Clinical, pathologic and molecular findings in 2 Rottweiler littermates with appendicular osteosarcoma.

Appendicular osteosarcoma was diagnosed and treated in a pair of littermate Rottweiler dogs, resulting in distinctly different clinical outcomes despite similar therapy within the context of a prospective, randomized clinical trial (NCI-COTC021/022). Histopathology, immunohistochemistry, mRNA sequencing, and targeted DNA hotspot sequencing techniques were applied to both dogs' tumors to define factors that could underpin their differential response to treatment. We describe the comparison of their clinical, histologic and molecular features, as well as those from a companion cohort of Rottweiler dogs, providing new insight into potential prognostic biomarkers for canine osteosarcoma.

Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial.

Background: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors.

Methods: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors.

Precision Medicine in Veterinary Science.

Precision medicine focuses on the clinical management of the individual patient, not on population-based findings. Successes from human precision medicine inform veterinary oncology. Early evidence of success for canines shows how precision medicine can be integrated into practice.

The logic of recurrent circuits in the primary visual cortex.

Recurrent cortical activity sculpts visual perception by refining, amplifying or suppressing visual input. However, the rules that govern the influence of recurrent activity remain enigmatic. We used ensemble-specific two-photon optogenetics in the mouse visual cortex to isolate the impact of recurrent activity from external visual input.

Genomic analysis across 53 canine cancer types reveals novel mutations and high clinical actionability potential.

A genomic understanding of the oncogenic processes and individual variability of human cancer has steadily fueled improvement in patient outcomes over the past 20 years. Mutations within tumour tissues are routinely assessed through clinical genomic diagnostic assays by academic and commercial laboratories to facilitate diagnosis, prognosis and effective treatment stratification. The application of genomics has unveiled a wealth of mutation-based biomarkers in canine cancers, suggesting that the transformative principles that have revolutionized human cancer medicine can be brought to bear in veterinary oncology.

Novel genomic prognostic biomarkers for dogs with cancer.

Background: Growing evidence from dogs and humans supports the abundance of mutation-based biomarkers in tumors of dogs. Increasing the use of clinical genomic diagnostic testing now provides another powerful data source for biomarker discovery.

Hypothesis: Analyzed clinical outcomes in dogs with cancer profiled using SearchLight DNA, a cancer gene panel for dogs, to identify mutations with prognostic value.

All-optical recreation of naturalistic neural activity with a multifunctional transgenic reporter mouse.

Determining which features of the neural code drive behavior requires the ability to simultaneously read out and write in neural activity patterns with high precision across many neurons. All-optical systems that combine two-photon calcium imaging and targeted photostimulation enable the activation of specific, functionally defined groups of neurons. However, these techniques are unable to test how patterns of activity across a population contribute to computation because of an inability to both read and write cell-specific firing rates.

Cases and context: Mask-related behaviors among U.S. trail visitors during the COVID-19 pandemic.

The challenge of simultaneously providing outdoor recreation opportunities while protecting the public from SARS-CoV-2 virus and COVID-19 transmission, as well as future pandemics, remains foremost on managers' minds. Safe spaces and cultures are paramount for managers and visitors alike. Recommended protective measures against COVID-19 included physically distancing 1.

COVID-19 compliance among urban trail users: Behavioral insights and environmental implications.

Unlabelled: Public green spaces provide physical and mental respite, which have become essential and elevated services during the COVID-19 pandemic. As visitation to public parks and recreation areas increased during the pandemic, the challenge of maintaining visitor safety and protecting environmental resources was exacerbated. A key visitor safety practice during the COVID-19 onset was maintaining a physical distance of six feet (1.

Predicting physical distancing on recreational trails during COVID-19.

Unlabelled: The emergence of Coronavirus 19 led to societal and behavioral changes, including intensified use of many public parks and trails for mental respite and leisure time physical activity. As visitors sought stress-relief in the great outdoors, they also encountered stressful situations as they navigated risk exposure. Recommendations to physically distance between parties was a key component to reduce risk, but compliance is unknown in the outdoor arena.

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel.

Background: A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors.

Methods: 10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m plus nab paclitaxel 220 mg/m every 3 weeks for up to 6 cycles.

Standing in the canine precision medicine knowledge gap: Improving annotation of canine cancer genomic biomarkers through systematic comparative analysis of human cancer mutations in COSMIC.

The accrual of cancer mutation data and related functional and clinical associations have revolutionised human oncology, enabling the advancement of precision medicine and biomarker-guided clinical management. The catalogue of cancer mutations is also growing in canine cancers. However, without direct high-powered functional data in dogs, it remains challenging to interpret and utilise them in research and clinical settings.

Genomic tumor analysis provides clinical guidance for the management of diagnostically challenging cancers in dogs.

Objective: To evaluate the diagnostic, prognostic, and therapeutic utility of a cancer genomic diagnostic assay (SearchLight DNA; Vidium Animal Health) for diagnostically ambiguous cancer cases.

Animals: 69 privately owned dogs with ambiguous cancer diagnoses and for which the genomic assay was performed.

Procedures: Genomic assay reports generated between September 28, 2020, and July 31, 2022, for dogs with malignancy or suspected malignancy were reviewed to determine the assay's clinical utility defined as providing diagnostic clarity, prognostic information, and/or therapeutic options.

Evaluation of a Novel System for RFID Intraoperative Cardiovascular Analytics.

To evaluate a novel technology for real time tracking of RF-Identified (RFID) surgical tools (Biotic System), providing intraoperative data analytics during simulated cardiovascular procedures. Ineffective asset management in the Operating Room (OR) leads to inefficient utilization of resources and contributes to prolonged operative times and increased costs. Analysis of captured data can assist in quantifying instrument utilization, procedure flow, performance and prevention of retained instruments.

Feasibility of circulating tumor DNA analysis in dogs with naturally occurring malignant and benign splenic lesions.

Comparative studies of naturally occurring canine cancers have provided new insight into many areas of cancer research. Development and validation of circulating tumor DNA (ctDNA) analysis in pet dogs can help address diagnostic needs in veterinary as well as human oncology. Dogs have high incidence of naturally occurring spontaneous cancers, demonstrate molecular heterogeneity and clonal evolution during therapy, allow serial sampling of blood from the same individuals during the course of disease progression, and have relatively compressed intervals for disease progression amenable to longitudinal studies.

A pilot study of genomic-guided induction therapy followed by immunotherapy with difluoromethylornithine maintenance for high-risk neuroblastoma.

Background: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies.

Aims: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy.

Methods: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial.

High-performance microbial opsins for spatially and temporally precise perturbations of large neuronal networks.

The biophysical properties of existing optogenetic tools constrain the scale, speed, and fidelity of precise optogenetic control. Here, we use structure-guided mutagenesis to engineer opsins that exhibit very high potency while retaining fast kinetics. These new opsins enable large-scale, temporally and spatially precise control of population neural activity.

Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.

Background: Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear.

Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm.

Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 reexpression.

Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines.

Objective: The development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors.

Methods: For COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available.

Identification of Genetic Susceptibility Factors Associated with Canine Gastric Dilatation-Volvulus.

Canine gastric dilatation-volvulus (GDV) is a common life-threatening condition occurring primarily in large and giant breeds with a 3.9% to 36.7% lifetime risk.

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer.

Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity.