Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER: NCT02376699.

Initial impacts of the COVID-19 pandemic on Australian fisheries production, research organisations and assessment: shocks, responses and implications for decision support and resilience.

Australia's fisheries have experience in responding individually to specific shocks to stock levels (for example, marine heatwaves, floods) and markets (for example, global financial crisis, food safety access barriers). The COVID-19 pandemic was, however, novel in triggering a series of systemic shocks and disruptions to the activities and operating conditions for all Australia's commercial fisheries sectors including those of the research agencies that provide the information needed for their sustainable management. While these disruptions have a single root cause-the public health impacts and containment responses to the COVID-19 pandemic-their transmission and effects have been varied. We examine both the impacts on Australian fisheries triggered by measures introduced by governments both internationally and domestically in response to the COVID-19 pandemic outbreak, and the countermeasures introduced to support continuity in fisheries and aquaculture production and supply chains. Impacts on fisheries production are identified by comparing annual and monthly catch data for Australia's commercial fisheries in 2020 with averages for the last 4-5 years. We combine this with a survey of the short-term disruption to and impacts on research organisations engaged in fisheries monitoring and assessment and the adaptive measures they deployed. The dominant impact identified was triggered by containment measures both within Australia and in export receiving countries which led to loss of export markets and domestic dine-in markets for live or fresh seafood. The most heavily impact fisheries included lobster and abalone (exported live) and specific finfishes (exported fresh or sold live domestically), which experienced short-term reductions in both production and price. At the same time, improved prices and demand for seafood sold into domestic retail channels were observed. The impacts observed were both a function of the disruptions due to the COVID-19 pandemic and the countermeasures and support programs introduced by various national and state-level governments across Australia to at least partly mitigate negative impacts on harvesting activities and supply chains. These included protecting fisheries activities from specific restrictive COVID-19 containment measures, pro-actively re-establishing freight links, supporting quota roll-overs, and introducing wage and businesses support packages. Fisheries research organisations were impacted to various degrees, largely determined by the extent to which their field monitoring activities were protected from specific restrictive COVID-19 containment measures by their state-level governments. Responses of these organisations included reducing fisheries dependent and independent data collection as required while developing strategies to continue to provide assessment services, including opportunistic innovations to harvest data from new data sources. Observed short run impacts of the COVID-19 pandemic outbreak has emphasised both the vulnerability of fisheries dependent on export markets, live or fresh markets, and long supply chains and the resilience of fisheries research programs. We suggest that further and more comprehensive analysis over a longer time period of the long-run impacts of subsequent waves of variants, extended pandemic containment measures, autonomous and planned adaptive responses would be beneficial for the development of more effective counter measures for when the next major external shock affects Australian fisheries.

Outpatient administration of paclitaxel, ifosfamide, and cisplatin (TIP) for germ cell tumor.

PURPOSE: The combination of paclitaxel, ifosfamide, and cisplatin (TIP) is frequently used for the treatment of metastatic germ cell tumors. Due to complex supportive care and infusion requirements, TIP is typically given in the inpatient setting. This analysis describes the development and implementation of a protocol for complete outpatient administration of TIP chemotherapy. METHODS: From July 2020 to June 2021, adults receiving TIP for germ cell tumor at University of Michigan Rogel Cancer Center were evaluated for outpatient administration. The primary outcome was number of inpatient bed days saved by giving outpatient TIP chemotherapy, with the goal of giving 75% of TIP cycles outpatient. Patients receiving outpatient TIP were also assessed for chemotherapy dose reduction or delays and acute toxicities of kidney injury, encephalopathy, and hemorrhagic cystitis. RESULTS: From July 2020 to July 2021, three patients received 13 cycles of TIP. Ten cycles (77%) were administered in the outpatient setting, resulting in a savings of 50 inpatient bed days in one year. No patients required a dose reduction or delay in chemotherapy or experienced acute kidney injury, encephalopathy, or hemorrhagic cystitis during outpatient TIP treatment. CONCLUSION: Despite logistic and supportive care challenges, TIP can be administered completely in the outpatient setting.

