Sclerosing epithelioid fibrosarcoma of bone with hybrid features: clinicopathologic, radiologic, and molecular analysis of three cases.

Sclerosing epithelioid fibrosarcoma (SEF) occurring as a primary bone tumor is exceptionally uncommon. Even more rare are cases of SEF that show morphologic overlap with low-grade fibromyxoid sarcoma (LGFMS). Such hybrid lesions arising within the bone have only rarely been reported in the literature. Due to their variegated histomorphology and non-specific radiologic features, these tumors may pose diagnostic difficulties. Herein we describe three molecularly confirmed primary bone cases of sclerosing epithelioid fibrosarcoma that demonstrated prominent areas showing the features of LGFMS and with areas resembling so-called hyalinizing spindle cell tumor with giant rosettes (HSCTGR). Two patients were female and one was male aged 26, 47, and 16, respectively. The tumors occurred in the femoral head, clavicle, and temporal bone. Imaging studies demonstrated relatively well-circumscribed radiolucent bone lesions with enhancement on MRI. Cortical breakthrough and soft tissue extension were present in one case. Histologically the tumors all demonstrated hyalinized areas with SEF-like morphology as well as spindled and myxoid areas with LGFMS-like morphology. Two cases demonstrated focal areas with rosette-like architecture as seen in HSCTGR. The tumors were all positive for MUC4 by immunohistochemistry and cytogenetics, fluorescence in-situ hybridization, and next-generation sequencing studies identified EWSR1 gene rearrangements confirming the diagnosis in all three cases.Hybrid SEF is exceedingly rare as a primary bone tumor and can be difficult to distinguish from other low-grade spindled and epithelioid lesions of bone. MUC4 positivity and identification of underlying EWSR1 gene rearrangements help support this diagnosis and exclude other tumor types.

Self-organization and information transfer in Antarctic krill swarms.

Antarctic krill swarms are one of the largest known animal aggregations, and yet, despite being the keystone species of the Southern Ocean, little is known about how swarms are formed and maintained. Understanding the local interactions between individuals that provide the basis for these swarms is fundamental to knowing how swarms arise in nature, and what potential factors might lead to their breakdown. Here, we analysed the trajectories of captive, wild-caught krill in 3D to determine individual-level interaction rules and quantify patterns of information flow. Our results demonstrate that krill align with near neighbours and that they regulate both their direction and speed relative to the positions of groupmates. These results suggest that social factors are vital to the formation and maintenance of swarms. Furthermore, krill operate a novel form of collective organization, with measures of information flow and individual movement adjustments expressed most strongly in the vertical dimension, a finding not seen in other swarming species. This research represents a vital step in understanding the fundamentally important swarming behaviour of krill.

The Study of Developmental Risk Factors for Early Fire Involvement.

Child fireplay may be regarded as developmentally appropriate, yet can negatively impact those who engage in it and those around them. This study discusses the mental health, fire-specific, and psychosocial risk factors of children who set fires. Fifty-seven caregivers reported on their children's demographics, firesetting behaviors, mental health symptoms, and family history. Children were aged 2-6 years and the majority were male. Most children used lighters and matches on paper and small objects. The majority of the children were motivated by curiosity. Children who set more fires had more externalizing symptoms, and were more likely to have accomplices, to have been exposed to firesetting media, and to have been disciplined or punished for their firesetting behaviors. The study identifies important psychosocial risk factors among young children who set fires. Given the long-term implications of firesetting, understanding firesetting in children will set the foundation of intervention and prevention models.

Advances in Analyzing the Breast Cancer Lipidome and Its Relevance to Disease Progression and Treatment.

Abnormal lipid metabolism is common in breast cancer with the three main subtypes, hormone receptor (HR) positive, human epidermal growth factor 2 (HER2) positive, and triple negative, showing common and distinct lipid dependencies. A growing body of studies identify altered lipid metabolism as impacting breast cancer cell growth and survival, plasticity, drug resistance, and metastasis. Lipids are a class of nonpolar or polar (amphipathic) biomolecules that can be produced in cells via de novo synthesis or acquired from the microenvironment. The three main functions of cellular lipids are as essential components of membranes, signaling molecules, and nutrient storage. The use of mass spectrometry-based lipidomics to analyze the global cellular lipidome has become more prevalent in breast cancer research. In this review, we discuss current lipidomic methodologies, highlight recent breast cancer lipidomic studies and how these findings connect to disease progression and therapeutic development, and the potential use of lipidomics as a diagnostic tool in breast cancer. A better understanding of the breast cancer lipidome and how it changes during drug resistance and tumor progression will allow informed development of diagnostics and novel targeted therapies.

Image-Guided Core Needle Biopsy of Adipocytic Tumors: Diagnostic Accuracy and Concordance With Final Surgical Pathology.

