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Objectives: Farmers are faced with many stressors, along with numerous barriers to accessing traditional forms of mental health support. The ifarmwell online intervention was co-designed with farmers and is informed by Acceptance and Commitment Therapy to equip farmers with transferable coping strategies, particularly to help them cope with circumstances beyond their control. We aimed to evaluate the effect of ifarmwell on farmers’ short- and long-term distress and mental wellbeing. Methods: Australian farmers (21–73 years) who registered on www.ifarmwell.com.au completed measures at the commencement of module 1 (N = 228), the end of the intervention (N = 77) and 6-months post-intervention (N = 61). Primary outcomes included distress (Kessler Psychological Distress Scale) and mental wellbeing (Mental Health Continuum – Short Form). We also examined the relationship between distress, mental wellbeing, neuroticism (Quickscales-R) and ACT-based psychological mechanisms; psychological inflexibility (Acceptance and Action Questionnaire-II), cog-nitive fusion (Cognitive Fusion Questionnaire), believability of automatic thoughts (Automatic Thoughts Questionnaire-B), coping via acceptance (4 items from the situational COPE) and mind-fulness (Five Facet Mindfulness Questionnaire-Short Form). Secondary outcomes of acceptability (Client Satisfaction Questionnaire-8) and usability (System Usability Scale) were also explored. Results: Pre- to post-intervention, farmers’ distress decreased and mental wellbeing increased. These effects were maintained at 6-month follow-up. Changes in these outcomes were greatest for participants who entered the intervention with high baseline distress (^β= −0.59, 95%CI =[−0.70, −0.47]) and low mental wellbeing (^β= −0.33, 95%CI = [−0.47, −0.19]). Decreases in distress and increases in mental wellbeing were associated with decreases in psychological inflexibility, cognitive fusion, and believability of thoughts, and increases in coping via acceptance and mindfulness. Levels of satisfaction (M = 26.92/32) and usability (M = 84.70/100) were high, and 94.6% of participants said they would recommend ifarmwell to a friend in need of similar advice and tools. Conclusions: ifarmwell is an effective and usable intervention that is likely to help farmers reduce their levels of distress and improve their mental wellbeing, by improving their psychological flexibility, ability to focus on the present and accept things beyond their control, as well as by reducing the extent to which they believe unhelpful thoughts. Refereed/Peer-reviewed

This paper presents the experimental investigation of the load-resisting characteristics of damaged columns repaired with glass reinforced polymer (GFRP) jacketing. The high-strength columns were made with ground granulated blast furnace slag (GGBS) used at 15%, 25%, and 35% as a partial substitute for cement. Cube specimens of size 100 mm × 100 mm × 100 mm and columns of size 600 mm × 120 mm were cast to perform the study. Considering the practical difficulties in the construction field in obtaining river sand, industrial sand was used for making the specimens eco-friendly. On completion of the prescribed curing period of 28 days, the cube specimens were subjected to a compression test to ensure the grade of the mix design, and the column specimens were subjected to axial loading and were tested in two categories, with and without wrapping of GFRP sheets’ split tensile strength. Compression tests on cubes and columns were done. The nondestructive test was also performed with the ultrasonic pulse velocity (UPV) method to check the dense nature of the concrete before and after wrapping with GFRP. On comparing the results, it was observed that it is possible to obtain a higher strength using industrial sand when supported with suitable admixtures and strengthening processes.

