Intricacies of Human-AI Interaction in Dynamic Decision-Making for Precision Oncology: A Case Study in Response-Adaptive Radiotherapy.

Background: Adaptive treatment strategies that can dynamically react to individual cancer progression can provide effective personalized care. Longitudinal multi-omics information, paired with an artificially intelligent clinical decision support system (AI-CDSS) can assist clinicians in determining optimal therapeutic options and treatment adaptations. However, AI-CDSS is not perfectly accurate, as such, clinicians' over/under reliance on AI may lead to unintended consequences, ultimately failing to develop optimal strategies. To investigate such collaborative decision-making process, we conducted a Human-AI interaction case study on response-adaptive radiotherapy (RT). Methods: We designed and conducted a two-phase study for two disease sites and two treatment modalities-adaptive RT for non-small cell lung cancer (NSCLC) and adaptive stereotactic body RT for hepatocellular carcinoma (HCC)-in which clinicians were asked to consider mid-treatment modification of the dose per fraction for a number of retrospective cancer patients without AI-support (Unassisted Phase) and with AI-assistance (AI-assisted Phase). The AI-CDSS graphically presented trade-offs in tumor control and the likelihood of toxicity to organs at risk, provided an optimal recommendation, and associated model uncertainties. In addition, we asked for clinicians' decision confidence level and trust level in individual AI recommendations and encouraged them to provide written remarks. We enrolled 13 evaluators (radiation oncology physicians and residents) from two medical institutions located in two different states, out of which, 4 evaluators volunteered in both NSCLC and HCC studies, resulting in a total of 17 completed evaluations (9 NSCLC, and 8 HCC). To limit the evaluation time to under an hour, we selected 8 treated patients for NSCLC and 9 for HCC, resulting in a total of 144 sets of evaluations (72 from NSCLC and 72 from HCC). Evaluation for each patient consisted of 8 required inputs and 2 optional remarks, resulting in up to a total of 1440 data points. Results: AI-assistance did not homogeneously influence all experts and clinical decisions. From NSCLC cohort, 41 (57%) decisions and from HCC cohort, 34 (47%) decisions were adjusted after AI assistance. Two evaluations (12%) from the NSCLC cohort had zero decision adjustments, while the remaining 15 (88%) evaluations resulted in at least two decision adjustments. Decision adjustment level positively correlated with dissimilarity in decision-making with AI [NSCLC: ρ = 0.53 ( p < 0.001); HCC: ρ = 0.60 ( p < 0.001)] indicating that evaluators adjusted their decision closer towards AI recommendation. Agreement with AI-recommendation positively correlated with AI Trust Level [NSCLC: ρ = 0.59 ( p < 0.001); HCC: ρ = 0.7 ( p < 0.001)] indicating that evaluators followed AI's recommendation if they agreed with that recommendation. The correlation between decision confidence changes and decision adjustment level showed an opposite trend [NSCLC: ρ = -0.24 ( p = 0.045), HCC: ρ = 0.28 ( p = 0.017)] reflecting the difference in behavior due to underlying differences in disease type and treatment modality. Decision confidence positively correlated with the closeness of decisions to the standard of care (NSCLC: 2 Gy/fx; HCC: 10 Gy/fx) indicating that evaluators were generally more confident in prescribing dose fractionations more similar to those used in standard clinical practice. Inter-evaluator agreement increased with AI-assistance indicating that AI-assistance can decrease inter-physician variability. The majority of decisions were adjusted to achieve higher tumor control in NSCLC and lower normal tissue complications in HCC. Analysis of evaluators' remarks indicated concerns for organs at risk and RT outcome estimates as important decision-making factors. Conclusions: Human-AI interaction depends on the complex interrelationship between expert's prior knowledge and preferences, patient's state, disease site, treatment modality, model transparency, and AI's learned behavior and biases. The collaborative decision-making process can be summarized as follows: (i) some clinicians may not believe in an AI system, completely disregarding its recommendation, (ii) some clinicians may believe in the AI system but will critically analyze its recommendations on a case-by-case basis; (iii) when a clinician finds that the AI recommendation indicates the possibility for better outcomes they will adjust their decisions accordingly; and (iv) When a clinician finds that the AI recommendation indicate a worse possible outcome they will disregard it and seek their own alternative approach.