First-in-Human Study of INCB062079, a Fibroblast Growth Factor Receptor 4 Inhibitor, in Patients with Advanced Solid Tumors.

INTRODUCTION: Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. METHODS: This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. RESULTS: Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations < 40.9 ng/mL and concomitant prophylactic bile acid sequestrant treatment. No additional DLTs were reported at 10 and 15 mg twice daily; higher doses were not assessed. The most common toxicity was diarrhea (60.9%). INCB062079 exposure was dose-proportional; FGF19 and bile acid/C4 concentrations increased with exposure. One partial response was achieved (15 mg twice daily; ovarian cancer; FGF/FGFR status unknown; duration of response, 7.5 months); two patients had stable disease. CONCLUSIONS: With C4 cut-off and prophylactic bile acid sequestrant implementation, INCB062079 demonstrated a manageable safety profile and evidence of target inhibition. In view of the rarity of FGF19/FGFR4 alterations and slow patient accrual, the study was terminated before establishing an MTD.

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab.

PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

A Phase 2 Trial of Nab-paclitaxel in Combination With Anti-PD1 Therapy in Advanced Urothelial Cancer.

PURPOSE: Immune checkpoint inhibitor therapy and nab-paclitaxel have each shown efficacy in platinum-refractory advanced urothelial cancer. We conducted a single-arm phase 2 trial of the combination of nab-paclitaxel and pembrolizumab in platinum-refractory or cisplatin-ineligible advanced urothelial cancer (NCT03240016). MATERIALS AND METHODS: Eligible patients had RECIST 1.1 measurable and cisplatin-ineligible or platinum-refractory advanced urothelial cancer. Patients received nab-paclitaxel at starting dose of 125 mg/m2 intravenously on days 1 and 8 and pembrolizumab 200 mg intravenously on day 1 in 21-day cycles until progression, intolerable toxicity, or death. Nab-paclitaxel was permitted to be discontinued after 6 cycles. The nab-paclitaxel starting dose was reduced to 100 mg/m2 after planned interim analysis. Primary end point was overall response rate by RECIST 1.1. Secondary end points included safety/toxicity, duration of response, progression-free survival), and overall survival. RESULTS: Between February 2018 and April 2021, 36 response-evaluable patients were enrolled. There was an equal split of platinum-refractory and cisplatin-ineligible patients. Confirmed overall response rate was 50.0% (18/36) including 3 complete and 15 partial responses; 31/36 patients experienced some tumor shrinkage. At a median follow-up of 19.7 months, median duration of response was 4.4 months (95% CI: 4.0-8.6), median progression-free survival 6.8 months (95% CI: 4.4-not reached), and median overall survival 18.2 months (95% CI: 10.6-not reached). Grade ≥3 adverse events occurred in 21/36 patients including fatigue (n=6) and anemia (n=4). Ten patients had immune-mediated adverse events. CONCLUSIONS: The combination of nab-paclitaxel and pembrolizumab exhibited promising activity in advanced urothelial cancer and warrants further study in this population. After reduction in nab-paclitaxel starting dose, no unanticipated or unexpected toxicities emerged.

Confining the growth of mesoporous silica films into nanospaces: towards surface nanopatterning.

The combination of lithographic methods and sol gel bottom-up techniques is a promising approach for nanopatterning substrates. The integration and scalable fabrication of such substrates are of great interest for the development of nanowire-based materials opening potentialities in new technologies. We demonstrate the deposition of ordered mesoporous silica into nanopatterned silica substrates by dip coating. Using scanning electron microscopy and grazing incidence small angle X-ray scattering, the effect of the sol composition on the pore ordering was probed. Optimising the sol composition using anodic alumina membranes as confined spaces, we showed how the pH controlled the transformation from circular to columnar mesophase. Vertical mesopores were obtained with very good repeatability. The effect of the sol chemistry on the surfactant curvature was then shown to be similar in nanopatterned substrates made by e-beam lithography.

Prostate Cancer With Peritoneal Carcinomatosis: A Robotic-assisted Radical Prostatectomy-based Case Series.

