Synthetic aperture sonar (SAS) intensity statistics are dependent upon the sensing geometry at the time of capture. Estimating bathymetry from acoustic surveys is challenging. While several methods ...have been proposed to estimate seabed relief via intensity, we develop the first large-scale study that relies on deep learning models. In this work, we pose bathymetric estimation from SAS surveys as a domain translation problem of translating intensity to height. Since no dataset of coregistered seabed relief maps and sonar imagery previously existed to learn this domain translation, we produce the first large simulated dataset containing coregistered pairs of seabed relief and intensity maps from two unique sonar data simulation techniques. We apply four types of models, with varying complexity, to translate intensity imagery to seabed relief: a shape-from-shading (SFS) approach, a Gaussian Markov random field (GMRF) approach, a conditional Generative Adversarial Network (cGAN), and UNet architectures. Each model is applied to datasets containing sand ripples, rocky, mixed, and flat sea bottoms. Methods are compared in reference to the coregistered simulated datasets using L1 error. Additionally, we provide results on simulated and real SAS imagery. Our results indicate that the proposed UNet architectures outperform an SFS, a GMRF, and a pix2pix cGAN model.
Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we ...report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC.
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•Dinaciclib is a potent inhibitor of CDK12 and disrupts homologous recombination•Residual HR is a cause of de novo PARP inhibitor resistance in BRCA-mutated cancer•Dinaciclib sensitizes resistant BRCA-mutated breast cancer models to PARP inhibition•In HR-deficient cancer, dinaciclib augments the response afforded by PARP inhibition
Johnson et al. show that CDK12 inhibition, mediated by the small molecule dinaciclib, disrupts residual or restored homologous recombination (HR) in BRCA-associated breast cancer, sensitizing to PARP inhibition. CDK12 inhibition also augments the degree of PARP inhibitor response in HR-deficient breast cancer. Combined CDK12-PARP inhibition is well tolerated in preclinical models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction ...and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the ...development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1 -mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1 -mutant tumors acquire anticancer therapy resistance.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Medical students demonstrate their passion for participating in and improving health care both within and outside the classroom. As the COVID-19 pandemic swept across the world, medical students in ...the United States engaged in student-led service-learning initiatives to contribute to medicine and their local communities, including collecting and distributing personal protective equipment, creating and translating pandemic-related educational materials, and providing childcare for frontline workers. Their impact was recognized and appreciated. Service learning is an education method that incorporates community outreach with didactic coursework and student reflection. In this commentary, the authors argue for including service learning as a required component in the medical school curriculum to provide students with the tools and support to be advocates and leaders within society, as no such curriculum currently exists. The authors also discuss the history of medical student-led service-learning efforts through to the present day, barriers to implementing and sustaining student-led service-learning initiatives, and solutions to prepare students for service-learning initiatives.
Abstract
Financial toxicity describes the financial burden and distress that can arise for patients, and their family members, as a result of cancer treatment. It includes direct out-of-pocket costs ...for treatment and indirect costs such as travel, time, and changes to employment that can increase the burden of cancer. While high costs of cancer care have threatened the sustainability of access to care for decades, it is only in the past 10 years that the term “financial toxicity” has been popularized to recognize that the financial burdens of care can be just as important as the physical toxicities traditionally associated with cancer therapy. The past decade has seen a rapid growth in research identifying the prevalence and impact of financial toxicity. Research is now beginning to focus on innovations in screening and care delivery that can mitigate this risk. There is a need to determine the optimal strategy for clinicians and cancer centers to address costs of care in order to minimize financial toxicity, promote access to high value care, and reduce health disparities. We review the evolution of concerns over costs of cancer care, the impact of financial burdens on patients, methods to screen for financial toxicity, proposed solutions, and priorities for future research to identify and address costs that threaten the health and quality of life for many patients with cancer.
Abstract
Background
The Coronavirus disease 2019 (Covid-19) pandemic caused an abrupt disruption in clinical care and medical education, putting patients at increased risk for social stressors and ...displacing medical students from traditional clerkships. The pandemic also exposed the need for virtual tools to supplement clinical care and an opportunity to create meaningful roles for learners.
Methods
An interdisciplinary group designed a student-led virtual outreach program for patients with HIV whose care was limited by the pandemic. Patients were identified by clinicians and social workers using a clinic-based registry. Students called patients to conduct needs assessments, provide Covid-19 education, and to facilitate connection to services. Students participated in case-based didactics and workshops on motivational interviewing and patient engagement using virtual tools. Facilitated team meetings were held weekly during which themes of calls were identified.
Results
During a three-month period, five students participated in the outreach program. Two hundred sixteen patients were identified for outreach calls, of which 174 (75.9%) were successfully reached by telephone. Rate of completed phone call did not differ by age or gender. Sixty patients had a preferred language other than English of which 95.6% were reached in their preferred language.
Conclusions
Virtual proactive outreach can be used as a tool to support patients and engage students in clinical care when access to in-person care is limited. This model of care could be adapted to other ambulatory practices and integrated into pre-clerkship curriculum as an introduction to the social history and structural drivers of health (SDOH) (245/350).
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