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Background Past studies have shown a commission bias for cancer treatment, a tendency to choose active treatment even when watchful waiting is less risky. This bias suggests motivations for action beyond mortality statistics, but recent evidence suggests that individuals differ in their emotional sensitivity to probabilities (ESP), the tendency to calibrate emotional reactions to probability. The current study aims to examine the role of ESP in the commission bias, specifically whether those higher in ESP are more likely to choose watchful waiting when risk probabilities align with that choice. Methods Participants ( N = 1,055) read a scenario describing a hypothetical cancer diagnosis and chose between surgery and watchful waiting, with random assignment between versions where the mortality rate was either lower for surgery or for watchful waiting. We modeled choice using the Possibility Probability Questionnaire (PPQ), a measure of ESP, and several other individual differences in a logistic regression. Results We observed a commission bias as in past studies with most participants choosing surgery both when surgery was optimal (71%) and when watchful waiting was optimal (58%). An ESP × Condition interaction indicated that the predictive role of ESP depended on condition. Those higher in ESP were more likely to choose surgery when probabilities favored surgery, β = 0.57, P < 0.001, but when probabilities favored watchful waiting, ESP had a near-zero relationship with choice, β = 0.05, P < 0.99. Conclusions The role of ESP in decision making is context specific. Higher levels of ESP predict choosing action when that action is warranted but do not predict a shift away from surgery when watchful waiting offers better chances of survival. ESP does not overcome the commission bias. Highlights Past studies have identified a “commission bias,” a tendency to choose active treatment over watchful waiting, even when mortality rate is lower for waiting. Evaluation of risk probabilities is related to individual differences in emotional sensitivity to probabilities (ESP) and has been shown to predict reactions to and decisions about health risk situations. ESP appears to be selectively factored into decision making. ESP was a robust predictor of choosing surgery when probability information supported surgery but did not predict decisions when probability information supported watchful waiting. Those who are most emotionally attuned to probabilities are just as susceptible to the commission bias as those who are less attuned.

Purpose: Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Experimental Design: Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated. Results: Mean age was 50 years (35–64); median Eastern Cooperative Oncology Group 0 (0–1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients’ blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible. Significance: Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.

Maintenance of calcium homeostasis is important for proper endoplasmic reticulum (ER) function. When cellular stress conditions deplete the high concentration of calcium in the ER, ER-resident proteins are secreted into the extracellular space in a process called exodosis. Monitoring exodosis provides insight into changes in ER homeostasis and proteostasis resulting from cellular stress associated with ER calcium dysregulation. To monitor cell-type specific exodosis in the intact animal, we created a transgenic mouse line with a Gaussia luciferase (GLuc)—based, secreted ER calcium-modulated protein, SERCaMP, preceded by a LoxP-STOP-LoxP (LSL) sequence. The Cre-dependent LSL-SERCaMP mice were crossed with albumin (Alb)-Cre and dopamine transporter (DAT)-Cre mouse lines. GLuc-SERCaMP expression was characterized in mouse organs and extracellular fluids, and the secretion of GLuc-SERCaMP in response to cellular stress was monitored following pharmacological depletion of ER calcium. In LSL-SERCaMP × Alb-Cre mice, robust GLuc activity was observed only in the liver and blood, whereas in LSL-SERCaMP × DAT-Cre mice, GLuc activity was seen in midbrain dopaminergic neurons and tissue samples innervated by dopaminergic projections. After calcium depletion, we saw increased GLuc signal in the plasma and cerebrospinal fluid collected from the Alb-Cre and DAT-Cre crosses, respectively. This mouse model can be used to investigate the secretion of ER-resident proteins from specific cell and tissue types during disease pathogenesis and may aid in the identification of therapeutics and biomarkers of disease.

Evidence suggests that yoga may help improve cancer-related symptoms though knowledge of the experiences, barriers and preferences of people diagnosed with cancer is limited. This study sought to examine the use of yoga in an Australian sample and identify the experiences and preferences associated with undertaking yoga practice as formative research to help inform a future yoga intervention.Adults diagnosed with any type of cancer completed a cross-sectional survey including questions regarding their demographics, experiences and preferences for yoga practice.Sixty-eight people who had been diagnosed with cancer completed the survey. Most of the participants (70.8%) had practiced yoga since their diagnosis. A variety of reasons for practice were endorsed, and benefits experienced included physical and psychological factors. The most common barrier to practice was related to the physical ability to undertake yoga. Participants indicated a preference for group classes (44.1%), with a frequency of practice of 2-3 times per week (60.3%), 60 min in length (75%). The preferred time of practice was 9am-12pm (51.5%) and travel distance 5-10 km (44.1%). Online yoga delivery was endorsed, with participants preferring pre-recorded sessions.Results from this study provide insights into the experiences, barriers and preferences for yoga practice in people with cancer which will assist in developing yoga programs in this cohort to investigate the effects on cancer and treatment-related symptoms.

