling. These results will be correlated with clinical response to therapy to determine biomarkers of response and resistance. Clinical trial information: NCT05440942 .

Non-faradaic capacitive cation sensing under flow.

The ability to continually monitor target ion species in real-time is a highly sought-after endeavour in the field of host-guest chemistry, given its direct pertinence to medical and environmental applications. Developing methodologies which support sensitive and continuous ion sensing in aqueous media, however, remains a challenge. Herein, we present a versatile and facile, proof-of-concept electrochemical sensing methodology based on non-faradaic capacitance, which can be operated continuously with high temporal resolution (≈1.4 s), in conjunction with custom-designed integrated microfluidics. The potential of this method is demonstrated for cation sensing at a chemically simple benzo-15-crown-5-based molecular film (B15C5SAM) as a representative redox-inactive, receptive interface. Detection limits as low as 4 μM are obtained for Na+ by these entirely reagentless analyses, and are additionally characterised by exceptional baseline stabilities that are able to support continuous sensing over multiple days. The platform performs well in artificial sweat across physiologically relevant spans of sodium concentration, and provides meaningful dose-dependent responses in freshwater samples. Finally, the high assay temporal resolution affords an ability to resolve both the kinetics of binding (association/dissociation) and notably characteristic fingerprints for different alkali metals which may be diagnostic of different interfacial ion binding modes.

Patient Perceptions of Psychological and Rehabilitation Experiences After Anterior Cruciate Ligament Reconstruction: A Qualitative Study.

Over 80% of patients anticipate fully returning to sport (RTS) within 1year after anterior cruciate ligament reconstruction (ACLR), but only one quarter of patients succeed. Although several factors influence the RTS process, this study focused on how psychological responses to injury, such as injury-related fear and self-determined motivation, help to explain variation in rehabilitation experiences. There is limited information about how these meaningful psychological responses to injury are connected to responses such as athlete burnout or how patient perceptions of these responses relate to rehabilitation. The purpose of this qualitative study was to explore how patient perceptions of injury-related fear, self-determined motivation, and athlete burnout influence individual psychological and rehabilitation experiences at 4 to 6 months post-ACLR. Qualitative study. Eight patients (female = 4, age = 16.3 ± 1.9) between 4 and 6 months post-ACLR who injured their knee playing or training for sports were included in the study. Patients completed the Sport Motivation Scale-6, Athlete Burnout Questionnaire, Perceived Stress Scale 4, and Tampa Scale of Kinesiophobia-11 to measure self-determined motivation, athlete burnout, stress, and injury fear. These questionnaires collected descriptive data used to guide audio- and video-recorded semistructured interviews. The interviews were transcribed and analyzed in a 6-stage process of thematic analysis. Thematic analysis revealed 3 themes related to how participants perceived their rehabilitation experiences: (1)acknowledging recurring struggles during recovery, (2)finding motivation to RTS and normal life, and (3)successfully navigating the recovery process. In particular, participants described the impact of positive shifts in their psychological perceptions at 4 to 6 months post-ACLR. Patients 4 to 6 months post-ACLR described how struggles during their recovery and rehabilitation experiences were improved by positive shifts in their psychological perceptions. Increasing positive psychological awareness within a supportive rehabilitation environment may improve rehabilitation experiences and RTS rates after ACLR.

Assessing the performance of large language models (LLMs) in answering medical questions regarding breast cancer in the Chinese context.