Two parallel versions (A and B) of the Oxford Cognitive Screen (OCS) were developed in the United Kingdom (UK) as a stroke-specific screen of five key cognitive domains commonly affected post-stroke. We aimed to develop the Australian versions A and B (OCS-AU), including Australian cut-scores indicative of impairment. We hypothesised there to be no difference in performance between the UK and Australian normative data cohorts.Our multidisciplinary expert panel used the UK pre-defined process to develop the OCS-AU versions A and B. We then conducted a cross-sectional normative study. We purposively recruited community-dwelling, Australian-born, and educated adults; with no known cognitive impairment; representative of age, sex, education level, and living location; at seven sites (four metropolitan, three regional) across four Australian states. Participants completed one or both OCS-AU versions in a randomised order. Australian cohorts were compared with the corresponding UK cohorts for demographics using Pearson's chi-squared test for sex and education, and Welch two-sample t test for age. For the cut-scores indicating cognitive impairment, the fifth (95th) percentiles and group mean performance score for each scored item were compared using Welch two-sample t tests. The pre-defined criteria for retaining OCS cut-scores had no statistically significant difference in either percentile or group mean scores for each scored item.Participants (n = 83) were recruited: fifty-eight completed version A [age (years) mean = 61,SD = 15; 62% female], 60 completed version B [age (years) mean = 62,SD = 13, 53% female], and 35 completed both [age (years) mean = 64,SD = 11, 54% female]. Education was different between the cohorts for version B (12 years, p = 0.002). Cut-scores for all 16 scored items for the OCS-AU version B and 15/16 for version A met our pre-defined criteria for retaining the OCS cut scores.The OCS-AU provides clinicians with an Australian-specific, first-line cognitive screening tool for people after stroke. Early screening can guide treatment and management.

Osteoarthritis (OA) is a major cause of chronic pain and disability worldwide. Treatment generally focuses on symptom relief through nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, which may incur side effects. Krill oil, rich in anti-inflammatory long-chain (LC) omega-3 ( ω-3) PUFAs and astaxanthin, may be a safe and effective alternative treatment.This study sought to investigate the effects of a commercially available krill oil supplement on knee pain in adults with mild to moderate knee OA. Secondary outcomes were knee stiffness; physical function; NSAID use; Omega-3 Index; and lipid, inflammatory, and safety markers.Healthy adults (n = 235, 40-65 y old, BMI18.5 to35 kg/m2), clinically diagnosed with mild to moderate knee OA, regular knee pain, and consuming0.5 g/d LC ω-3 PUFAs, participated in a 6-mo double-blind, randomized, placebo-controlled, multicenter trial. Participants consumed either 4 g krill oil/d (0.60 g EPA/d, 0.28 g DHA/d, 0.45 g astaxanthin/d) or placebo (mixed vegetable oil). Knee outcomes were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) numeric scale (normalized to scores of 0-100). Outcomes were assessed at baseline, 3 mo, and 6 mo.Omega-3 Index increased with the krill oil supplement compared with placebo (from 6.0% to 8.9% compared with from 5.5% to 5.4%, P 0.001). Knee pain score improved in both groups with greater improvements for krill oil than for placebo (difference in adjusted mean change between groups at 6 mo: -5.18; 95% CI: -10.0, -0.32; P = 0.04). Knee stiffness and physical function also had greater improvements with krill oil than with placebo (difference in adjusted mean change between groups at 6 mo: -6.45; 95% CI: -12.1, -0.9 and -4.67; 95% CI: -9.26, -0.05, respectively; P 0.05). NSAID use, serum lipids, and inflammatory and safety markers did not differ between groups.Krill oil was safe to consume and resulted in modest improvements in knee pain, stiffness, and physical function in adults with mild to moderate knee OA.This trial was registered at clinicaltrials.gov as NCT03483090.

To determine whether functional lung avoidance based onPatients with stage III non-small cell lung cancer (or oligometastatic disease treated with curative intent) undergoing CCRT with at least a 10 pack-year smoking history were eligible. Patients underwent pretreatmentTwenty-seven patients were randomized before the trial was closed due to slower-than-expected accrual, with 11 randomized to the standard arm and 16 to the avoidance arm. Baseline patient characteristics were well-balanced. At 3 months post-RT, the mean ± SD LCS scores were 17.4 ± 2.8 versus 17.3 ± 6.1 for the standard and avoidance arms, respectively (P = .485). A clinically meaningful, prespecified decline of ≥3 points in the LCS score was observed in 50% (4/8) in the standard arm and 33% (4/12) in the avoidance arm (P = .648). Two patients in each arm developed grade ≥2 radiation pneumonitis, with no grade ≥4 toxicities.Although this trial did not reach full accrual, QOL scores were very similar between arms. Due to the scarcity of