This study provides a statistical basis to determine the most influencing parameters on forces and overtopping over vertical walls, as well as to showcase the usability of machine learning modelling in coastal engineering. To this end, horizontal force and overtopping data for regular waves of varying height (0.63–1.65 m), period (4–8 s), and water depth (3.37–3.97 m) over a vertical wall were studied using redundancy analysis (RDA) and regressed using multiple linear regression, support vector regression (SVR), and random forest regression (RFR). The RDA showed that about 60% of the output variable variance can be explained by the structure dimensions and 15% by the incoming wave characteristics. The SVR approach better predicted the average force (mean relative error (MRE) = 39.9% and R2 = 0.346), whereas the RFR technique better predicted overtopping discharges (MRE = 46.7% and R2 = 0.802). By expanding the database, the error on overtopping prediction was reduced to 22.1% and 27.5%, respectively, for the SVR and RFR.

Grime music has been central to British youth culture since the beginning of the 21st century. It is an Afrodiasporic form that developed on street corners, on pirate radio and at raves. An emergent body of academic and popular literature has concentrated on the music’s socio-political contexts. However, there has to date been no extended study of the form’s performance techniques and values. \ud \ud This thesis intends to enrich musical understandings of grime, and approaches to the study of (popular) music more broadly. It makes an original contribution to knowledge in three ways: 1) by providing the first exploration of the ways MCs and DJs perform in the live domain, and theorising the creative workings of improvisation and interaction in demanding performance environments; 2) through offering the first musicological ethnography of the form, allowing for rich documentation of practitioner perspectives and performance data; 3) by demonstrating how its very performance environments, principally pirate radio, inflect upon and influence creative practice. These advances are facilitated by my long-standing role as a DJ within the London grime scene \ud \ud Entitled Level Up, this thesis constructs a framework for the performance of grime music. The resultant model offers new ways to conceptualise emergent improvisatory practice within ensembles, across the spectrum of creative arts. It opens with a critique of incipient histories of the form, before outlining grime’s performance conventions. Three of the music’s most fundamental interactional processes are explored—the reload, the rally and the through ball—with respect to their multidirectionality and collaborative character. A study of its radio network from 2016–18 follows, demonstrating how its interrelatedness stimulates creativity and incubates group practice. It concludes with a study of collective social learning in two grime crews: Shellyvnne and Over The Edge.

The discovery of the resoruclins, new 3,5-dihydroxybenzoic acid containing macrolides for Steptomyces sp. MST-91080, and their putative biosynthetic pathway.

Despite the many mistakes we make while speaking, people can effectively communicate because we monitor our speech errors. However, the cognitive abilities and brain structures that support speech error monitoring are unclear. There may be different abilities and brain regions that support monitoring phonological speech errors versus monitoring semantic speech errors. We investigated speech, language, and cognitive control abilities that relate to detecting phonological and semantic speech errors in 41 individuals with aphasia who underwent detailed cognitive testing. Then, we used support vector regression lesion symptom mapping to identify brain regions supporting detection of phonological versus semantic errors in a group of 76 individuals with aphasia. The results revealed that motor speech deficits as well as lesions to the ventral motor cortex were related to reduced detection of phonological errors relative to semantic errors. Detection of semantic errors selectively related to auditory word comprehension deficits. Across all error types, poor cognitive control related to reduced detection. We conclude that monitoring of phonological and semantic errors relies on distinct cognitive abilities and brain regions. Furthermore, we identified cognitive control as a shared cognitive basis for monitoring all types of speech errors. These findings refine and expand our understanding of the neurocognitive basis of speech error monitoring.

