Comprehensive Analysis of Hypermutation in Human Cancer.

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

Recent progress in the treatment of cancer in children.

Although significant improvements have been made in the outcomes of children with cancer, the pace of improvement has slowed in recent years as the limits of therapy intensification may have been reached for many pediatric cancers. Furthermore, with increasing numbers of pediatric cancer survivors, the long-term side effects of treatment have become increasingly apparent. Therefore, attention has shifted to the use of molecularly targeted agents and immunotherapies to improve the outcomes of children who are not cured by traditional cytotoxic chemotherapies and to decrease exposure to cytotoxic chemotherapy and reduce late effects. This review describes the recent progress in the treatment of children with cancer, focusing in particular on diseases in which targeted and immunotherapeutic agents have made an impact.

Graphical models for identifying pore-forming proteins.

Pore-forming toxins (PFTs) are proteins that form lesions in biological membranes. Better understanding of the structure and function of these proteins will be beneficial in a number of biotechnological applications, including the development of new pest control methods in agriculture. When searching for new pore formers, existing sequence homology-based methods fail to discover truly novel proteins with low sequence identity to known proteins. Search methodologies based on protein structures would help us move beyond this limitation. As the number of known structures for PFTs is very limited, it's quite challenging to identify new proteins having similar structures using computational approaches like deep learning. In this article, we therefore propose a sample-efficient graphical model, where a protein structure graph is first constructed according to consensus secondary structures. A semi-Markov conditional random fields model is then developed to perform protein sequence segmentation. We demonstrate that our method is able to distinguish structurally similar proteins even in the absence of sequence similarity (pairwise sequence identity < 0.4)-a feat not achievable by traditional approaches like HMMs. To extract proteins of interest from a genome-wide protein database for further study, we also develop an efficient framework for UniRef50 with 43 million proteins.

Immunolocalization and ultrastructure shows ingestion of Cry protein expressed in Glycine max by Heterodera glycines and its mode-of-action.

Great interest exists in developing a transgenic trait that controls the economically important soybean (Glycine max) pest, soybean cyst nematode (SCN, Heterodera glycines), due to its adaptation to native resistance. Soybean plants expressing the Bacillus thuringiensis delta-endotoxin, Cry14Ab, were recently demonstrated to control SCN in both growth chamber and field testing. In that communication, ingestion of the Cry14Ab toxin by SCN second stage juveniles (J2) was demonstrated using fluorescently labeled Cry14Ab in an in vitro assay. Here, we show that consistent with expectations for a Cry toxin, Cry14Ab has a mode-of-action unique from the native resistance sources Peking and PI 88788. Further, we demonstrate in planta the ingestion and localization of the Cry14Ab toxin in the midgut of nematodes feeding on roots expressing Cry14Ab, using immunogold labeling and transmission electron microscopy. We observed immunolocalization of the toxin and resulting intestinal damage primarily in the microvillus-like (MvL)-containing region of the midgut intestine, but not in nematodes feeding on roots lacking toxin. This demonstrated that Cry14Ab was taken up by the J2 SCN, presumably through the feeding tube within the plant root cell that serves as its feeding site. This suggests that relatively large proteins can be taken up through the feeding tube. Electron microscopy showed that Cry14Ab caused lysis of the midgut MvL membrane, and eventual degradation of the MvL and the lysate, forming particulate aggregates. The accumulated electron dense aggregate in the posterior midgut intestine was not observed in SCN in non-Cry14Ab expressing plants.

Foxn1 is not essential for T-cell development in teleosts.

In mammals, T-cell development depends on the activity of the Foxn1 transcription factor in the thymic epithelium; mutations in the vertebrate-specific Foxn1 gene are associated with profound T-cell lymphopenia and fatal immunodeficiency. Here, we examined the extent of T-cell development in teleosts lacking a functional foxn1 gene. In zebrafish carrying a deleterious internal deletion of foxn1, reduced but robust lymphopoietic activity is maintained in the mutant thymus. Moreover, pseudogenization or loss of foxn1 in the genomes of deep-sea anglerfishes is independent of the presence or absence of the canonical signatures of the T-cell lineage. Thus, in contrast to the situation in mammals, the teleost thymus can support foxn1-independent lymphopoiesis, most likely through the activity of the Foxn4, an ancient metazoan paralog of Foxn1. Our results imply that during the early stages of vertebrate evolution, genetic control of thymopoiesis was functionally redundant and thus robust; in mammals, the genetic network was reorganized to become uniquely dependent on the FOXN1 transcription factor.