Introduction To evaluate the associations between neurocognitive and psychiatric health outcomes with mefloquine or any antimalarial exposure. Materials and Methods Medical records were systematically reviewed to identify veterans that indicated antimalarial medication use. Linear regression was performed to examine associations between mefloquine/antimalarial exposure and health outcomes. The mefloquine-exposed group was further compared with normative populations for the same health outcomes. Results In the adjusted models, no significant differences were noted between the two exposure groups and the unexposed group for any of the health measures (P-value > 0.05). When compared to normative population samples, the mefloquine-exposed group had poorer health and greater neurobehavioral symptom severity or cognitive complaints. Conclusion This study suggests that mefloquine use by veterans referred for intensive evaluation of their military deployment exposures and health was not associated with increased, long-term, neurocognitive/psychiatric symptoms compared to unexposed veterans.

Blood-based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remain a barrier to ctDNA replacing tissue-based testing. We hypothesized that testing immediately after starting treatment would yield an increased abundance of ctDNA in plasma because of tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing.Three prospective cohorts of patients with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained patients starting platinum doublet chemoradiation (n = 10) and cohort 2 (C2) initiating platinum doublet cytotoxic chemotherapy ± immunotherapy (n = 10). Cohort 3 (C3) contained patients receiving palliative radiation. Two baseline samples were collected. In C1 and C2, subsequent samples were collected 3, 6, 24 and 48 h post initiation of chemotherapy. Patients in C3 had samples collected immediately prior to the next three radiotherapy fractions. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst®-Lung assay.A total of 40 patients were enrolled. Detectable ctDNA was present at baseline in 32 patients (80%), 4 additional patients (50%) had detectable ctDNA in post-treatment samples. Seven patients with detectable ctDNA at baseline (23%) had new genetic alterations detected in post-treatment samples. Mutant molecule numbers increased with treatment in 24 of 31 (77%) pts with detectable ctDNA. ctDNA levels peaked a median of 7 h (IQR:2-26 h) after the initiation of chemotherapy and a median of 2 days (IQR:1-3 days) after radiation was commenced.ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post-treatment phase can yield results that were not evident in pre-treatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.(NCT03986463).

Results of lipid association analyses

Supplementary Figures S1-S6

Patient and sample clinical characteristics

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the “lipidome” in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting.Significance:This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.

Coactivator complexes regulate chromatin accessibility and transcription. SAGA (Spt-Ada-Gcn5 Acetyltransferase) is an evolutionary conserved coactivator complex. The core module scaffolds the entire SAGA complex and adopts a histone octamer-like structure, which consists of six histone-fold domain (HFD)-containing proteins forming three histone-fold (HF) pairs, to which the double HFD-containing SUPT3H adds one HF pair. Spt3, the yeast ortholog of SUPT3H, interacts genetically and biochemically with the TATA binding protein (TBP) and contributes to global RNA polymerase II (Pol II) transcription. Here we demonstrate that (i) SAGA purified from human U2OS or mouse embryonic stem cells (mESC) can assemble without SUPT3H, (ii) SUPT3H is not essential for mESC survival, but required for their growth and self-renewal, and (iii) the loss of SUPT3H from mammalian cells affects the transcription of only a specific subset of genes. Accordingly, in the absence of SUPT3H no major change in TBP accumulation at gene promoters was observed. Thus, SUPT3H is not required for the assembly of SAGA, TBP recruitment, or overall Pol II transcription, but plays a role in mESC growth and self-renewal. Our data further suggest that yeast and mammalian SAGA complexes contribute to transcription regulation by distinct mechanisms.