The COVID-19 pandemic galvanized national regulatory authorities (NRAs) to adopt innovative and cooperative vaccine approval approaches. Against a backdrop of deaths, economic paralysis, and political instability, it became clear that legacy approaches to vaccine approvals would no longer suffice. Regulatory cooperation between NRAs has developed since the 1960s in Europe and later in other regions. But the crisis wrought by COVID-19 has instilled a new sense of the value of networking, work-sharing, reliance, and recognition among NRAs in all countries and regions. Regional and multilateral collaboration — particularly in the Asia-Pacific — have also enabled shared knowledge and resources while contributing to some degree of harmonization in rules and procedures. Indeed, this will likely pave the way for dealing with future global health crises. Yet, amidst the detritus, there is much to learn.

Highly imperiled unionids have a complex life cycle including the metamorphosis of an obligate parasite life stage, larval glochidia, to the juvenile stage. Despite the known vulnerabilities of both glochidia and juveniles to pollutants, little is known on how metamorphosis success may be affected by chemical stress. Disruption of the transformation process in which glochidia encyst on the gills of a host fish, could lead to lowered recruitment and population declines. Transformation rates of Lampsilis cardium on host fish Micropterus salmoides were empirically derived from experimental exposures to low, medium, or high concentrations of an agricultural or urban mixture of contaminants of emerging concern (CECs) over two exposure durations. Transformation was characterized by: (1) a zero-inflated Poisson general linear mixed effects model to compare difference in transformation between exposure durations and (2) time response curves to describe the transformation curve using long-term exposure data. Lampsilis cardium transformation was similar between exposure durations. When compared to controls, CEC stress significantly reduced juvenile production (p « 0.05) except for the agricultural medium treatment and tended to increased encapsulation duration which while statistically insignificant (p = 0.16) may have ecological relevancy. Combining the empirically derived reduction of transformation rates with parameters values from the literature, a Lefkovich stage-based population model predicted strong declines in population size of L. cardium for all treatments if these results hold in nature. Management focus on urban CECs may lead to best conservation efforts though agricultural CECs may also have a concentration dependent impact on transformation and therefore overall recruitment and conservation success.

Co-clinical trials are the concurrent or sequential evaluation of therapeutics in both patients clinically and patient-derived xenografts (PDX) pre-clinically, in a manner designed to match the pharmacokinetics and pharmacodynamics of the agent(s) used. The primary goal is to determine the degree to which PDX cohort responses recapitulate patient cohort responses at the phenotypic and molecular levels, such that pre-clinical and clinical trials can inform one another. A major issue is how to manage, integrate, and analyze the abundance of data generated across both spatial and temporal scales, as well as across species. To address this issue, we are developing MIRACCL (molecular and imaging response analysis of co-clinical trials), a web-based analytical tool. For prototyping, we simulated data for a co-clinical trial in “triple-negative” breast cancer (TNBC) by pairing pre- (T0) and on-treatment (T1) magnetic resonance imaging (MRI) from the I-SPY2 trial, as well as PDX-based T0 and T1 MRI. Baseline (T0) and on-treatment (T1) RNA expression data were also simulated for TNBC and PDX. Image features derived from both datasets were cross-referenced to omic data to evaluate MIRACCL functionality for correlating and displaying MRI-based changes in tumor size, vascularity, and cellularity with changes in mRNA expression as a function of treatment.

Background Community wellness coalitions are an important part of functioning program infrastructure and have been effective in promoting policy, systems, and environmental (PSE) change, especially when paired with technical support by a community champion or Extension staff. PSE strategies are critical to support long-lasting behavior change but can be challenging to implement. Extension is an established and equipped organization that has potential to help community overcome those challenges. The aim of this article was to identify and describe experiences of Extension staff working as community coaches. Methods A mixed-methods design to assess the impact of Extension staff working with Community Champions included a quantitative Extension Coaching Confidence Scorecard and an Extension Key Informant Interview. Results The total Extension Coaching Confidence score significantly increased from pre- to post-intervention (55.1 ± 35.3 vs. 81.7 ± 37.7, p = .03). Five facilitators and two barriers to wellness coalition development were identified by Extension staff. Discussion The results of this study indicate that the model of community coaching used was effective at addressing the foundational components of the Component Model of Infrastructure (CMI). However, comprehensive training for Extension staff in the CMI and technical assistance are needed in order to build capacity, achieve outcomes, and promote sustainability. Implications for Practice Individuals seeking to transition to PSE work should be provided with a foundation of specific, targeted training in the CMI and evidence-based technical assistance methods. Practitioners should recognize the essential role of community champions in PSE work. Completing the Extension Coaching Confidence Scorecard periodically can inform evolving training needs.