Supervised and unsupervised machine learning approaches for monitoring subvisible particles within an aluminum-salt adjuvanted vaccine formulation.

Suspensions of protein antigens adsorbed to aluminum-salt adjuvants are used in many vaccines and require mixing during vial filling operations to prevent sedimentation. However, the mixing of vaccine formulations may generate undesirable particles that are difficult to detect against the background of suspended adjuvant particles. We simulated the mixing of a suspension containing a protein antigen adsorbed to an aluminum-salt adjuvant using a recirculating peristaltic pump and used flow imaging microscopy to record images of particles within the pumped suspensions. Supervised convolutional neural networks (CNNs) were used to analyze the images and create "fingerprints" of particle morphology distributions, allowing detection of new particles generated during pumping. These results were compared to those obtained from an unsupervised machine learning algorithm relying on variational autoencoders (VAEs) that were also used to detect new particles generated during pumping. Analyses of images conducted by applying both supervised CNNs and VAEs found that rates of generation of new particles were higher in aluminum-salt adjuvant suspensions containing protein antigen than placebo suspensions containing only adjuvant. Finally, front-face fluorescence measurements of the vaccine suspensions indicated changes in solvent exposure of tryptophan residues in the protein that occurred concomitantly with new particle generation during pumping.

Absolute neutrophil count clinical trial eligibility criteria for pediatric oncology phase I and phase I/II trials by sponsorship.

Normal absolute neutrophil count (ANC) variations, as seen with Duffy-null associated neutrophil count (DANC), are not accounted for in trial eligibility, which may contribute to racial enrollment disparities. We describe ANC eligibility for pediatric oncology phase I/II clinical trials according to primary sponsorship from 2010 to 2023 using ClinicalTrials.gov. Out of 438 trials, 20% were industry-sponsored. Total 17% of trials required ANC ≥1500 cells/µL for enrollment; however, industry-sponsored trials were significantly more likely to require ANC ≥1500 cells/µL than non-industry-sponsored trials (odds ratio 2.53, 95% confidence interval: 1.39-4.62; p < .001). These data suggest laboratory exclusion criteria are one possible mechanism for pediatric clinical trial enrollment disparities.

Pediatric Asthma Exacerbations: 14-Day Emergency Department Return Visit Risk Factors.

BACKGROUND: Asthma, the most common chronic disease of childhood, can affect a child's physical and mental health and social and emotional development. OBJECTIVE: The aim of this study was to identify factors associated with emergency department (ED) return visits for asthma exacerbations within 14 days of an initial visit. METHODS: This was a retrospective review from Cerner Real-World Data for patients aged from 5 to 18 years and seen at an ED for an asthma exacerbation and discharged home at the index ED visit. Asthma visits were defined as encounters in which a patient was diagnosed with asthma and a beta agonist, anticholinergic, or systemic steroid was ordered or prescribed at that encounter. Return visits were ED visits for asthma within 14 days of an index ED visit. Data, including demographic characteristics, ED evaluation and treatment, health care utilization, and medical history, were collected. Data were analyzed via logistic regression mixed effects model. RESULTS: A total of 80,434 index visits and 17,443 return visits met inclusion criteria. Prior ED return visits in the past year were associated with increased odds of a return visit (odds ratio [OR] 2.12; 95% CI 2.07-2.16). History of pneumonia, a concomitant diagnosis of pneumonia, and fever were associated with increased odds of a return visit (OR 1.19; 95% CI 1.10-1.29; OR 1.15; 95% CI 1.04-1.28; OR 1.20; 95% CI 1.11-1.30, respectively). CONCLUSIONS: Several variables seem to be associated with statistically significant increased odds of ED return visits. These findings indicate a potentially identifiable population of at-risk patients who may benefit from additional evaluation, planning, or education prior to discharge.

Observational Behavioral Coding in the Pediatric Emergency Department: Development of the Emergency Department Child Behavior Coding System.

BACKGROUND: Despite improvements over the past decade, children continue to experience significant pain and distress surrounding invasive procedures in the emergency department (ED). To assess the impact of newly developed interventions, we must create more reliable and valid behavioral assessment tools that have been validated for the unique settings of pediatric EDs. OBJECTIVE: This study aimed to create and test the Emergency Department Child Behavior Coding System (ED-CBCS) for the assessment of child distress and nondistress behaviors surrounding pediatric ED procedures. METHODS: Via an iterative process, a multidisciplinary expert panel developed the ED-CBCS, an advanced time-based behavioral coding measure. Inter-rater reliability and concurrent validity were examined using 38 videos of children aged from 2 to 12 years undergoing laceration procedures. Face, Legs, Activity, Cry, Consolability (FLACC) scale scores were used to examine concurrent validity. RESULTS: The final ED-CBCS included 27 child distress and nondistress behaviors. Time-unit κ values from 0.64 to 0.98 and event alignment κ values from 0.62 to 1.00 indicated good to excellent inter-rater reliability for all but one of the individual codes. ED-CBCS distress (B = 1.26; p < 0.001) and nondistress behaviors (B = -0.69, p = 0.025) were independently significantly associated with FLACC scores, indicating concurrent validity. CONCLUSIONS: We developed a psychometrically sound tool tailored for pediatric ED procedures. Future work could use this measure to better identify behavioral targets and test the effects of interventions to relieve pediatric ED pain and distress.

Paediatric laceration repair in the emergency department: post-discharge pain and maladaptive behavioural changes.

BACKGROUND: Paediatric laceration repair procedures are common in the ED; however, post-discharge recovery remains understudied. Perioperative research demonstrates that children exhibit maladaptive behavioural changes following stressful and painful medical procedures. This study examined post-discharge recovery following paediatric laceration repair in the ED. METHODS: This prospective observational study included a convenience sample of 173 children 2-12 years old undergoing laceration repair in a paediatric ED in Orange, California, USA between April 2022 and August 2023. Demographics, laceration and treatment data (eg, anxiolytic medication), and caregiver-reported child pre-procedural and procedural pain (Numerical Rating Scale (NRS)) were collected. On days 1, 3, 7 and 14 post-discharge, caregivers reported children's pain and new-onset maladaptive behavioural changes (eg, separation anxiety) via the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery. Univariate and logistic regression analyses were conducted to identify variables associated with the incidence of post-discharge maladaptive behavioural change. RESULTS: Post-discharge maladaptive behavioural changes were reported in 43.9% (n=69) of children. At 1 week post-discharge, approximately 20% (n=27) of children exhibited maladaptive behavioural changes and 10% (n=13) displayed behavioural changes 2 weeks post-discharge. Mild levels of pain (NRS ≥2) were reported in 46.7% (n=70) of children on post-discharge day 1, 10.3% (n=14) on day 7 and 3.1% (n=4) on day 14. An extremity laceration (p=0.029), pre-procedural midazolam (p=0.020), longer length of stay (p=0.043) and post-discharge pain on day 1 (p<0.001) were associated with incidence of maladaptive behavioural changes. Higher pain on post-discharge day 1 was the only variable independently associated with an increased likelihood of maladaptive behavioural change (OR=1.32 (95% CI 1.08 to 1.61), p=0.001). CONCLUSION: Over 40% of children exhibited maladaptive behavioural changes after ED discharge. Although the incidence declined over time, 10% of children continued to exhibit behavioural changes 2 weeks post-discharge. Pain on the day following discharge emerged as a key predictor, highlighting the potential critical role of proactive post-procedural pain management in mitigating adverse behavioural changes.

Upside-down swimming: in situ observations of inverted orientation in Gigantactis, with a new depth record for the Ceratioidei.

This note reports on eight observations of inverted swimming behavior by species of ceratioid whipnose anglerfishes in the genus Gigantactis, from the Caribbean, tropical east Atlantic, tropical western Indian Ocean, the north-east and north-west Pacific and south-west Pacific. It covers four putative species and strongly suggests that this is the normal behavior for the genus. A possible reason is briefly discussed. In addition, a new depth record of 5866 m for the ceratioid anglerfish is recorded.

Children's Oncology Group's 2023 blueprint for research: Rare tumors.

The Children's Oncology Group (COG) Rare Tumor Committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that do not fall within another COG disease committee. Current therapeutic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes.

Cognitive function and the longitudinal hippocampal axis in mesial temporal sclerosis.

OBJECTIVE: The relationship of preoperative memory deficits in patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) to the distribution of neuronal loss is uncertain. Building on the material specificity theory, we tested the hypothesis that visual memory deficits are associated with posterior hippocampal atrophy, whereas verbal memory deficits are associated with anterior hippocampal atrophy. METHODS: We studied 22 adults with mTLE and HS, calculating hippocampal head, body, and tail volumes, correcting for estimated total intracranial volume, using automated segmentation. Preoperative memory ability was evaluated with the Wechsler Memory Scale (WMS-II: logical memory, verbal paired associates, family pictures, and faces subtests). We correlated memory ability with hippocampal division volumes using SPSS 26.1 (repeated measures ANOVAs, one-way ANOVAs, Pearson r correlations) for statistical analysis. RESULTS: We found a significant main effect of hippocampal subdivision, reporting volumetric differences between the head, body, and tail. Pairwise comparisons reported that the hippocampal head had significantly greater volume than both the body and tail (p < 0.001). For both left and right focus groups, the ipsilateral hippocampi were significantly smaller than the contralateral. Linear regression reported a left hippocampal model (head, body, and tail volumes) predicted performance on logical memory with the left hippocampal tail volume being the strongest predictor. A right hippocampal model (head, body, and tail volumes) predicted memory ability for family pictures and verbal paired associates at a trend level. CONCLUSIONS: Ipsilateral hippocampal head and tail seem more vulnerable to injury than the body in both the left and right mTLE. Our study suggests there may be functional differences along the hippocampal longitudinal axis, particularly for the left hippocampal tail with verbal memory. Our findings are consistent with material-specific right-left differences in memory processing.

Community based multi-disease health screening as an opportunity for early detection of HIV cases and linking them to care.

BACKGROUND: The 95-95-95 UNAIDS global strategy was adapted to end the AIDS epidemic by 2030. The target is based on the premise that early detection of HIV-infected persons and linking them to treatment regardless of their CD4 counts will lead to sustained viral suppression. HIV testing strategies to increase uptake of testing in Western and Central Africa remain inadequate. Hence, a high proportion of people living with HIV in this region do not know their status. This report describes the implementation of a community based multi-disease health screening (also known as "Know Your Status" -KYS), as part of basic science research, in a way that contributed to achieving public health goals. METHODS: A community based multi-disease health screening was conducted in 7 communities within the Eastern region of Ghana between November 2017 and April 2018, to recruit and match HIV seronegative persons to HIV seropositive persons in a case-control HIV gut microbiota study. Health assessments included blood pressure, body mass index, blood sugar, Hepatitis B virus, syphilis, and HIV testing for those who consented. HIV seronegative participants who consented were consecutively enrolled in an ongoing HIV gut microbiota case-control study. Descriptive statistics (percentages) were used to analyze data. RESULTS: Out of 738 people screened during the exercise, 700 consented to HIV testing and 23 (3%) were HIV positive. Hepatitis B virus infection was detected in 4% (33/738) and Syphilis in 2% (17/738). Co-infection of HIV and HBV was detected in 4 persons. The HIV prevalence of 3% found in these communities is higher than both the national prevalence of 1.7% and the Eastern Regional prevalence of 2.7 in 2018. CONCLUSION: Community based multi-disease health screening, such as the one undertaken in our study could be critical for identifying HIV infected persons from the community and linking them to care. In the case of HIV, it will greatly contribute to achieving the first two 95s and working towards ending AIDS by 2030.

Hierarchical routing in carbon metabolism favors iron-scavenging strategy in iron-deficient soil Pseudomonas species.