OBJECTIVE: To aid in the diagnosis and treatment of patients with metastatic tumor seeding, an exceedingly rare phenomenon following minimally invasive urological surgery, additional case reports are needed. MATERIALS AND METHODS: We report our experience with patients determined to have peritoneal carcinomatosis following robotic-assisted radical prostatectomy (RARP) and provide a descriptive summary of these unique cases. RESULTS: Five cases of peritoneal carcinomatosis were identified, all of which occurred relatively late-between 8 and 13 years-following RARP. Four of the 5 cases had T3 disease at the time of prostatectomy. 68Ga-PSMA PET identified peritoneal carcinomatosis in 3 of 5 cases. CONCLUSION: Certain clinical factors, such as advanced pathologic stage at the time of prostatectomy, may predict risk for carcinomatosis following RARP. Additionally, next-generation imaging modalities, such as PSMA PET, may aid in identifying these metastases and are likely to identify increasing numbers of these patients as next-generation imaging becomes more widely available. Continued documentation and classification of this atypical presentation are needed to improve our understanding and management of this phenomenon.

Brucella suis and farm biosecurity: assessing risk in pigs raised outdoors in New York State.

OBJECTIVE: To evaluate the Brucella suis exposure status of pigs raised with outdoor access on farms in New York State and assess biosecurity and management practices of those farms. ANIMALS: 250 pigs that were raised for commercial purposes, had access to the outdoors, and were > 4 months of age on 24 farms in New York State. PROCEDURES: Farms were randomly selected from a sampling frame generated for the study and contacted to recruit them to participate. Participating farms were provided a questionnaire to complete. Up to 30 pigs per farm were tested for serum anti-Brucella antibodies. RESULTS: Farm were classified as seasonal and year round. Seasonal farms raised pigs for slaughter, and year-round farms bred pigs, raised them for slaughter, and sold live pigs to others to raise. None of the 250 pigs had antibodies to Brucella spp. Nevertheless, the biosecurity assessment revealed a need for enhanced practices in procurement and management of swine in a wide range of areas. CLINICAL RELEVANCE: There was no evidence for ongoing B suis infection on these swine farms in New York State, but biosecurity and preventive practices at these facilities could be improved to prevent the introduction and spread of B suis and other pathogens.

The Effects of Hydrogen Annealing on Carbon Nanotube Field-Effect Transistors.

We have systematically investigated the effects of hydrogen annealing on Ni- and Al-contacted carbon nanotube field-effect transistors (CNTFETs), whose work functions have not been affected by hydrogen annealing. Measured results show that the electronic properties of single-walled carbon nanotubes are modified by hydrogen adsorption. The Ni-contacted CNTFETs, which initially showed metallic behavior, changed their p-FET behavior with a high on-current over 10 µA after hydrogen annealing. The on-current of the as-made p-FETs is much improved after hydrogen annealing. The Al-contacted CNTFETs, which initially showed metallic behavior, showed unipolar p-FET behavior after hydrogen annealing. We analyzed the energy band diagrams of the CNTFETs to explain experimental results, finding that the electron affinity and the bandgap of single-walled carbon nanotubes changed after hydrogen annealing. These results are consistent with previously reported ab initio calculations.

Ecological causes of fluctuating natural selection on habitat choice in an amphibian.

We estimated natural selection targeting three traits related to habitat choice in a frog (Pseudacris maculata) breeding in pools on the rocky shores of Isle Royale, Michigan, over 16 years. Our aim was to identify the form and ecological causes of annual variation in directional and correlational selection as expressed in the survival and growth of tadpoles. We found directional selection favoring early breeding, but pool choice was under weak stabilizing selection. However, the form of stabilizing selection and the position of the optimum trait value shifted among years with the severity of disturbance and the intensity of biotic interactions. In years when wave wash and pool desiccation were severe, selection shifted to favor tadpoles in habitats where these risks were less pronounced. If predatory dragonfly larvae were abundant, selection favored tadpoles in small pools where dragonflies did not occur. When intraspecific competition was strong, selection favored early broods within a broader range of pool types. The agents of selection in this study-biotic interactions and disturbance-are common to many ecological systems and frequently exhibit temporal variation; this suggests that fluctuating selection may be widespread in natural populations.

Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.

BACKGROUND: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. METHODS: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules. RESULTS: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8). CONCLUSIONS: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity. CLINICAL TRIAL REGISTRATION: NCT01351103.

The contribution of water radiolysis to marine sedimentary life.

Water radiolysis continuously produces H2 and oxidized chemicals in wet sediment and rock. Radiolytic H2 has been identified as the primary electron donor (food) for microorganisms in continental aquifers kilometers below Earth's surface. Radiolytic products may also be significant for sustaining life in subseafloor sediment and subsurface environments of other planets. However, the extent to which most subsurface ecosystems rely on radiolytic products has been poorly constrained, due to incomplete understanding of radiolytic chemical yields in natural environments. Here we show that all common marine sediment types catalyse radiolytic H2 production, amplifying yields by up to 27X relative to pure water. In electron equivalents, the global rate of radiolytic H2 production in marine sediment appears to be 1-2% of the global organic flux to the seafloor. However, most organic matter is consumed at or near the seafloor, whereas radiolytic H2 is produced at all sediment depths. Comparison of radiolytic H2 consumption rates to organic oxidation rates suggests that water radiolysis is the principal source of biologically accessible energy for microbial communities in marine sediment older than a few million years. Where water permeates similarly catalytic material on other worlds, life may also be sustained by water radiolysis.

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.

IMPORTANCE: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. OBJECTIVE: To determine which patients derived the greatest degree of clinical benefit from NGS profiling. DESIGN, SETTING, AND PARTICIPANTS: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. MAIN OUTCOMES AND MEASURES: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. RESULTS: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. CONCLUSIONS AND RELEVANCE: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.

PURPOSE: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC). METHODS: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). RESULTS: The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT. CONCLUSION: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

Propensity-Matched Cost of Clostridioides difficile Infection Overdiagnosis.

BACKGROUND: Clostridioides difficile is the leading health care-associated pathogen, but clinicians lack a test that can reliably differentiate colonization from infection. Health care costs attributed to C. difficile are substantial, but the economic burden associated with C. difficile false positives is poorly understood. METHODS: A propensity score matching model for cost per hospitalization was developed to estimate the costs of both true infection and false positives. Predictors of C. difficile positivity used to estimate the propensity score were age, Charlson comorbidity index, white cell count, and creatinine. We used polymerase chain reaction (PCR) cycle threshold to identify and compare 3 groups: (1) true infection, (2) C. difficile colonization, and (3) C. difficile negative. RESULTS: A positive test was associated with $3018 higher unadjusted hospital cost. Among the 3 comparisons made with propensity-matched negative controls (all positives [+$179; P = .934], true positives [-$1892; P = .100], and colonized positives), only colonization was associated with significantly increased (+$3418; P = .012) cost. Differences in lengths of stay (all positives 0 days, P = .126; true 0 days, P = .919; colonized 1 day, P = .019) appeared to underly cost differences. CONCLUSIONS: In the first C. difficile cost analysis to utilize PCR cycle threshold to differentiate colonization, we found high propensity-matched hospital costs associated with colonized but not true positives. This unexpected finding may be due to misdiagnosis of non-C. difficile diarrhea or unadjusted factors associated with colonization.

Multigene Profiling of Circulating Tumor Cells (CTCs) for Prognostic Assessment in Treatment-Naïve Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.

Atribacteria Reproducing over Millions of Years in the Atlantic Abyssal Subseafloor.