Obesity prevalence is higher among rural populations than urban, which may be related to differences in environments. Rural counties face barriers to accessing healthy foods and physical activity opportunities including isolation, transportation distances, and lack of facilities. As part of the Centers for Disease Control and Prevention Division of Nutrition, Physical Activity, and Obesity High Obesity Program, community-based wellness coalitions were established in six South Dakota counties with adult obesity prevalence >40%. The community coalitions were charged with improving access to healthy foods and safe and accessible places to participate in physical activity within their rural, underserved communities. Coalitions were created and members were recruited by Cooperative Extension staff who had existing relationships with key stakeholders within the community. Within these coalitions, champions were identified to provide leadership and ensure project implementation. Ongoing support and technical assistance were provided to the community coalitions by Cooperative Extension staff as they completed a community needs assessment, disseminated results of the needs assessment with the community, created action plans based on needs assessment data, implemented evidence-based interventions to support nutrition and physical activity policy, system and environmental changes, and assessed impact within their community. Overall, the purpose of this article is to share the project methodology, which capitalized on using Cooperative Extension, to build capacity to improve the nutrition and physical activity environment in rural, unserved communities. Sustainability of this work, along with lessons learned, is also discussed.

Purpose Open-source automated insulin delivery (AID) is used by thousands of people with type 1 diabetes (T1D), but has unknown generalisability to marginalised ethnic groups. This study explored experiences of Indigenous Māori participants in the CREATE trial with use of an open-source AID system to identify enablers/barriers to health equity. Methods The CREATE randomised trial compared open-source AID (OpenAPS algorithm on an Android phone with a Bluetooth-connected pump) to sensor-augmented pump therapy. Kaupapa Māori Research methodology was used in this sub-study. Ten semi-structured interviews with Māori participants (5 children, 5 adults) and whānau (extended family) were completed. Interviews were recorded and transcribed, and data were analysed thematically. NVivo was used for descriptive and pattern coding. Results Enablers/barriers to equity aligned with four themes: access (to diabetes technologies), training/support, operation (of open-source AID), and outcomes. Participants described a sense of empowerment, and improved quality of life, wellbeing, and glycaemia. Parents felt reassured by the system’s ability to control glucose, and children were granted greater independence. Participants were able to use the open-source AID system with ease to suit whānau needs, and technical problems were manageable with healthcare professional support. All participants identified structures in the health system precluding equitable utilisation of diabetes technologies for Māori. Conclusion Māori experienced open-source AID positively, and aspired to use this therapy; however, structural and socio-economic barriers to equity were identified. This research proposes strength-based solutions which should be considered in the redesign of diabetes services to improve health outcomes for Māori with T1D. Trial Registration: The CREATE trial, encompassing this qualitative sub-study, was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12620000034932p) on the 20th January 2020.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Boat-based acoustic and visual surveys for harbour porpoises (Phocoena phocoena) were conducted during the summers of 2001 and 2002 in order to investigate their distribution and relative abundance in the Baltic Sea, and to compare the results with the adjacent Kiel and Mecklenburg Bights and the Little Belt. Harbour porpoises are subject to year-round bycatch in gillnets and other fishing gear in these waters. This is of particular concern in the Baltic Sea where a survey carried out in 1995 indicated that the population is low and current levels of anthropogenic mortality are believed to be unsustainable. Polish coastal waters were not included in the 1995 survey and it has been hypothesised that these unsurveyed waters may contain a significant uncounted part of the Baltic Sea population. Results show that the porpoise detection rate was two orders of magnitude lower in the Baltic Sea than in other waters surveyed. No evidence was found that Polish waters contain a significant, previously uncounted part of the Baltic Sea population. The results confirm the endangered status of the Baltic Sea population, and stress the urgency of preventing future anthropogenic mortalities that threaten the survival of the population.