Clinical Outcomes of Patients with Non-Small Cell Lung Cancer Leptomeningeal Disease Following Receipt of EGFR-Targeted Therapy, Immune-Checkpoint Blockade, Intrathecal Chemotherapy, or Radiation Therapy Alone.

BACKGROUND: EGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD). PATIENTS AND METHODS: This is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021. Patients were grouped based on initial LMD treatment: radiotherapy (RT) alone, ETT, ICB, and intrathecal chemotherapy (ITC). RESULTS: EGFR mutation was present in 22 patients (28%). Twenty patients had positive cytology in cerebrospinal fluid, while 60 patients were diagnosed based on MRI with clinical correlation. The RT alone group consisted primarily of whole brain radiation (n = 20; 77%), stereotactic radiation (n = 3; 12%), and palliative spine radiation (n = 2; 7%). There were no significant differences amongst the treatment groups in age, performance status, or neurologic symptoms. Overall, the 6-month overall survival (OS) and craniospinal progression free survival (CS-PFS) were 35% and 24%, respectively. The 6-month OS for the ETT, ICB, ITC, and RT alone groups was 64%, 33%, 57%, and 29% respectively (log-rank P = .026). The 6-month CS-PFS for the ETT, ICB, ITC, and RT alone groups was 43%, 33%, 29%, and 19% respectively (log-rank P = .049). Upon univariate analysis, receipt of ETT compared to RT alone reached significance for OS (HR 0.35, P = .006) and CS-PFS (HR 0.39, P = .013). CONCLUSIONS: The prognosis for patients with NSCLC LMD remains poor overall. However, the receipt of ETT for patients with EGFR-positive disease was associated with improved outcomes.

Novel Definitive Hypofractionated Accelerated Radiation Dose-painting (HARD) for Unresected Soft Tissue Sarcomas.

Purpose: Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/ß, STS may be more responsive to hypofractionated radiation therapy (RT), which is often limited by long-term toxicity risk to surrounding normal tissue. An isotoxic approach using a hypofractionated accelerated radiation dose-painting (HARD) regimen allows for dosing based on clinical risk while sparing adjacent organs at risk. Methods and Materials: We retrospectively identified patients from 2019 to 2022 with unresected STS who received HARD with dose-painting to high, intermediate, and low-risk regions of 3.0 Gy, 2.5 Gy, and 2.0 to 2.3 Gy, respectively, in 20 to 22 fractions. Clinical endpoints included local control, locoregional control, progression free survival, overall survival, and toxicity outcomes. Results: Twenty-seven consecutive patients were identified and had a median age of 68 years and tumor size of 7.0 cm (range, 1.2-21.0 cm). Tumors were most often high-grade (70%), stage IV (70%), located in the extremities (59%), and locally recurrent (52%). With a median follow-up of 33.4 months, there was a 3-year locoregional control rate of 100%. The 3-year overall and progression-free survival were 44.9% and 23.3%, respectively. There were 5 (19%) acute and 2 (7%) late grade 3 toxicities, and there were no grade 4 or 5 toxicities at any point. Conclusions: The HARD regimen is a safe method of dose-escalating STS, with durable 3-year locoregional control. This approach is a promising alternative for unresected STS, though further follow-up is required to determine long-term control and toxicity.

The endosymbiont of Epithemia clementina is specialized for nitrogen fixation within a photosynthetic eukaryote.

