Simultaneous invasive and non-invasive recordings in humans: a novel Rosetta stone for deciphering brain activity.

Simultaneous noninvasive and invasive electrophysiological recordings provide a unique opportunity to achieve a comprehensive understanding of human brain activity, much like a Rosetta stone for human neuroscience. In this review we focus on the increasingly-used powerful combination of intracranial electroencephalography (iEEG) with scalp electroencephalography (EEG) or magnetoencephalography (MEG). We first provide practical insight on how to achieve these technically challenging recordings. We then provide examples from clinical research on how simultaneous recordings are advancing our understanding of epilepsy. This is followed by the illustration of how human neuroscience and methodological advances could benefit from these simultaneous recordings. We conclude with a call for open data sharing and collaboration, while ensuring neuroethical approaches and argue that only with a true collaborative approach the promises of simultaneous recordings will be fulfilled.

Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy.

Characterization of the diverse malignant and stromal cell states that make up soft tissue sarcomas and their correlation with patient outcomes has proven difficult using fixed clinical specimens. Here, we employed EcoTyper, a machine-learning framework, to identify the fundamental cell states and cellular ecosystems that make up sarcomas on a large scale using bulk transcriptomes with clinical annotations. We identified and validated 23 sarcoma-specific, transcriptionally defined cell states, many of which were highly prognostic of patient outcomes across independent datasets. We discovered three conserved cellular communities or ecotypes associated with underlying genomic alterations and distinct clinical outcomes. We show that one ecotype defined by tumor-associated macrophages and epithelial-like malignant cells predicts response to immune-checkpoint inhibition but not chemotherapy and validate our findings in an independent cohort. Our results may enable identification of patients with soft tissue sarcomas who could benefit from immunotherapy and help develop new therapeutic strategies.

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.

Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.

Investigating the tissue specificity and prognostic impact of cis-regulatory cancer risk variants.

The tissue-specific incidence of cancers and their genetic basis are poorly understood. Although prior studies have shown global correlation across tissues for cancer risk single-nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS), any shared functional regulation of gene expression on a per SNP basis has not been well characterized. We set to quantify cis-mediated gene regulation and tissue sharing for SNPs associated with eight common cancers. We identify significant tissue sharing for individual SNPs and global enrichment for breast, colorectal, and Hodgkin lymphoma cancer risk SNPs in multiple tissues. In addition, we observe increasing tissue sharing for cancer risk SNPs overlapping with super-enhancers for breast cancer and Hodgkin lymphoma providing further evidence of tissue specificity. Finally, for genes under cis-regulation by breast cancer SNPs, we identify a phenotype characterized by low expression of tumor suppressors and negative regulators of the WNT pathway associated with worse freedom from progression and overall survival in patients who eventually develop breast cancer. Our results introduce a paradigm for functionally annotating individual cancer risk SNPs and will inform the design of future translational studies aimed to personalize assessment of inherited cancer risk across tissues.

Monitoring Sarcoma Response to Immune Checkpoint Inhibition and Local Cryotherapy with Circulating Tumor DNA Analysis.

PURPOSE: Immune checkpoint inhibition has led to promising responses in soft tissue sarcomas (STS), but the majority of patients do not respond and biomarkers of response will be crucial. Local ablative therapies may augment systemic responses to immunotherapy. We evaluated circulating tumor DNA (ctDNA) as a biomarker of response in patients treated on a trial combining immunotherapy with local cryotherapy for advanced STS. PATIENTS AND METHODS: We enrolled 30 patients with unresectable or metastatic STS to a phase II clinical trial. Patients received ipilimumab and nivolumab for four doses followed by nivolumab alone with cryoablation performed between cycles 1 and 2. The primary endpoint was objective response rate (ORR) by 14 weeks. Personalized ctDNA analysis using bespoke panels was performed on blood samples collected prior to each immunotherapy cycle. RESULTS: ctDNA was detected in at least one sample for 96% of patients. Pretreatment ctDNA allele fraction was negatively associated with treatment response, progression-free survival (PFS), and overall survival (OS). ctDNA increased in 90% of patients from pretreatment to postcryotherapy, and patients with a subsequent decrease in ctDNA or undetectable ctDNA after cryotherapy had significantly better PFS. Of the 27 evaluable patients, the ORR was 4% by RECIST and 11% by irRECIST. Median PFS and OS were 2.7 and 12.0 months, respectively. No new safety signals were observed. CONCLUSIONS: ctDNA represents a promising biomarker for monitoring response to treatment in patients with advanced STS, warranting future prospective studies. Combining cryotherapy and immune checkpoint inhibitors did not increase the response rate of STS to immunotherapy.