BACKGROUND: Nearly 50% of patients with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) retain residual tumors resulting in high rates of metastatic relapse and poor overall survival. Residual tumors surviving NACT (Adriamycin plus cyclophosphamide; AC) were found to undergo a metabolic transition to heightened mitochondrial oxidative phosphorylation (oxphos; PMID: 30996079). Pharmacologic inhibition of mitochondrial electron transport chain (ETC) complex I with IACS-010759 (PMID: 29892070) had enhanced efficacy in residual, rather than treatment-naïve, tumors of orthotopic patient-derived xenograft (PDX) models. Our analyses of mitochondrial structure and function in human TNBC cell lines revealed differing adaptations in residual cells surviving treatment with conventional NACT agents. While DNA-damaging chemotherapies (e.g.Adriamycin, carboplatin) induced mitochondrial fusion and oxphos, taxanes (e.g.paclitaxel, docetaxel) induced mitochondrial fragmentation and reduced oxphos (Baek et al., Biorxiv Doi 10.1101/2022.02.25.481996). The mechanistic basis of these mitochondrial adaptations is not yet understood. The mitochondrial ETC consists of 92 proteins, 13 of which are encoded in the mitochondrial genome (mtDNA) and translated by the mitoribosome, while the remaining are encoded by the nuclear genome (nDNA), translated by the cytoribosome, and inserted into the inner mitochondrial membrane by accessory proteins, namely Oxidase (Cytochrome C) Assembly 1-Like (OXA1L). Disruption of OXA1L in mammalian cells has been shown to affect the levels and activity of ETC complexes I, III, IV, and V, and thus diminish oxphos. We aim to determine whether mitochondrial translation and OXA1L activity represent therapeutic vulnerabilities to overcome pro-survival metabolic adaptations in chemoresistant TNBC thereby augmenting treatment response. METHODS: Weare evaluating the effects of conventional TNBC chemotherapies singly, and in standard combinations, on mitochondrial translation and ETC formation in human TNBC cells and PDX models(PIM001-P, WHIM14, BCM15116) using metabolomic and proteomic profiling. To perturb these processes genetically, we knocked down (KD) OXA1Lwith siRNA. We are complementing these studies pharmacologically using conventional antibiotics, such as tigecycline, as previous studies showed they inhibit mitochondrial translation in breast and other cancers (PMID: 25625193). These studies will reveal whether OXA1L and mitochondrial translation are required for metabolic adaption and chemotherapy resistance of residual TNBC cells. PDX preclinical trials based on our published residual tumor testing schema (PMID: 30996079), will reveal whether the sequential combination of NACT followed by tigecycline can effectively perturb residual tumor relapse. RESULTS: Proteomic profiling of longitudinally harvested PDX tumors demonstrates substantial disruption of mitochondria-and nuclear-encoded ETC components in residual vs. treatment-naïve tumors. Interestingly, these patterns are distinct between different chemotherapy treatments, with an increase of ETC components in carboplatin-treated residual tumors compared to a decrease in docetaxel-treated residual tumors. Western blot analyses of human cell lines show OXA1LKD perturbs levels of both nuclear-and mitochondria-encoded ETC components. Preliminary findings suggest OXA1LKD increases sensitivity to chemotherapies in human TNBC cell lines. Finally, tigecycline effectively inhibits TNBC cell growth. We next will evaluate whether residual cells not killed by conventional chemotherapies have enhanced tigecycline susceptibility. CONCLUSION: These data suggest targeting mitochondrial translation may be a promising approach to overcome pro-survival metabolic adaptations in residual TNBC cells not killed by conventional chemotherapies. Citation Format: Mariah J. Berner, Lily Baek, Junegoo Lee, Philip L. Lorenzi, Mei Leng, Alexander B. Saltzman, Anna Malovannaya, Lacey E. Dobrolecki, Christina Sallas, Michael T. Lewis, Gloria V. Echeverria. Investigating the role of mitochondrial protein translation in the metabolic adaptation of chemoresistant triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-10.

Background: Triple-negative breast cancer (TNBC) patients frequently receive combination chemotherapy treatment, but a direct comparison of response to carboplatin, docetaxel, and their combination in 50 TNBC patient-derived xenografts (PDXs) showed that combination treatment was largely ineffective at generating enhanced responses over the best single agent. This suggests de-escalation of chemotherapy may be possible if molecular mechanisms and biomarkers underlying response to individual treatments can be identified. To this end, we performed multi-omics profiling for the 50 TNBC PDXs. Methods: Orthotopic TNBC PDXs were treated with four weekly cycles of docetaxel, carboplatin, or the combination. Changes in tumor volume after 4 weeks of treatment were assessed quantitatively and by modified RECIST criteria. Genomic, transcriptomic, and mass-spectrometry-based proteomic profiling were performed on baseline tumors prior to treatments to identify associations with chemotherapy response at the gene and pathway level. ProMS was used to integrate both RNA and protein data to select a 5 RNA feature combination for optimized prediction of carboplatin response in a logistic regression model. Publicly available neoadjuvant chemotherapy clinical datasets with transcriptomic data and response information used for validation/testing included TNBC samples from: GSE18864, I-SPY2 (GSE194040), and BrighTNess (GSE164458). Results: Proteogenomic profiles revealed distinct genes associated with response to each agent and their combination, respectively, suggesting distinct molecular mechanisms underlying response to each treatment. A substantial number of genes associated with single agent and combination treatment were validated in multiple independent patient cohorts receiving platinum and taxane containing neoadjuvant therapy, confirming clinical relevance of our PDX panel. For the same treatment, different types of molecular data identified distinct sets of associated genes, providing highly complementary information. At the pathway level, RNA and protein data converged to metabolic and E2F/G2M related pathways which were upregulated in PDXs resistant or responsive to all treatment types, respectively, while variable levels of MYC-related proliferation pathways were observed across all treatments suggesting pathways that are common across and unique to different treatments. Several individual genes found to be higher in PDXs with better response to either single-agent had discriminatory power in external clinical TNBC datasets treated with similar neoadjuvant chemotherapy regimens. In addition, a logistic regression-based carboplatin response prediction model trained to select a group of 5 RNA markers (TKT, MAGI2, ATF6B, MCM7, LRP6) using both RNA and protein data performed the best in predicting response to cisplatin in a clinical TNBC dataset vs predicting response to other datasets with taxane and platinum + taxane combination containing chemotherapy regimens, demonstrating specificity of the prediction model. These results suggest potential individual biomarkers or biomarker combinations to select TNBC tumors that may respond to either single agent carboplatin, docetaxel, or their combination. PDXs refractory to all treatment arms had higher levels of proteostasis-related pathways including proteasome degradation and the unfolded protein response (UPR) related to endoplasmic reticulum stress and altered levels of chromatin regulation. Subsequent pharmacological targeting of the UPR pathway and targeting HDACs enhanced chemotherapy response. Conclusion: Proteogenomic characterization identifies molecular mechanisms and putative biomarkers for stratifying TNBC tumors for single or combination chemotherapy treatments, suggests targeted therapies to augment chemotherapy response, and provides a valuable resource for researchers and clinicians. Citation Format: Jonathan T. Lei, Chen Huang, Ramakrishnan R. Srinivasan, Suhas Vasaikar, Lacey E. Dobrolecki, Alaina N. Lewis, Na Zhao, Jin Cao, Susan G. Hilsenbeck, C. Kent Osborne, Mothaffar Rimawi, Matthew J. Ellis, Varduhi Petrosyan, Alexander B. Saltzman, Anna Malovannaya, John D. Landua, Bo Wen, Antrix Jain, Gerburg M. Wulf, Shunqiang Li, Daniel C. Kraushaar, Tao Wang, Xi Chen, Gloria V. Echeverria, Meenakshi Anurag, Bing Zhang, Michael T. Lewis. Patient-derived xenografts allow deconvolution of single agent and combination chemotherapy responses in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-01.