Large language models (LLMs) are deep learning models designed to comprehend and generate meaningful responses, which have gained public attention in recent years. The purpose of this study is to evaluate and compare the performance of LLMs in answering questions regarding breast cancer in the Chinese context. ChatGPT, ERNIE Bot, and ChatGLM were chosen to answer 60 questions related to breast cancer posed by two oncologists. Responses were scored as comprehensive, correct but inadequate, mixed with correct and incorrect data, completely incorrect, or unanswered. The accuracy, length, and readability among answers from different models were evaluated using statistical software. ChatGPT answered 60 questions, with 40 (66.7%) comprehensive answers and six (10.0%) correct but inadequate answers. ERNIE Bot answered 60 questions, with 34 (56.7%) comprehensive answers and seven (11.7%) correct but inadequate answers. ChatGLM generated 60 answers, with 35 (58.3%) comprehensive answers and six (10.0%) correct but inadequate answers. The differences for chosen accuracy metrics among the three LLMs did not reach statistical significance, but only ChatGPT demonstrated a sense of human compassion. The accuracy of the three models in answering questions regarding breast cancer treatment was the lowest, with an average of 44.4%. ERNIE Bot's responses were significantly shorter compared to ChatGPT and ChatGLM (p < .001 for both). The readability scores of the three models showed no statistical significance. In the Chinese context, the capabilities of ChatGPT, ERNIE Bot, and ChatGLM are similar in answering breast cancer-related questions at present. These three LLMs may serve as adjunct informational tools for breast cancer patients in the Chinese context, offering guidance for general inquiries. However, for highly specialized issues, particularly in the realm of breast cancer treatment, LLMs cannot deliver reliable performance. It is necessary to utilize them under the supervision of healthcare professionals.

Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models.

The small-molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical antitumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib showed stronger antitumor effects than some standard-of-care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical antitumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.

Mapping multi-decadal wetland loss: Comparative analysis of linear and nonlinear spatiotemporal characterization

Wetlands provide critical habitat for birds and endangered species, and can be influenced by shifts in water availability and land use. The Landsat image archive can help both document historical wetland change and monitor current dynamics, but multi-decadal retrospective studies face two important challenges: 1) many important ecohydrological processes occur at scales finer than the field of view of a 30 m Landsat pixel, and 2) ecologically meaningful wetland response units frequently exhibit spatiotemporal complexity in both vegetation and surface water which may not be well-represented by a simple study area spatial mean. Here we explore a novel method for contending with these challenges with application to the rapidly changing Andrade Mesa wetlands along the US-Mexico border. Using a 26-year (1995–2021) Landsat image time series, we track changes in surface water and vegetation using green vegetation (V) and dark (D) fractions estimated from spectral mixture analysis (SMA). Spatiotemporal dynamics in both V and D fractions were characterized using two techniques: linear Principal Component Analysis (PCA) and nonlinear manifold learning (via Uniform Manifold Approximation and Projection; UMAP). Bounding temporal endmembers were identified from PCA and used to construct a temporal mixture model which quantified total area of surface water and vegetation loss, including an uncertainty estimate. UMAP clearly distinguished areas with differing onset of vegetation and water loss which were not identifiable using PCA. Change maps were then associated with different mechanisms and outcomes, including possible mechanical clearing of vegetation and unexpected greening of woody vegetation. The overall timing of surface water and vegetation decline follows the lining of the All-American Canal, suggesting a potential cross-border hydrologic association between loss of a wetland in Mexico and water efficiency measures implemented in the United States.

REENGAGING AFRICAN AMERICAN AND BLACK OLDER ADULTS DURING THE COVID-19 ERA: A FOCUS GROUP STUDY

Abstract Churches and senior centers are social engagement hubs for older Black and African Americans (BAA) that can positively impact well-being. Although these facilities re-opened after the COVID-19 pandemic, engagement with these facilities has not returned to pre-pandemic levels. Our long-term goal is to develop a behavioral intervention to address the re-engagement needs/concerns of BAA older adults as a means of preventing/reducing depressive symptoms and disability. In the first phase of this work, we used a community-based participatory research approach to determine barriers to, and facilitators of, activity reengagement through the perspectives of leaders of BAA churches and senior centers around Hartford, Connecticut. We conducted three focus groups with key stakeholders (n=4 senior center staff; n=4 senior center staff; n=5 church staff) between May 2023 and July 2023. Using a Framework Method approach and semi-structured interviews, participants were asked to define engagement as it relates to senior center and church involvement since re-opening and to quantify, in their own words, the problem of disengagement. Participants were also asked about the effectiveness of online engagement vs. in-person engagement and members experience(s) with social isolation and loneliness. Line-by-line thematic analysis of the transcriptions was used to identify and group meaningful phrases and responses into major themes. Three organizing themes emerged: “transportation” concerns impacting members during COVID-19 pandemic, increased health issues among members; and issues and concerns related to family support. Leaders from churches and senior centers provided valuable insights into the overarching issues affecting re-engagement among older BAA senior center and church members.