Aortic valve surgery for native valve endocarditis in extreme obesity.

Surgical aortic valve replacement represents a class one indication in the setting of aortic valve endocarditis and decompensated heart failure secondary to aortic regurgitation as per the European Society of Cardiology. However, extreme obesity, whereby the body mass index (BMI) >40 kg/m2, represents a challenging cohort of patients. Performing cardiac surgery in the bariatric population is fraught with challenges pertaining to intraoperative issues of surgical access and approach. We describe the case of a 45-year-old gentleman who had previous been diagnosed with infective endocarditis of the aortic valve and with a BMI of 68.2 (228 kg). Surgical aortic valve replacement in extreme obesity is associated with deep sternal wound infection, requirement and duration of mechanical ventilation, atrial fibrillation and renal failure. The 'obesity paradox' of overweight and class I obesity (BMI <35) has demonstrated favourable long-term results compared with underweight patients or even those with normal BMI undergoing cardiac surgery.

A Century of Fractionated Radiotherapy: How Mathematical Oncology Can Break the Rules.

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the past century and does not account for the development of radioresistance during treatment. Even if under-optimized, deviating from a century of successful therapy delivered in FED can be difficult. One way of exploring the infinite space of fraction size and scheduling to identify optimal fractionation schedules is through mathematical oncology simulations that allow for in silico evaluation. This review article explores the evidence that current fractionation promotes the development of radioresistance, summarizes mathematical solutions to account for radioresistance, both in the curative and non-curative setting, and reviews current clinical data investigating non-FED fractionated radiotherapy.

Reinforcement learning and its connections with neuroscience and psychology.

Reinforcement learning methods have recently been very successful at performing complex sequential tasks like playing Atari games, Go and Poker. These algorithms have outperformed humans in several tasks by learning from scratch, using only scalar rewards obtained through interaction with their environment. While there certainly has been considerable independent innovation to produce such results, many core ideas in reinforcement learning are inspired by phenomena in animal learning, psychology and neuroscience. In this paper, we comprehensively review a large number of findings in both neuroscience and psychology that evidence reinforcement learning as a promising candidate for modeling learning and decision making in the brain. In doing so, we construct a mapping between various classes of modern RL algorithms and specific findings in both neurophysiological and behavioral literature. We then discuss the implications of this observed relationship between RL, neuroscience and psychology and its role in advancing research in both AI and brain science.

Laminated Object Manufacturing of 3D-Printed Laser-Induced Graphene Foams.

Laser-induced graphene (LIG), a graphene structure synthesized by a one-step process through laser treatment of commercial polyimide (PI) film in an ambient atmosphere, has been shown to be a versatile material in applications ranging from energy storage to water treatment. However, the process as developed produces only a 2D product on the PI substrate. Here, a 3D LIG foam printing process is developed on the basis of laminated object manufacturing, a widely used additive-manufacturing technique. A subtractive laser-milling process to yield further refinements to the 3D structures is also developed and shown here. By combining both techniques, various 3D graphene objects are printed. The LIG foams show good electrical conductivity and mechanical strength, as well as viability in various energy storage and flexible electronic sensor applications.

True Lumen Perfusion Technique for Extensive Aortic Dissections Involving the Neck and Femoral Vessels.

Cannulation and perfusion in extensive aortic dissection involving the neck and femoral vessels is challenging in view of false lumen cannulation and attendant malperfusion syndromes. Although a number of methods have been described, our technique of cannulation and perfusion through right atrial-to-left atrial bypass and innominate artery transection ensures adequate brain perfusion and visceral organ true lumen perfusion during the entire duration of cardiopulmonary bypass. This procedure can be applied to all varieties of extensive type A aortic dissections involving the neck and femoral vessels. A step-by-step of how to do it has been described.