Epithemia spp. diatoms contain obligate, nitrogen-fixing endosymbionts, or diazoplasts, derived from cyanobacteria. These algae are a rare example of photosynthetic eukaryotes that have successfully coupled oxygenic photosynthesis with oxygen-sensitive nitrogenase activity. Here, we report a newly-isolated species, E. clementina, as a model to investigate endosymbiotic acquisition of nitrogen fixation. We demonstrate that the diazoplast, which has lost photosynthesis, provides fixed nitrogen to the diatom host in exchange for fixed carbon. To identify the metabolic changes associated with this endosymbiotic specialization, we compared the Epithemia diazoplast with its close, free-living cyanobacterial relative, Crocosphaera subtropica. Unlike C. subtropica, in which nitrogenase activity is temporally separated from photosynthesis, we show that nitrogenase activity in the diazoplast is continuous through the day (concurrent with host photosynthesis) and night. Host and diazoplast metabolism are tightly coupled to support nitrogenase activity: Inhibition of photosynthesis abolishes daytime nitrogenase activity, while nighttime nitrogenase activity no longer requires cyanobacterial glycogen storage pathways. Instead, import of host-derived carbohydrates supports nitrogenase activity throughout the day-night cycle. Carbohydrate metabolism is streamlined in the diazoplast compared to C. subtropica with retention of the oxidative pentose phosphate pathway and oxidative phosphorylation. Similar to heterocysts, these pathways may be optimized to support nitrogenase activity, providing reducing equivalents and ATP and consuming oxygen. Our results demonstrate that the diazoplast is specialized for endosymbiotic nitrogen fixation. Altogether, we establish a new model for studying endosymbiosis, perform a functional characterization of this diazotroph endosymbiosis, and identify metabolic adaptations for endosymbiotic acquisition of a critical biological function.

Coral reefs in transition: Temporal photoquadrat analyses and validation of underwater hyperspectral imaging for resource-efficient monitoring in Guam.

The island of Guam in the west Pacific has seen a significant decrease in coral cover since 2013. Lafac Bay, a marine protected area in northeast Guam, served as a reference site for benthic communities typical of forereefs on the windward side of the island. The staghorn coral Acropora abrotanoides is a dominant and characteristic ecosystem engineer of forereef communities on exposed shorelines. Photoquadrat surveys were conducted in 2015, 2017, and 2019, and a diver-operated hyperspectral imager (i.e., DiveRay) was used to survey the same transects in 2019. Machine learning algorithms were used to develop an automated pipeline to assess the benthic cover of 10 biotic and abiotic categories in 2019 based on hyperspectral imagery. The cover of scleractinian corals did not differ between 2015 and 2017 despite being subjected to a series of environmental disturbances in these years. Surveys in 2019 documented the almost complete decline of the habitat-defining staghorn coral Acropora abrotanoides (a practically complete disappearance from about 10% cover), a significant decrease (~75%) in the cover of other scleractinian corals, and a significant increase (~55%) in the combined cover of bare substrate, turf algae, and cyanobacteria. The drastic change in community composition suggests that the reef at Lafac Bay is transitioning to a turf algae-dominated community. However, the capacity of this reef to recover from previous disturbances suggests that this transition could be reversed, making Lafac Bay an excellent candidate for long-term monitoring. Community analyses showed no significant difference between automatically classified benthic cover estimates derived from the hyperspectral scans in 2019 and those derived from photoquadrats. These findings suggest that underwater hyperspectral imagers can be efficient and effective tools for fast, frequent, and accurate monitoring of dynamic reef communities.

Novel Postoperative Hypofractionated Accelerated Radiation Dose-Painting Approach for Soft Tissue Sarcoma.

Purpose: Hypofractionated radiation therapy (RT) offers benefits in the treatment of soft tissue sarcomas (STS), including exploitation of the lower α/ß, patient convenience, and cost. This study evaluates the acute toxicity of a hypofractionated accelerated RT dose-painting (HARD) approach for postoperative treatment of STS. Methods and Materials: This is a retrospective review of 53 consecutive patients with STS who underwent resection followed by postoperative RT. Standard postoperative RT dosing for R0/R1/gross disease with sequential boost (50 Gy + 14/16/20 Gy in 32-35 fractions) were replaced with dose-painting, which adapts dose based on risk of disease burden, to 50.4 and 63, 64.4, 70 Gy in 28 fractions, respectively. The first 10 patients were replanned with a sequential boost RT approach and dosimetric indices were compared. Time-to-event outcomes, including local control, regional control, distant control, and overall survival, were estimated with Kaplan-Meier analysis. Results: Median follow-up was 25.2 months. Most patients had high-grade (59%) STS of the extremity (63%) who underwent resection with either R1 (40%) or close (36%) margins. Four patients experienced grade 3 acute dermatitis which resolved by the 3-month follow-up visit. The 2-year local control, regional control, distant control, and overall survival were 100%, 92%, 68%, and 86%, respectively. Compared with the sequential boost plan, HARD had a significantly lower field size (total V50 Gy; P = .002), bone V50 (P = .031), and maximum skin dose (P = .008). Overall treatment time was decreased by 4 to 7 fractions, which translated to a decrease in estimated average treatment cost of $3056 (range, $2651-$4335; P < .001). Conclusions: In addition to benefits in cost, convenience, and improved biologic effect in STS, HARD regimen offers a safe treatment approach with dosimetric advantages compared with conventional sequential boost, which may translate to improved long-term toxicity.

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Multi-institutional experience of MR-guided stereotactic body radiation therapy for adrenal gland metastases.

Purpose: While dose escalation is associated with improved local control (LC) for adrenal gland metastases (AGMs), the proximity of gastrointestinal (GI) organs-at-risk (OARs) limits the dose that can be safely prescribed via CT-based stereotactic body radiation therapy (SBRT). The advantages of magnetic resonance-guided SBRT (MRgSBRT), including tumor tracking and online plan adaptation, facilitate safe dose escalation. Methods: This is a multi-institutional review of 57 consecutive patients who received MRgSBRT on a 0.35-T MR linac to 61 AGMs from 2019 to 2021. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and LC, and the Cox proportional hazards model was utilized for univariate analysis (UVA). Results: Median follow up from MRgSBRT was 16.4 months (range [R]: 1.1-39 months). Median age was 67 years (R: 28-84 years). Primary histologies included non-small cell lung cancer (N = 38), renal cell carcinoma (N = 6), and melanoma (N = 5), amongst others. The median maximum diameter was 2.7 cm (R: 0.6-7.6 cm), and most AGMs were left-sided (N = 32). The median dose was 50 Gy (R: 30-60 Gy) in 5-10 fractions with a median BED10 of 100 Gy (R: 48-132 Gy). 45 cases (74 %) required adaptation for at least 1 fraction (median: 4 fractions, R: 0-10). Left-sided AGMs required adaptation in at least 1 fraction more frequently than right-sided AGMs (88 % vs 59 %, p = 0.018). There were 3 cases of reirradiation, including 60 Gy in 10 fractions (N = 1) and 40 Gy in 5 fractions (N = 2). One-year LC, PFS, and OS were 92 %, 52 %, and 78 %, respectively. On UVA, melanoma histology predicted for inferior 1-year LC (80 % vs 93 %, p = 0.012). There were no instances of grade 3+ toxicity. Conclusions: We demonstrate that MRgSBRT achieves favorable early LC and no grade 3 + toxicity despite prescribing a median BED10 of 100 Gy to targets near GI OARs.

Assessment of the utility of underwater hyperspectral imaging for surveying and monitoring coral reef ecosystems.

Technological innovations that improve the speed, scale, reproducibility, and accuracy of monitoring surveys will allow for a better understanding of the global decline in tropical reef health. The DiveRay, a diver-operated hyperspectral imager, and a complementary machine learning pipeline to automate the analysis of hyperspectral imagery were developed for this purpose. To evaluate the use of a hyperspectral imager underwater, the automated classification of benthic taxa in reef communities was tested. Eight reefs in Guam were surveyed and two approaches for benthic classification were employed: high taxonomic resolution categories and broad benthic categories. The results from the DiveRay surveys were validated against data from concurrently conducted photoquadrat surveys to determine their accuracy and utility as a proxy for reef surveys. The high taxonomic resolution classifications did not reliably predict benthic communities when compared to those obtained by standard photoquadrat analysis. At the level of broad benthic categories, however, the hyperspectral results were comparable to those of the photoquadrat analysis. This was particularly true when estimating scleractinian coral cover, which was accurately predicted for six out of the eight sites. The annotation libraries generated for this study were insufficient to train the model to fully account for the high biodiversity on Guam's reefs. As such, prediction accuracy is expected to improve with additional surveying and image annotation. This study is the first to directly compare the results from underwater hyperspectral scanning with those from traditional photoquadrat survey techniques across multiple sites with two levels of identification resolution and different degrees of certainty. Our findings show that dependent on a well-annotated library, underwater hyperspectral imaging can be used to quickly, repeatedly, and accurately monitor and map dynamic benthic communities on tropical reefs using broad benthic categories.

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

PURPOSE: HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. METHODS: A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. RESULTS: A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8 months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2 months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3 months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. CONCLUSIONS: SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

Neoadjuvant Simultaneous Integrated Boost Radiation Therapy Improves Clinical Outcomes for Retroperitoneal Sarcoma.