BACKGROUND Background: Only a minority of adult males who experience depression or anxiety receive any formal help from a healthcare professional for these issues. While psychotherapeutic e-mental health interventions may circumvent or reduce many of the barriers males experience when accessing mental health care, the effects of these interventions in male populations have not been evaluated. OBJECTIVE Objectives: (1) Synthesise the characteristics of psychotherapeutic e-mental health interventions for depression or anxiety that have been trialled and evaluated in male populations; (2) synthesise and meta-analyse the effects of these interventions on depression and anxiety outcomes in males, including examining the influence of participant, intervention, and study characteristics. METHODS Methods: Systematic searches (January 2000-October 2020) of six online research databases, manual reference list searching, and citation searches of included articles. Study quality was assessed using the Qualsyst tool, with a minimum total score of 0.55 prespecified for inclusion. Data were narratively synthesised and, where possible, meta-analysed. RESULTS Results: Seven papers comprising 552 male participants were included. A total of 177 studies were excluded because although they met all other inclusion criteria, they did not present analysable data on male participants. With a lowest total score of 0.85, study quality was high and no exclusions were made due to poor quality. Four studies used a single-arm pre-post design and three were randomised controlled trials (all with inactive/care as usual control conditions); five studies were focused on treating existing symptoms, while two focused on prevention. The seven studied interventions varied in content, length, and format. Only one intervention was classified as gender sensitive, having been designed specifically for male needs. All of the studies used non-gendered, self-report symptom measures to measure the effects of their intervention. All three randomised controlled trials detected no post-trial difference in depression symptoms between male intervention and male control participants. All four treatment studies presenting pre-post data reported post-intervention improvements in depression or social anxiety symptoms; this was supported by our meta-analysis of the two pre-post design depression treatment studies, which found a medium-sized, positive effect of treatment interventions on depression symptoms in pre-post data (g=0.64, p CONCLUSIONS Conclusions: Limited data indicate that psychotherapeutic e-mental health treatment interventions resulted in pre- to post-intervention improvements in male depression symptoms; superior outcomes were not seen when compared to inactive/care as usual control conditions. There is urgent need for consideration of gender and sex throughout the development, evaluation, and dissemination of these interventions for males, and for additional information on their effects. CLINICALTRIAL

Background: Men are often viewed as a difficult group to recruit for psychological research, including in psycho-oncology. Whilst research has demonstrated the effectiveness of monetary incentives for encouraging research participation, little research has examined different large unconditional incentive amounts. Larger unconditional incentives may result in increased participation of men in psychological research. This randomised study within a case-control trial of men diagnosed with early-stage prostate cancer aimed to investigate whether (a) response rates to a 30-minute questionnaire completed via mail, online, or phone would vary with different unconditional incentive amounts, and (b) demographics would vary in those who responded within the different incentive groups. Methods: We conducted this randomised study within a case-control cross-sectional study aiming to identify the social-ecological factors influcing treatment discontinuation in prostate cancer patients. A total of 238 participants from the cross-sectional study were randomised to receive one of two unconditional incentives (n=121 received AUD$10, n=117 received AUD$20) with the study materials (consent form and survey). Results: Overall, 113 (47%) responded; n=61/121 (50.4%) in the AUD$10 group, and n=52/117 (44.4%) in the AUD$20 group. No difference was found in response rates by incentive group (odds ratio 1.27, 95% CI=0.76-2.12, p=0.36). Additionally, there were no differences in the demographics of the responders vs. non-responders within each incentive group (all p>0.05). Conclusions: Unlike previous research, we were unable to show that higher monetary incentives were more effective for increasing response rates. An AUD$20 unconditional incentive may be no more effective than a lesser amount for encouraging prostate cancer survivors to participate in research involving long questionnaires. Future research should consider the cost-benefits of providing large unconditional incentives, as non-responses will result in lost resources perhaps better utilised in other engagement strategies.

Background Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. Methods We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. Results CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p Conclusion The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

Background Despite anxiety disorders being the ninth leading cause of disability and associated with social inequities, little attention has been given to how intersections among social determinants of health and chronic stressors such as cumulative lifetime violence affect the likelihood of experiencing anxiety disorders. Our purpose was to explore the relationships among cumulative lifetime violence severity as target and perpetrator, social determinants of health and generalized anxiety disorder in Canadian men. Methods Using a community sample of 592 Canadian men who self-identified as having experienced violence, we developed and tested an evidence-based model of generalized anxiety disorder including indicators of cumulative lifetime violence, gender, social location, socio-economic disparity, personal resources and other chronic stressors using logistic regression. Results Most men (76.4%, n = 452) reported experiences as both target and perpetrator. The model accounted for 50.8% of the variance in anxiety severity χ2 (8) = 264.43, p = .000). The prevalence of probable generalized anxiety disorder was 30.9%, a rate higher than that found among Canadian men in general in the same period. Remarkably, the likelihood of generalized anxiety disorder increased by a factor of 5.30 for each increase of 1 in cumulative lifetime violence severity, and six-fold for feeling overwhelmed by demands of everyday life (aOR = 6.26). Masculine discrepancy stress, having been born in Canada, unemployment, and food insecurity also contributed significantly to increasing the likelihood of generalized anxiety disorder. Both social support and mastery had significant aORs Conclusions These findings are the first evidence that Canadian men with lifetime violence histories are a sub-group disproportionately affected by chronic stressors and socio-economic disparities and that together the presence and/or severity of these factors increases their vulnerability to generalized anxiety disorder. Our results highlight the importance of strengths-based trauma- and violence-informed approaches to care, including practical resources to reduce the stress of everyday life, improve social support, and reinforce personal control and choice.

We compared the health-related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I-III esophageal cancer.A total of 96 patients were randomized to standard neoadjuvant cisplatin and 5-fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5-fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection.There was no significant difference in the functional assessment of cancer therapy-esophageal (FACT-E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre-treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT-E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-OG25), and EuroQol 5-D-3 L in the dysphagia, reflux, pain, taste, and coughing domains (p 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30-day mortalities and 2% vs. 10% 90-day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5-year: 35% vs. 32%, p = 0.409) or disease-free survival (DFS) (5-year: 31% vs. 30%, p = 0.710).Trimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed.

Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.

Although combination chemotherapy treatments such as FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan), gem-abraxane (gemcitabine and nab-paclitaxel) and GTX (gemcitabine, docetaxel and capecitabine) have improved survival of pancreatic cancer patients incrementally, 5-year-survival for this disease remains dismal. New and more effective treatments are needed. Pancreatic stellate cells (PSCs), a form of fibroblasts that comprise much of the pancreatic tumor microenvironment, interact with the cancer cells via the cytokine leukemia inhibitory factor (LIF) and its receptor, LIF-R. This interaction contributes to tumor progression, survival, and resistance to various therapies, and is an important target for novel therapy. A small molecule inhibitor of LIF-R, EC359, inhibits growth of breast cancer cell line tumor explants in mice (Mol Cancer Ther 18: 1341-1354, 2019) and potentially modulates the activity of gemcitabine against such explants (Genes Cancer 10: 1-10, 2019). Given the involvement of the LIF axis in pancreatic cancer, EC359 was tested for its ability to inhibit proliferation of the human pancreatic cancer cell lines PANC-1, Capan-1, and Capan-2, and its possible influence on activity of chemotherapy drugs against these cell lines. Five-day drug exposures were conducted in 96-well plates. Relative cell density determined using vital stains (alamarBlue©, neutral red) was reported as a percent of the fluorescence/absorbance of control cultures. The 3 cell lines exhibited different sensitivities to EC359, with IC50 values ranging from 5 nM (Capan-1) to 150 nM (Capan-2). When combined with anti-pancreatic cancer standard-of-care drugs, EC359 yielded synergistic interactions in a concentration-dependent manner. Depending on the cell line, EC359 decreased the IC50 value for oxaliplatin by as much as 83%. Such enhancements of cytotoxicity for other drugs were up to 84% for docetaxel, 67% for paclitaxel, and 50% for irinotecan. EC359 was also synergistic with IBR120 (a novel small molecule inhibitor of RAD51) against PANC-1 cells. EC359 additively inhibited proliferation in combination with irinotecan or 5-FUdR. The nanomolar activity of EC359 against pancreatic cancer cell lines makes it a good candidate for potential treatment of this generally refractory disease. The synergistic interaction of EC359 with standard-of-care drugs provides an opportunity for increasing the therapeutic index for these agents, and ultimately improving clinical outcomes for pancreatic cancer and other cancers against which EC359 is currently in clinical trial. Citation Format: Peter J. Ferguson, Hareesh Nair, Mark D. Vincent, James Koropatnick. Antiproliferative activity of EC359, an inhibitor of leukemia inhibitory factor receptor (LIF-R), singly and in combination with chemotherapy drugs against pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1062.