THE QUALITY OF DAY SCALE AND THE LIVING WELL INVENTORY: TWO NEW MEASURES FOR INDIVIDUALS WITH DEMENTIA AND CAREGIVERS

Abstract Background Differences in adaptive strategies used by individuals living with dementia have the potential to impact wellbeing. Two new measures were developed using human-centered design to capture daily adaptive strategies and outcomes. The Living Well Inventory for Dementia (LWI-D) and the Quality of Day Scale (QODS) capture important aspects of wellbeing that illuminate options for care and support. Purpose: To provide results from the initial evaluation of the LWI-D and the QODS for face validity, content validity and user acceptability. Methods Acceptability and feasibility testing was conducted with a sample of 17 community-dwelling individuals with early stage dementia (MOCA scores 12-30). After measure optimization, a second pilot test was conducted with 30 dyads (persons living with dementia and family caregivers) in community and residential settings. Results Persons with dementia can use and accurately interpret the QODS, preferring a version with graphic icons. Of the 31 items on the development version of the LWI-D, 17 items were acceptable, meaningful, and easily answered. Additional items yielded meaningful qualitative responses but needed minor revision. Some participants disliked the Likert-type response format, and new administration guidelines were used for the second pilot. Additional outcomes include convergent validity between the LWI-D and the QODS with measures of positive affect-balance, quality of life and wellbeing. Conclusion The LWI-D and the QODS are rigorously developed promising measures that warrant further testing and may enhance the ability to a) identify strengths in living well with dementia and b) identify and test news interventions to bolster care and support.

Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma

The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.

A Study on the Situation and Learnings of the Precipitant Shortage in the German Wastewater Sector

Wastewater treatment companies are particularly confronted by the energy and supply crisis resulting from the war in the Ukraine. More specifically, production and supply problems with precipitant production have shown that today’s wastewater treatment technology in Germany is not crisis-proofed and must become more resilient. The aim of this paper was to determine a required precipitant quantity for Germany with regard to chemical phosphorus elimination, as well as the expected shortfalls due to the shortage situation. Furthermore, possible solutions were identified for how the precipitant can be saved or substituted. Study surveys were conducted to gather data for a meaningful response regarding the operators (wastewater treatment plants, industry, and water suppliers), manufacturers, and the German federal states. A recommendation is given on what a path to more resilient wastewater management with a focus on phosphorus elimination could look like. Based on the data obtained, the report focused on wastewater engineering issues for wastewater treatment plants and industry. The results of the study are relevant for decision-makers, researchers, and operators in the wastewater sector in order to intervene in the market themselves if necessary, e.g., money for production or conversion to biological phosphorus elimination.

A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma

Background and objectiveCheckpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC. MethodsThe 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1–38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously). Key findings and limitationsThe primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients. Conclusions and clinical implicationsSitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied. Patient summaryIn this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.

Standing Reactive Postural Responses of Lower Limbs With and Without Self-Balance Assistance in Individuals With Spinal Cord Injury Receiving Epidural Stimulation.