High-affinity iron (Fe) scavenging compounds, or siderophores, are widely employed by soil bacteria to survive scarcity in bioavailable Fe. Siderophore biosynthesis relies on cellular carbon metabolism, despite reported decrease in both carbon uptake and Fe-containing metabolic proteins in Fe-deficient cells. Given this paradox, the metabolic network required to sustain the Fe-scavenging strategy is poorly understood. Here, through multiple 13C-metabolomics experiments with Fe-replete and Fe-limited cells, we uncover how soil Pseudomonas species reprogram their metabolic pathways to prioritize siderophore biosynthesis. Across the three species investigated (Pseudomonas putida KT2440, Pseudomonas protegens Pf-5, and Pseudomonas putida S12), siderophore secretion is higher during growth on gluconeogenic substrates than during growth on glycolytic substrates. In response to Fe limitation, we capture decreased flux toward the tricarboxylic acid (TCA) cycle during the metabolism of glycolytic substrates but, due to carbon recycling to the TCA cycle via enhanced anaplerosis, the metabolism of gluconeogenic substrates results in an increase in both siderophore secretion (up to threefold) and Fe extraction (up to sixfold) from soil minerals. During simultaneous feeding on the different substrate types, Fe deficiency triggers a hierarchy in substrate utilization, which is facilitated by changes in protein abundances for substrate uptake and initial catabolism. Rerouted metabolism further promotes favorable fluxes in the TCA cycle and the gluconeogenesis-anaplerosis nodes, despite decrease in several proteins in these pathways, to meet carbon and energy demands for siderophore precursors in accordance with increased proteins for siderophore biosynthesis. Hierarchical carbon metabolism thus serves as a critical survival strategy during the metal nutrient deficiency.

Sitting, squatting, and the evolutionary biology of human inactivity.

Recent work suggests human physiology is not well adapted to prolonged periods of inactivity, with time spent sitting increasing cardiovascular disease and mortality risk. Health risks from sitting are generally linked with reduced levels of muscle contractions in chair-sitting postures and associated reductions in muscle metabolism. These inactivity-associated health risks are somewhat paradoxical, since evolutionary pressures tend to favor energy-minimizing strategies, including rest. Here, we examined inactivity in a hunter-gatherer population (the Hadza of Tanzania) to understand how sedentary behaviors occur in a nonindustrial economic context more typical of humans' evolutionary history. We tested the hypothesis that nonambulatory rest in hunter-gatherers involves increased muscle activity that is different from chair-sitting sedentary postures used in industrialized populations. Using a combination of objectively measured inactivity from thigh-worn accelerometers, observational data, and electromygraphic data, we show that hunter-gatherers have high levels of total nonambulatory time (mean ± SD = 9.90 ± 2.36 h/d), similar to those found in industrialized populations. However, nonambulatory time in Hadza adults often occurs in postures like squatting, and we show that these "active rest" postures require higher levels of lower limb muscle activity than chair sitting. Based on our results, we introduce the Inactivity Mismatch Hypothesis and propose that human physiology is likely adapted to more consistently active muscles derived from both physical activity and from nonambulatory postures with higher levels of muscle contraction. Interventions built on this model may help reduce the negative health impacts of inactivity in industrialized populations.

Negative Appendectomies: Evaluating Diagnostic Imaging Techniques at General versus Pediatric Emergency Departments.

BACKGROUND: Although appendicitis is the most common pediatric surgical emergency, the path to diagnosis remains equivocal, with utilization of imaging modalities largely institution dependent. OBJECTIVES: Our objective was to compare imaging practices and negative appendectomy rates between patients transferred from nonpediatric hospitals to our pediatric hospital and primary patients presenting directly to our institution. METHODS: We retrospectively reviewed all laparoscopic appendectomy cases performed at our pediatric hospital in 2017 for imaging and histopathologic results. Two-sample z-test was used to examine negative appendectomy rates between transfer and primary patients. The negative appendectomy rates of patients who received different imaging modalities were analyzed using the Fisher's exact test. RESULTS: Of 626 patients, 321 (51%) were transferred from nonpediatric hospitals. The negative appendectomy rate for transfer patients was 6.5% and 6.6% for primary patients (p = 0.99). Ultrasound (US) was the only imaging obtained in 31% of transfer and 82% of primary patients. The negative appendectomy rate of US performed at transfer hospitals compared with our pediatric institution was not significantly different (11% vs. 5%, p = 0.06). Computed tomography (CT) was the only imaging obtained in 34% of transfer and 5% of primary patients. Both US and CT were completed for 17% of transfer and 19% of primary patients. CONCLUSION: The negative appendectomy rates of transfer and primary patients were not significantly different despite more frequent CT use at nonpediatric facilities. It may be valuable to encourage US utilization at adult facilities given the potential to safely reduce CT use in the evaluation of suspected pediatric appendicitis.