PURPOSE: Neoadjuvant radiation therapy (RT) with standard techniques (ST) offers a modest benefit in retroperitoneal sarcoma (RPS). As the high-risk region (HRR) at risk for a positive surgical margin and recurrence is posterior and away from radiosensitive organs at risk, using a simultaneous integrated boost (SIB) allows targeted dose escalation to the HRR while sparing these organs. We hypothesized that neoadjuvant SIB RT can improve disease control compared with ST, without increasing toxicity. METHODS AND MATERIALS: We retrospectively identified patients with resectable nonmetastatic RPS from 2000 to 2021 who received neoadjuvant RT of 180 to 200 cGy/fraction to standard volumes. SIB patients received 205 to 230 cGy/fraction to the appropriate HRR. Clinical endpoints included abdominopelvic control (APC), recurrence-free survival (RFS), overall survival (OS), and acute toxicity. RESULTS: With a median follow-up of 57 months (95% confidence interval [CI], 50-64), there were 103 patients with RPS who received either ST (n = 69) or SIB (n = 34) RT. Median standard volume dose was 5000 cGy (ST) and 4500 cGy (SIB), with a median HRR SIB dose of 5750 cGy. Liposarcomas (79% vs 53%; P = .004) and cT4 tumors (59% vs 19%; P < .001) were more common in the SIB cohort, without a significant difference in the rate of resection (82% vs 81%; P = .88) or R1 margin (53.5% vs 50%; P = .36); there were no R2 resections. SIB was associated with a significant improvement in 5-year APC (96% vs 70%; P = .046) and RFS (60.2% vs 36.3%; P = .036), with a nonsignificant OS difference (90.1% vs 67.5%; P = .164). On multivariable analysis, SIB remained a predictor for APC (hazard ratio, 0.07; 95% CI, 0.01-0.74; P = .027) and RFS (hazard ratio, 0.036; 95% CI, 0.13-0.98; P = .045). SIB showed no significant detriment in toxicity, albeit with a lower rate of overall grade 3 acute toxicity (3% vs 22%; P = .023) compared with ST. CONCLUSIONS: In RPS, dose escalation with neoadjuvant SIB RT may be independently associated with improved APC and RFS, without a detriment in toxicity, compared with ST. With the addition of standard RT having only a modest benefit compared with surgery alone, our study suggests that future prospective studies evaluating for the benefit of SIB RT should be considered.

Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation.

Glucose is a universal bioenergy source; however, its role in controlling protein interactions is unappreciated, as are its actions during differentiation-associated intracellular glucose elevation. Azido-glucose click chemistry identified glucose binding to a variety of RNA binding proteins (RBPs), including the DDX21 RNA helicase, which was found to be essential for epidermal differentiation. Glucose bound the ATP-binding domain of DDX21, altering protein conformation, inhibiting helicase activity, and dissociating DDX21 dimers. Glucose elevation during differentiation was associated with DDX21 re-localization from the nucleolus to the nucleoplasm where DDX21 assembled into larger protein complexes containing RNA splicing factors. DDX21 localized to specific SCUGSDGC motif in mRNA introns in a glucose-dependent manner and promoted the splicing of key pro-differentiation genes, including GRHL3, KLF4, OVOL1, and RBPJ. These findings uncover a biochemical mechanism of action for glucose in modulating the dimerization and function of an RNA helicase essential for tissue differentiation.

Non-cyanobacterial diazotrophs: global diversity, distribution, ecophysiology, and activity in marine waters.

Biological dinitrogen (N2) fixation supplies nitrogen to the oceans, supporting primary productivity, and is carried out by some bacteria and archaea referred to as diazotrophs. Cyanobacteria are conventionally considered to be the major contributors to marine N2 fixation, but non-cyanobacterial diazotrophs (NCDs) have been shown to be distributed throughout ocean ecosystems. However, the biogeochemical significance of marine NCDs has not been demonstrated. This review synthesizes multiple datasets, drawing from cultivation-independent molecular techniques and data from extensive oceanic expeditions, to provide a comprehensive view into the diversity, biogeography, ecophysiology, and activity of marine NCDs. A NCD nifH gene catalog was compiled containing sequences from both PCR-based and PCR-free methods, identifying taxa for future studies. NCD abundances from a novel database of NCD nifH-based abundances were colocalized with environmental data, unveiling distinct distributions and environmental drivers of individual taxa. Mechanisms that NCDs may use to fuel and regulate N2 fixation in response to oxygen and fixed nitrogen availability are discussed, based on a metabolic analysis of recently available Tara Oceans expedition data. The integration of multiple datasets provides a new perspective that enhances understanding of the biology, ecology, and biogeography of marine NCDs and provides tools and directions for future research.

Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. METHODS: In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. FINDINGS: 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. INTERPRETATION: First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. FUNDING: Bristol Myers Squibb Rare Population Malignancy Program.

Community assessment of crustose calcifying red algae as coral recruitment substrates.

Successful recruitment of invertebrate larvae to reef substrates is essential to the health of tropical coral reef ecosystems and to their capacity to recover from disturbances. Crustose calcifying red algae (CCRA) are a species rich group of seaweeds that have been identified as important recruitment substrates for scleractinian corals. Most studies on the settlement preference of coral larvae on CCRA use morphological species identifications that can lead to unreliable species identification and do not allow for examining species-specific interactions between coral larvae and CCRA. Accurate identifications of CCRA species is important for coral reef restoration and management to assess CCRA community composition and to detect CCRA species that are favored as coral recruitment substrates. In this study, DNA sequence analysis, was used to identify CCRA species to (1) investigate the species richness and community composition of CCRA on experimental coral recruitment tiles and (2) assess if the coral Acropora surculosa preferred any of these CCRA species as recruitment substrates. The CCRA community assemblages on the coral recruitment tiles was species-rich, comprising 27 distinct CCRA species of the orders Corallinales and Peyssonneliales which constitute new species records for Guam. Lithophylloideae sp. 1 (Corallinales) was the CCRA species that was significantly favored by coral larvae as a recruitment substrate. Lithophylloideae sp. 1 showed to hold a valuable ecological role for coral larval recruitment preference. Lithophylloideae sp. 1 had the highest benthic cover on the recruitment tiles and contained most A. surculosa recruits. DNA barcoding revealed a high taxonomic diversity of CCRA species on a microhabitat scale and provided detailed insight into the species-specific ecological interactions between CCRA and corals. With a steady decline in coral cover, detailed information on species interactions that drive reef recovery is valuable for the planning of marine management actions and restoration efforts.

Diffractive deep neural network adjoint assist or (DNA)2: a fast and efficient nonlinear diffractive neural network implementation.

The recent advent of diffractive deep neural networks or D2NNs has opened new avenues for the design and optimization of multi-functional optical materials; despite the effectiveness of the D2NN approach, there is a need for making these networks as well as the design algorithms more general and computationally efficient. The work demonstrated in this paper brings significant improvements to both these areas by introducing an algorithm that performs inverse design on fully nonlinear diffractive deep neural network - assisted by an adjoint sensitivity analysis which we term (DNA)2. As implied by the name, the procedure optimizes the parameters associated with the diffractive elements including both linear and nonlinear amplitude and phase contributions as well as the spacing between planes via adjoint sensitivity analysis. The computation of all gradients can be obtained in a single GPU compatible step. We demonstrate the capability of this approach by designing several types of three layered D2NN to classify 8800 handwritten digits taken from the MNIST database. In all cases, the D2NN was able to achieve a minimum 94.64% classification accuracy with 192 minutes or less of training.

Evolving management of HER2+ breast cancer brain metastases and leptomeningeal disease.

Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach. Herein, a team of radiation oncologists, medical oncologists, neuro-oncologists, and breast surgeon created a review of the evolving management of HER2-positive BCBM and LMD. We assess the epidemiology, diagnosis, and evolving treatment options for patients with HER2-positive BCBM and LMD, as well as the ongoing prospective clinical trials enrolling these patients. The management of HER2-positive BCBM and LMD represents an increasingly common challenge that involves the coordination of local and systemic therapy. Advances in systemic therapy have resulted in an improved prognosis, and promising targeted therapies currently under prospective investigation have the potential to further benefit these patients.

Development of a ligand for in vivo imaging of mutant huntingtin in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.