Spinal cord epidural stimulation can promote the recovery of motor function in individuals with severe spinal cord injury (SCI) by enabling the spinal circuitry to interpret sensory information and generate related neuromuscular responses. This approach enables the spinal cord to generate lower limb extension patterns during weight bearing, allowing individuals with SCI to achieve upright standing. We have shown that the human spinal cord can generate some standing postural responses during self-initiated body weight shifting. In this study, we investigated the ability of individuals with motor complete SCI receiving epidural stimulation to generate standing reactive postural responses after external perturbations were applied at the trunk. A cable-driven robotic device was used to provide constant assistance for pelvic control and to deliver precise trunk perturbations while participants used their hands to grasp onto handlebars for self-balance support (hands-on) as well as when participants were without support (free-hands). Five individuals with motor complete SCI receiving lumbosacral spinal cord epidural stimulation parameters specific for standing (Stand-scES) participated in this study. Trunk perturbations (average magnitude: 17 ± 3% body weight) were delivered randomly in the four cardinal directions. Participants attempted to control each perturbation such that upright standing was maintained and no additional external assistance was needed. Lower limb postural responses were generally more frequent, larger in magnitude, and appropriately modulated during the free-hands condition. This was associated with trunk displacement and lower limb loading modulation that were larger in the free-hands condition. Further, we observed discernible lower limb muscle synergies that were similar between the two perturbed standing conditions. These findings suggest that the human spinal circuitry involved in postural control retains the ability to generate meaningful lower limb postural responses after SCI when its excitability is properly modulated. Moreover, lower limb postural responses appear enhanced by a standing environment without upper limb stabilization that promotes afferent inputs associated with a larger modulation of ground reaction forces and trunk kinematics. These findings should be considered when developing future experimental frameworks aimed at studying upright postural control and activity-based recovery training protocols aimed at promoting neural plasticity and sensory-motor recovery.

Think with the virus

This essay proposes that analyses of the pandemic caused by Covid-19 can be clarified by reflections from the field of anthropology over recent decades regarding the plural effects of the interaction between human and non-human animals. These human–nonhuman relationships are intimate and unpredictable; between entities whose agency and modes of existence are not always precisely identifiable. Our contention is that ‘more than human’ perspective, as a relational marker, expresses a counterpoint defined by interspecific alterities that we humans establish with certain animal species. Furthermore, these relationships are configured as a ‘category-metaphor’ enabling us to perceive the multiple and complex ways in which we compose our lives in relation to the ‘nature’ of everything around us. We argue that events such as the appearance of SARS-CoV-2 have a reflective potential that can draw the attention of those who do Animal Studies to these relations. We highlight the limiting effects of a narrowly defined (‘absolutely animal’) disciplinary rhetoric, when instead we need to formulate meaningful responses to the consequences of our relationships with other beings. We address the valorization of relations between humans and non-humans in their vital contexts; that is, what is necessary and available to survive. They consider the access and utilization of available resources, and how they are unequal around the world. Our anthropological perspective asks what it means to simultaneously address issues of power and marginality in the face of capitalism and globalization, to consider humans and non-humans as companion species, and to take the benefits offered by anthropology learned from the lived world, without separating it from politics and history.

Mythmaking in audit regulation: the Canadian initiative on ‘enhancing audit quality’

Although extant literature has provided accounts of regulatory processes that failed to produce new or improved regulation, we know less about how regulators attempt to devise an ‘illusion of regulatory action’ to prevent their initiatives from being labelled failures and deflect public criticism. This study’s focus is on the regulatory initiative in Canada in response to a global post-crisis regulatory trend seeking to address the problem of low audit quality. Despite decisive regulatory responses elsewhere, the Canadian project leaders not only concluded with weak regulation based on problematic assumptions, but they also actively pursued efforts to argue the opposite, thereby creating an illusion of a meaningful regulatory response. By reference to Barthes’s work on mythmaking, we examine the relevant project documents to make sense of such arguments and claims essentially as instances of regulatory actors’ mythmaking designed to diffuse criticism and garner public support. Our findings enable us to offer insights into and consider the role of regulatory myths as important elements in the discursive repertoires by which regulators maintain their legitimacy and authority. We also discuss certain conjectures which increase the likelihood of regulatory mythmaking.

Searching for Meaning in the Life of Ellen Johnson-Sirleaf: A Call to Meaningful Responses to Tragedies.

Ellen Johnson-Sirleaf, born in 1938, is Africa's first elected female head of state. She navigated stressful and traumatic events, including bullying, domestic abuse, persecution, a civil war, witnessing the effects of genocide and navigating a patriarchal system. Nonetheless, Johnson-Sirleaf's determination established her as a global icon who played a significant role in women's empowerment. Johnson-Sirleaf was purposively selected for this study as she is an extraordinary female political leader. Frankl's dimensional ontology is employed to describe and explore the life of Johnson-Sirleaf from a psychobiographical perspective using publicly available information. The study focused on the period between 1938 and 2005. The findings suggest that Johnson-Sirleaf transcended psychophysical and psychosocial limitations and crafted a meaningful life. It seems Johnson-Sirleaf was guided by a sense of purpose and used her will to meaning to overcome psychosocial injustices and psychophysical issues. This study illustrates the value of Frankl's existential theory in illuminating the life histories of extraordinary political leaders and its potential contribution to contemporary mental health challenges.