Predictors of parental anxiety in a paediatric emergency department.

BACKGROUND: Children experience significant anxiety in the paediatric ED. Although research from preoperative and primary care samples indicates that parents experience anxiety surrounding their children's medical procedures, less is known about parental anxiety and factors that contribute to higher parental anxiety in the ED. This study aimed to assess parental anxiety in families presenting to a paediatric ED with a variety of presenting concerns and examine demographic and psychological factors associated with parental anxiety. METHODS: This cross-sectional study included parents of children <18 years old presenting to a paediatric ED in Orange County, California, USA, for a non-psychiatric complaint between 20 January 2021 and 26 March 2021. Parents were, on average, 34.76±9.10 years old, 87.5% were mothers, 59.2% identified as non-Latinx and parents reported average levels of mental health (T-score=51.21±9.84). Parent state anxiety was assessed via the State-Trait Anxiety Inventory and validated instruments were used to measure child temperament (ie, emotionality, activity, sociability, shyness), previous medical anxiety, and parent physical and mental health. Data were analysed using multiple linear regression models. RESULTS: Out of 201 families screened, 150 were eligible, and 120 enrolled. In the sample, 42.5% of parents endorsed clinically significant levels of anxiety in the ED. Regression analyses indicated that lower child activity temperament (ie, tendency to be less active/energetic; B=-3.20, 95% CI -5.70 to -0.70, p=0.012) and poorer parent mental health (B=-0.31, 95% CI -0.52 to -0.09, p=0.006) were independently associated with higher parent anxiety (F(5, 99)=6.77, p=0.004). CONCLUSION: Over 40% of parents sampled endorsed clinically significant anxiety in the paediatric ED. Child temperament, specifically lower activity temperament, and poorer parental mental health were identified as contributors to parent anxiety, whereas clinical condition or severity did not influence parent anxiety. Current results may help identify families in need of additional intervention and may improve patient outcomes.

Evolutionary relationships of anglerfishes (Lophiiformes) reconstructed using ultraconserved elements.

The macroevolutionary consequences of evolving in the deep-sea remain poorly understood and are compounded by the fact that convergent adaptations for living in this environment makes elucidating phylogenetic relationships difficult. Lophiiform anglerfishes exhibit extreme habitat and predatory specializations, including the use of a fin-spine system as a luring device and unique reproductive strategies where parasitic males attach and fuse to females. Despite their notoriety for these odd characteristics, evolutionary relationships among these fishes remain unclear. We sought to clarify the evolutionary history of Lophiiformes using data from 1000 ultraconserved elements and phylogenomic inference methods with particular interest paid to the Ceratioidei (deep-sea anglerfishes) and Antennarioidei (frogfishes and handfishes). At the suborder level, we recovered similar topologies in separate phylogenomic analyses: The Lophioidei (monkfishes) are the sister group to the rest of the Lophiiformes, Ogcocephaloidei (batfishes) and Antennarioidei (frogfishes) form a sister group, and Chaunacioidei (coffinfishes) and Ceratioidei (deep-sea anglerfishes) form a clade. The relationships we recover within the ceratioids disagree with most previous phylogenetic investigations, which used legacy phylogenetic markers or morphology. We recovered non-monophyletic relationships in the Antennarioidei and proposed three new families based on molecular and morphological evidence: Histiophrynidae, Rhycheridae, and Tathicarpidae. Antennariidae was re-evaluated to include what was known as Antennariinae, but not Histiophryninae. Non-bifurcating signal in splits network analysis indicated reticulations among and within suborders, supporting the complicated history of the Lophiiformes previously found with morphological data. Although we resolve relationships within Antennarioidei, Ceratioidei relationships remain somewhat unclear without better taxonomic sampling.

Temsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001).

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.