Background: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which limited targeted therapies are available. Therefore, conventional chemotherapy remains the backbone of standard neoadjuvant treatment (NACT) for TNBC patients. Unfortunately, ~45% of patients will have substantial residual tumor burden post neoadjuvant chemotherapy, leading to poor prognoses (PMID: 28135148). Recently, it has been demonstrated that mitochondrial oxidative phosphorylation (oxphos) is upregulated and is a therapeutic vulnerability in chemoresistant TNBC (PMID: 30996079; Baek et al., BioRxiv doi.org/10.1101/2022.02.25.481996). However, mechanisms driving increased oxphos in chemoresistant TNBC are not understood. Upregulated fatty acid (FA) metabolism is a common adaptation in tumors, providing an energy source through fatty acid β-oxidation (FAO), and promoting lipid accumulation after fatty acid synthesis (FAS) when energy needs are met. Chemotherapy can induce oxidative stress through the generation of reactive oxygen species. Cancer cells adapt to these damaging molecules by increasing de novo lipogenesis, resulting in the accumulation of lipid droplets (LDs) in the cytosol (PMID: 32782526, 20876798). We hypothesize that TNBC cells metabolically adapt to the stress of NACT by upregulating lipid metabolic pathways, providing highly energetic molecules that can be utilized to drive oxphos in chemoresistant TNBC. Methods: Using orthotopic patient-derived xenograft (PDX) models of TNBC (PIM001-P, PMID: 30996079, HCI-010, PMID: 22019887; WHIM14, PMID:24055055), we are measuring protein levels of fatty acid synthase (FASN) in vehicle tumors vs residual tumors surviving treatment with the standard front-line neoadjuvant chemotherapy regimens (Adriamycin plus cyclophosphamide (AC), docetaxel, carboplatin, or docetaxel+carboplatin) using immunohistochemistry (IHC). Vectra 3 microscopy (Akoya) is being used to quantify tumor cell-specific staining. We complemented our IHC analysis with reverse-phase protein array (RPPA). To assess LD accumulation in residual PDX tumors, we conducted transmission electron microscopy (TEM). To complement these PDX studies, we modeled the residual tumor metabolic state in cultured human TNBC cells. Following treatment with the IC50 of standard chemotherapeutic agents (AC, carboplatin, paclitaxel, docetaxel), we assessed oxphos by measuring oxygen consumption rate (OCR) using a Seahorse Bioanalyzer (Agilent). Further, we tested LD accumulation using LipidTOX staining. In ongoing studies, we are measuring incorporation of 13C palmitate into the tricarboxylic acid cycle (TCA) prior to and following chemotherapy treatments to assess if lipids fuel mitochondrial metabolism in residual TNBC cells. Results/Discussion: IHC in the PIM001-P PDX model after in vivo AC treatment revealed increased levels of FASN in post-AC residual tumors compared to the treatment-naive tumors. Further, key proteins involved in fatty acid synthesis, FASN and Acetyl-CoA carboxylase, were significantly increased in residual PIM001-P cells that survived AC compared to vehicle by RPPA. TEM analysis of the HCI-010 PDX revealed significantly more LDs in carboplatin-treated tumors compared to vehicle. This finding was supported by increased LDs observed in TNBC cell lines treated with NACT compared to vehicle in our LipidTOX analyses. Taken together, these data indicate that NACT induces increased expression of key lipid metabolism proteins and accumulation of cytosolic LDs. Our future experiments will reveal if chemoresistant TNBC cells preferentially utilize and incorporate lipids into the tricarboxylic acid cycle, in turn driving oxphos. These data have the potential to provide rationale for the incorporation of FAO/LD inhibitors in sequential combinations with conventional chemotherapies to more effectively kill TNBC cells that are chemo-refractory. Citation Format: Katherine E. Pendleton, Mokryun L. Baek, Junegoo Lee, Lin Tan, Hannah L. Johnson, Lacey E. Dobrolecki, James P. Barrish, Michael T. Lewis, Philip L. Lorenzi, Fabio Stossi, Gloria V. Echeverria. Lipid accumulation in residual triple negative breast cancer cells surviving chemotherapy treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-15.

To understand how the risk of different assisted reproductive technology (ART) failure types varies by ethnic group and explore the role of mediation by maternal age and suspected etiology.An observational study of 48,750 women who undertook treatment with ART in the United Kingdom between January 2017 and December 2018.The Human Fertilisation and Embryology Authority national ART registry of the United Kingdom.Women who commenced a first cycle of ART for the purpose of primary fresh embryo transfer using their own oocytes were included.Maternal ethnic group.The ART failure types were modeled on the maternal ethnic group using the Poisson regression to produce relative risks (RRs) with 95% confidence intervals. The potential indirect effects of maternal age and etiology of subfertility were estimated, and the RRs with 95% confidence intervals were produced.Black women were at greater risk of treatment failure with respect to live birth than women who were white: cycle cancellation, RR of 2.15 (1.78-2.62); failed fertilization, RR of 2.36 (1.90-2.93); unintended freeze-all, RR of 1.71 (1.43-2.05); failed implantation, RR of 1.23 (1.12-1.34); and pregnancy loss, RR of 1.38 (1.15-1.64). Women who were Asian were at moderately increased risk: RRs of 1.31 (1.17-1.47), 1.60 (1.42-1.80), 1.25 (1.14-1.38), 1.11 (1.07-1.16), and 1.13 (1.03-1.23), across the same outcomes, respectively. Inequality may have been reduced had women of all ethnicities initiated treatment at the same age.Black women were at greatest risk of all failure types, and women who were Asian were at intermediate risk compared with women who were white. Some of the risks among women who were black may be mediated by maternal age.