The inherent genetic instability of cancer cells and the dependence of many tumor types on oncogenic drivers contribute selectivity of anticancer agents against tumor cells. That selectivity is limited, and toxicity to normal cells remains a major limitation to the success of chemotherapy. To increase selectivity by exploiting cancer cell genetic instability, we demonstrated that the small molecule IBR2 (an inhibitor of the DNA repair protein RAD51) enhanced cytotoxicity of numerous anticancer drugs including agents that do not directly target DNA (J Pharmacol Expt Ther, 364: 46-54, 2018. doi.org/10.1124/jpet.117.241661). We demonstrated the ability of IBR2 and a derivative [IBR120, (R)-3-(2-(benzylsulfonyl)isoindolin-1-yl)-1h-indole] to synergistically inhibit proliferation of a wider range of cancer cell lines in combination with a broad range of anticancer drugs (Proc. Amer. Assoc. Cancer Res., 60: Abst. 3057, 2019). To improve the activity and potentially increase selectivity for inhibiting RAD51, modifications were made to the structure of IBR120 using a virtual drug-protein docking program, yielding the compound JKYN-1. JKYN-1 inhibits proliferation of cancer cell lines approximately 5 times more strongly than IBR120. Given the potential importance of combining JKYN-1 with targeted anticancer drugs to increase therapeutic index, and the synergy previously observed between IBR120 and agents targeted against specific tumor types, JKYN-1 was tested in combination with targeted agents against a panel of tumor cell lines. Four- to five-day drug exposures were conducted in 96-well plates. Relative cell density determined using vital stains (alamarBlue©, neutral red) was reported as a percent of the fluorescence/absorbance of control cultures. Cell lines were representative of tumors from breast (MCF-7), prostate (DU145, LNCaP), stomach (N87), pancreas (PANC-1, Capan-1, Capan-2) and lung (A549b, H1650). The chemotherapy agents included inhibitors of epidermal growth factor receptor (osimertinib, afatinib), other tyrosine kinases (regorafenib, imatinib), sex steroid receptors (4-OH-tamoxifen, enzalutamide), and microtubule function (docetaxel). To improve solubility, a methylsulfonate salt of JKYN-1 was used for most experiments. JKYN-1-mesylate decreased the concentration of drugs that inhibited proliferation by 50% (IC50) by up to 90%, depending on the drug and cell line, indicating synergy between the agents. There were some combinations in which additivity but no synergy was observed, indicating selectivity for this interaction. Individual combinations will be presented. The ability of JKYN-1 to enhance antiproliferative activity of a wide variety of anticancer agents, and its potential selectivity for cancer cells, make possible the future use of RAD51 inhibitors as systemic therapy potentiators to improve clinical outcomes. Citation Format: Peter J. Ferguson, Mark D. Vincent, Yousef Najajreh, Brian Shilton, Stephen Ritter, Rima Al-awar, Richard Marcellus, Mohammed Mohammed, Methvin Isaac, James Koropatnick. Synergistic antiproliferative activity of novel RAD51 inhibitor JKYN-1 and its mesylate salt with standard-of-care cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 346.