Abstract PR013: First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer

Abstract Background Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since alternative or redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-man dose escalation (Part A) and expansion (Part B) study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously over 70 minutes, QW4 followed by a 2-week rest period. Part A of the study enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Results from advanced KRAS-mutated NSCLC patients enrolled in NBF-006-001 are reported here. Results Thirty-four KRAS-mutated NSCLC patients received treatment at 0.6 mg/kg [n=12], 1.2 mg/kg [n=11], or 1.6 mg/kg [n=11]. NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia and bilateral pleural effusions (both at 0.6 mg/kg). The most common (&amp;gt;10 % of patients) NBF-006-related AEs were Grade 1 or 2 infusion related reactions (low grade IRRs) (20.6 %) and nausea (11.8 %). There was no dose relationship in the number of AEs or any observed AEs. Low grade IRRs (n=8 in seven patients), occurred in the first cycle of therapy and were generally well-managed. Only one patient discontinued study therapy due to recurring IRR. Substantial cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. PK analysis indicated a mean terminal half-life of 41 (± 13) hours with no accumulation. Cmax and AUC demonstrated dose-proportionality up to 1.2 mg/kg and no apparent increase in exposure at 1.6 mg/kg. Patients had received 1-7 prior lines of therapy (average 2.6; 1 line [n=10], 2 lines [n=9], and ≥ 3 lines [n=15] respectively). Two patients (treated at 1.2 and 1.6 mg/kg) experienced a durable PR, 14 patients experienced SD. One patient with PR and one patient with a mixed response stayed on study for &amp;gt;12 months. Conclusion The expansion part of the NBF-006-001 study confirmed the favorable safety profile of NBF-006 and demonstrated early signs of antitumor activity in KRAS-mutated NSCLC. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted. Citation Format: Hirva Mamdani, Alberto Chiappori, Lyudmila Bazhenova, Alexander Spira, Wade Iams, Minal Barve, Anthony W Tolcher, Eli Gabayan, Andrae Vandross, Annie Huynh, Yael Cohen-Arazi, Zachary Albaugh, Joachim Gullbo, Sonya Zabludoff. First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR013.

Abstract A136: Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles

Abstract Single-cell sequencing techniques have greatly advanced our current understanding of intratumoral heterogeneity through identifying tumor subpopulations with distinct biologies and therapeutic responses. However, translating biological differences into treatment strategies is challenging, as we still lack tools to facilitate efficient drug discovery that tackles heterogeneous tumors. One key step in development of such approaches centers around accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we present a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual-cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening datasets. Our method detects shared expression patterns between the two data sources and utilizes such information to project cellular drug response. This method achieves high accuracy, with predicted sensitivities easily able to separate cells into their true cellular drug resistance status as measured by effect size (Cohen's d &amp;gt; 1.0); this holds when using single-cell RNA-seq from both cell line and in vivo models. More importantly, we examine our method’s utility with three distinct prospective tests, and in each our predicted results are accurate and mirrored biological expectations. In the first two tests, we investigated predicting drugs for cell subpopulations that are resistant to standard-of-care (SOC) therapies due to intrinsic resistance or effects of tumor microenvironments. In both, our results showed high consistency with results from the original studies. In the third test, we generated SOC therapy resistant cell lines, used scIDUC to identify drugs predicted effective on the resistant line, and validated the predictions with in vitro experiments. Together, scIDUC quickly and directly translates scRNA-seq data into meaningful cellular drug response for individual cells, displaying the potential to be used by researchers as a first-line tool for nuanced and heterogeneity-aware drug discovery. Citation Format: Weijie Zhang, Danielle Maeser, Adam Lee, Yingbo Huang, Robert F Gruener, Sampreeti Jena, Anand G Patel, R. Stephanie Huang. Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A136.