Purpose Platinum-based chemotherapies used to treat many types of cancers are ototoxic. Ototoxicity management (OtoM) to mitigate the ototoxic outcomes of cancer survivors is recommended practice yet it is not a standard part of oncologic care. Although more than 10,000 patients each year are treated with platinum-based chemotherapies at the US Veterans Health Administration (VA), the current state of OtoM in VA is not well-defined. This study reports on a national survey of VA audiologists’ perceptions regarding OtoM in cancer patients. Methods A 26-item online survey was administered to VA audiologists and service chiefs across the VA’s 18 regional systems of care. Descriptive statistics and deductive thematic analysis were used to analyze the data. Results The 61 respondents included at least one from each VA region. All reported they felt some form of OtoM was necessary for at-risk cancer patients. A pre-treatment baseline, the ability to detect ototoxicity early, and management of ototoxic effects both during and after treatment were considered high value objectives of OtoM by respondents. Roughly half reported routinely providing these services for patients receiving cisplatin and carboplatin. Respondents disagreed regarding appropriate hearing testing schedules and how to co-manage OtoM responsibilities with oncology. They identified barriers to care that conformed to three themes: care and referral coordination with oncology, audiology workload, and lack of protocols. Conclusions Although VA audiologists value providing OtoM for cancer patients, only about half perform OtoM for highly ototoxic treatment regimens. The OtoMIC survey provides clinician perspectives to benchmark and address OtoM care gaps. Implications for cancer survivors Collaboration between oncology and audiology is needed to improve current OtoM processes, so that cancer survivors can have more control over their long term hearing health.

Purpose This purpose of this study is to outline an inclusive development strategy for crime prevention interventions. Crime prevention interventions are delivered to the target audience to convey an evidence-based message to dissuade would-be offenders from carrying out crimes. However, rarely is the target audience involved when designing crime prevention interventions. Design/methodology/approach Using the Delphi method, this paper documents the design of an intervention aimed at improving young drivers’ compliance with road rules, incorporating feedback from both a panel of experts and the target audience of the intervention. While expert feedback guided the content and the context of the intervention, the feedback from the target audience was critical in ensuring that effective delivery and messaging of the crafted intervention would occur. Findings By drawing on expert and experiential insights, this exploratory method of intervention design provided a simple and effective way of ensuring the effective delivery of a crime prevention message. Research limitations/implications Although this study focussed on a road safety intervention, the crime prevention applications of this method are broad. Originality/value This paper outlines a collaborative methodology that utilises expert and experiential knowledge towards the design and development of a crime prevention intervention, in this case, targeted at young drivers.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disease with hypogonadism and infertility caused by the defects in embryonic migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, hypothalamic GnRH secretion or GnRH signal transduction. PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the Gαq, Gαs and ERK1/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of Gαq, instead of MAPK/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to Gαq signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according Gαq pathway functionality: (i) neutral (N, >80% activity); (ii) low pathogenicity (L, 50–80% activity); (iii) medium pathogenicity (M, 20–50% activity) and (iv) high pathogenicity (H

The Mediterranean sub-population of sperm whales is believed to be isolated and is classified as Endangered on the IUCN Red List. Although there is evidence to suggest the population is declining, there is a lack of abundance data. A series of acoustic line-transect surveys were undertaken between 2004 and 2013. In 2004, 3,946km of acoustic effort was conducted in the southern Western Mediterranean basin, resulting in the detection of 159 sperm whales. While in 2007 and 2013, 10,276km of acoustic effort was conducted in the Eastern Mediterranean basin, resulting in the detection of 24 sperm whales. A pooled detection function gave an effective strip half-width of 9.8km. A correction for availability bias was made for each block based on published simulations using data on sperm whale acoustic behaviour: estimates of g(0) were 0.95–0.96. Estimated abundances were: Southern Western Mediterranean Block 634 animals [374–1,077] (95% log-normal confidence interval); Hellenic Trench Block 41 [17–100]; Central Aegean Sea Block 33 [5–203]; Herodotus Rise Block 5 [1–28] and Southern Adriatic Sea Block 2 [0–12]. Estimates for all other blocks were zero. The density of sperm whales in the surveyed Southern Western Mediterranean Block was over 17 times higher than for the surveyed Eastern Mediterranean (2.12 and 0.12 whales per 1,000km² respectively). These results, combined with an acoustic survey of the northern Ionian Sea in 2003 and aerial surveys in the northern Western Mediterranean basin in 2010–11, covered approximately 57% of the likely sperm whale habitat in the Western Mediterranean and 75% in the Eastern Mediterranean. Approximate total estimates of sperm whale abundance in the Western and Eastern Mediterranean basins based on extrapolation to the unsurveyed areas are 1,678 and 164 whales respectively. This gives an estimate for the whole Mediterranean Sea of 1,842 animals.