OBJECTIVE. Diagnostic accuracy of core needle biopsy (CNB) for adipocytic tumors can be low because of sampling error from these often large, heterogeneous lesions. The purpose of this study was to evaluate the diagnostic accuracy of image-guided CNB for various adipocytic tumors in comparison with excisional pathology. MATERIALS AND METHODS. Adipocytic tumors (n = 77) of all adult patients undergoing image-guided CNB and subsequent surgical excision of an adipocytic tumor at a tertiary referral center between 2005 and 2019 were studied. To determine concordance, we compared pathologic diagnoses based on CNB to the reference standard of pathologic diagnoses after surgical excision. Tumors were divided into three categories (benign lipomatous tumors [lipoma, lipoma variants, hibernomas], atypical lipomatous tumors [ALTs] or well-differentiated liposarcomas [WDLs], and higher grade liposarcomas [myxoid, dedifferentiated, pleomorphic]), and diagnostic accuracy was calculated for each category. RESULTS. In 73 of 77 adipocytic tumors (95%), diagnosis at CNB and diagnosis after excision were concordant. Accuracy of diagnosis was poorer for ALTs and WDLs than for the other two categories, and the difference was statistically significant (p < .002). For the 29 benign lipomatous tumors and the 27 higher-grade liposarcomas, diagnoses at CNB and after excision were concordant in all cases (100%). Seventeen of the 21 tumors (81%) diagnosed as ALTs or WDLs at CNB had a concordant diagnosis after excision; four of the 21 were upgraded (dedifferentiated liposarcoma, n = 3; myxoid liposarcoma, n = 1). CONCLUSION. CNB provides high diagnostic accuracy for adipocytic tumors, particularly for benign lipomatous tumors and higher grade liposarcomas. However, though still high at 81%, diagnostic accuracy of CNB is not as high for tumors diagnosed as ALTs or WDLs. Awareness of this limitation is important when determining management, particularly of cases of ALT or WDL for which surgery is not planned.

FDA Accelerated Approval of Pembrolizumab for Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma.

On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc., Whitehouse Station, NJ) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Approval was based on Cancer Immunotherapy Trials Network protocol 9, also known as KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% confidence interval: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months. The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for the Food and Drug Administration's accelerated approval of pembrolizumab for the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma, including efficacy and safety information. This approval provides patients and physicians with an additional treatment option for this aggressive and life-threatening carcinoma.

Fine-scale behavioural adjustments of prey on a continuum of risk.

In the wild, prey species often live in the vicinity of predators, rendering the ability to assess risk on a moment-to-moment basis crucial to survival. Visual cues are important as they allow prey to assess predator species, size, proximity and behaviour. However, few studies have explicitly examined prey's ability to assess risk based on predator behaviour and orientation. Using mosquitofish, Gambusia holbrooki, and their predator, jade perch, Scortum barcoo, under controlled conditions, we provide some of the first fine-scale characterization of how prey adapt their behaviour according to their continuous assessment of risk based on both predator behaviour and angular distance to the predator's mouth. When these predators were inactive and posed less of an immediate threat, prey within the attack cone of the predator showed reductions in speed and acceleration characteristic of predator-inspection behaviour. However, when predators became active, prey swam faster with greater acceleration and were closer together within the attack cone of predators. Most importantly, this study provides evidence that prey do not adopt a uniform response to the presence of a predator. Instead, we demonstrate that prey are capable of rapidly and dynamically updating their assessment of risk and showing fine-scale adjustments to their behaviour.

Mid-sized groups perform best in a collective decision task in sticklebacks.

Numerous studies have reported functional improvements in collective behaviour with increasing group size, however, the possibility that such improvements may saturate or even decline as group size continues to grow have seldom been tested experimentally. Here, we tested the ability of solitary three-spined sticklebacks and those in groups, ranging from 2 to 29 fish, to leave an unfavourable patch of habitat. Our results replicate the findings of previous studies at low group sizes, with the fish initially showing a reduction in their latency to leave the unfavourable habitat as group size increased. As group size continued to increase, however, latency to leave the habitat increased, so that the functional relationship between group size and latency to depart was U-shaped. Our results suggest an optimum group size in this context of between 12 and 20 fish. Underlying this group-level trend was a similar U-shaped relationship between group size and the first fish to leave the habitat, suggesting that at larger group sizes, social conformity to the behaviour of the majority can stifle the ability of fish to innovate-in this case, to induce a collective movement from the unfavourable habitat.

The impact of heat exposure on reduced gestational age in pregnant women in North Carolina, 2011-2015.

Research on the impact of heat on pregnant women has focused largely on outcomes following extreme temperature events, such as particular heat waves or spells of very cold weather on pregnant women. Consistently, the literature has shown a statistically significant relationship between heat with shortened gestational age with studies concentrated largely in the western states of the USA or other nations. The association between heat and shortened gestational age has not been examined in the Southeastern US where maternal outcomes are some of the most challenging in the nation. Unlike previous studies that focus on the impacts of a single heat wave event, this study seeks to understand the impact of high heat over a 5-year period during the annual warm season (May-September). To achieve this goal, a case-crossover study design is employed to understand the impact of heat on preterm labor across regions in North Carolina (NC). Temperature thresholds for impact and the underlying relationships between preterm labor and heat are investigated using generalized additive models (GAM). Gridded temperature data (PRISM) is used to establish exposure classifications. The results reveal significant impacts to pregnant women exposed to heat with regional variations. The exposure variable with the most stable and significant result was minimum temperature, indicating high overnight temperatures have the most impact on preterm birth. The magnitude of this impact varies across regions from a 1% increase in risk to 6% increase in risk per two-degree increment above established minimum temperature thresholds.