How microbial metabolism is translated into cellular reproduction under energy-limited settings below the seafloor over long timescales is poorly understood. Here, we show that microbial abundance increases an order of magnitude over a 5 million-year-long sequence in anoxic subseafloor clay of the abyssal North Atlantic Ocean. This increase in biomass correlated with an increased number of transcribed protein-encoding genes that included those involved in cytokinesis, demonstrating that active microbial reproduction outpaces cell death in these ancient sediments. Metagenomes, metatranscriptomes, and 16S rRNA gene sequencing all show that the actively reproducing community was dominated by the candidate phylum "Candidatus Atribacteria," which exhibited patterns of gene expression consistent with fermentative, and potentially acetogenic, metabolism. "Ca. Atribacteria" dominated throughout the 8 million-year-old cored sequence, despite the detection limit for gene expression being reached in 5 million-year-old sediments. The subseafloor reproducing "Ca. Atribacteria" also expressed genes encoding a bacterial microcompartment that has potential to assist in secondary fermentation by recycling aldehydes and, thereby, harness additional power to reduce ferredoxin and NAD+ Expression of genes encoding the Rnf complex for generation of chemiosmotic ATP synthesis were also detected from the subseafloor "Ca Atribacteria," as well as the Wood-Ljungdahl pathway that could potentially have an anabolic or catabolic function. The correlation of this metabolism with cytokinesis gene expression and a net increase in biomass over the million-year-old sampled interval indicates that the "Ca Atribacteria" can perform the necessary catabolic and anabolic functions necessary for cellular reproduction, even under energy limitation in millions-of-years-old anoxic sediments.IMPORTANCE The deep subseafloor sedimentary biosphere is one of the largest ecosystems on Earth, where microbes subsist under energy-limited conditions over long timescales. It remains poorly understood how mechanisms of microbial metabolism promote increased fitness in these settings. We discovered that the candidate bacterial phylum "Candidatus Atribacteria" dominated a deep-sea subseafloor ecosystem, where it exhibited increased transcription of genes associated with acetogenic fermentation and reproduction in million-year-old sediment. We attribute its improved fitness after burial in the seabed to its capabilities to derive energy from increasingly oxidized metabolites via a bacterial microcompartment and utilize a potentially reversible Wood-Ljungdahl pathway to help meet anabolic and catabolic requirements for growth. Our findings show that "Ca Atribacteria" can perform all the necessary catabolic and anabolic functions necessary for cellular reproduction, even under energy limitation in anoxic sediments that are millions of years old.

From People to Panthera: Natural SARS-CoV-2 Infection in Tigers and Lions at the Bronx Zoo.

Despite numerous barriers to transmission, zoonoses are the major cause of emerging infectious diseases in humans. Among these, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and ebolaviruses have killed thousands; the human immunodeficiency virus (HIV) has killed millions. Zoonoses and human-to-animal cross-species transmission are driven by human actions and have important management, conservation, and public health implications. The current SARS-CoV-2 pandemic, which presumably originated from an animal reservoir, has killed more than half a million people around the world and cases continue to rise. In March 2020, New York City was a global epicenter for SARS-CoV-2 infections. During this time, four tigers and three lions at the Bronx Zoo, NY, developed mild, abnormal respiratory signs. We detected SARS-CoV-2 RNA in respiratory secretions and/or feces from all seven animals, live virus in three, and colocalized viral RNA with cellular damage in one. We produced nine whole SARS-CoV-2 genomes from the animals and keepers and identified different SARS-CoV-2 genotypes in the tigers and lions. Epidemiologic and genomic data indicated human-to-tiger transmission. These were the first confirmed cases of natural SARS-CoV-2 animal infections in the United States and the first in nondomestic species in the world. We highlight disease transmission at a nontraditional interface and provide information that contributes to understanding SARS-CoV-2 transmission across species.IMPORTANCE The human-animal-environment interface of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important aspect of the coronavirus disease 2019 (COVID-19) pandemic that requires robust One Health-based investigations. Despite this, few reports describe natural infections in animals or directly link them to human infections using genomic data. In the present study, we describe the first cases of natural SARS-CoV-2 infection in tigers and lions in the United States and provide epidemiological and genetic evidence for human-to-animal transmission of the virus. Our data show that tigers and lions were infected with different genotypes of SARS-CoV-2, indicating two independent transmission events to the animals. Importantly, infected animals shed infectious virus in respiratory secretions and feces. A better understanding of the susceptibility of animal species to SARS-CoV-2 may help to elucidate transmission mechanisms and identify potential reservoirs and sources of infection that are important in both animal and human health.

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

BACKGROUND: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. METHODS: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). RESULTS: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. CONCLUSIONS: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058707.