Youth homelessness and housing stability: What outcomes should we be looking for?

In North America, the key performance indicator of success in community strategies to address homelessness is whether a homeless person is housed or not. In this article, we argue that for young people experiencing homelessness, we need to advance a broader consideration of outcomes to include a range of well-being indicators designed to understand the needs of developing adolescents and young adults and contribute to housing stability. We articulate that the positive outcomes of young people across life domains that include housing stability as well as their safety and security, health and well-being, social connections to peers, family and meaningful adults, connections to groups/neighbourhoods/communities, interests and recreation and leisure, and school and career/work aspirations and goals must be at the centre of these efforts. The Making the Shift project is designed to test this outcomes framework in order to enhance service and measurement capacity and ultimately improve outcomes for youth.

Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways.

BACKGROUND: Despite recent advances in diagnosis and treatment, prostate cancer (PCa) remains the leading cause of cancer-related deaths in men. Current treatments offered in the clinics are often toxic and have severe side effects. Hence, to treat and manage PCa, new agents with fewer side effects or having potential to reduce side effects of conventional therapy are needed. In this study, we show anti-cancer effects of quercetin, an abundant bioflavonoid commonly used to treat prostatitis, and defined quercetin-induced cellular and molecular changes leading to PCa cell death. METHODS: Cell viability was assessed using MTT. Cell death mode, mitochondrial outer membrane potential, and oxidative stress levels were determined by flow cytometry using Annexin V-7 AAD dual staining kit, JC-1 dye, and ROS detection kit, respectively. Antibody microarray and western blot were used to delineate the molecular changes induced by quercetin. RESULTS: PCa cells treated with various concentrations of quercetin showed time- and dose-dependent decrease in cell viability compared to controls, without affecting normal prostate epithelial cells. Quercetin led to apoptotic and necrotic cell death in PCa cells by affecting the mitochondrial integrity and disturbing the ROS homeostasis depending upon the genetic makeup and oxidative status of the cells. LNCaP and PC-3 cells that have an oxidative cellular environment showed ROS quenching after quercetin treatment while DU-145 showed rise in ROS levels despite having a highly reductive environment. Opposing effects of quercetin were also observed on the pro-survival pathways of PCa cells. PCa cells with mutated p53 (DU-145) and increased ROS showed significant reduction in the activation of pro-survival Akt pathway while Raf/MEK were activated in response to quercetin. PC-3 cells lacking p53 and PTEN with reduced ROS levels showed significant activation of Akt and NF-κB pathway. Although some of these changes are commonly associated with oncogenic response, the cumulative effect of these alterations is PCa cell death. CONCLUSIONS: Our results demonstrated quercetin exerts its anti-cancer effects by modulating ROS, Akt, and NF-κB pathways. Quercetin could be used as a chemopreventive option as well as in combination with chemotherapeutic drugs to improve clinical outcomes of PCa patients.

Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission.

Hepatitis C virus (HCV) is the world's most common blood-borne viral infection for which there is no vaccine. The rates of vertical transmission range between 3 and 6% with odds 90% higher in the presence of HIV coinfection. Prevention of vertical transmission is not possible because of lack of an approved therapy for use in pregnancy or an effective vaccine. Recently, HCV has been identified as an independent risk factor for preterm delivery, perinatal mortality, and other complications. In this study, we characterized the immune responses that contribute to the control of viral infection at the maternal-fetal interface (MFI) in the early gestational stages. In this study, we show that primary human trophoblast cells and an extravillous trophoblast cell line (HTR8), from first and second trimester of pregnancy, express receptors relevant for HCV binding/entry and are permissive for HCV uptake. We found that HCV-RNA sensing by human trophoblast cells induces robust upregulation of type I/III IFNs and secretion of multiple chemokines that elicit recruitment and activation of decidual NK cells. Furthermore, we observed that HCV-RNA transfection induces a proapoptotic response within HTR8 that could affect the morphology of the placenta. To our knowledge, for the first time, we demonstrate that HCV-RNA sensing by human trophoblast cells elicits a strong antiviral response that alters the recruitment and activation of innate immune cells at the MFI. This work provides a paradigm shift in our understanding of HCV-specific immunity at the MFI as well as novel insights into mechanisms that limit vertical transmission but may paradoxically lead to virus-related pregnancy complications.

Evidence for the Use of Epoprostenol to Treat Raynaud's Phenomenon With or Without Digital Ulcers.

OBJECTIVE: To review the evidence for using intravenous (IV) epoprostenol to treat Raynaud's phenomenon (RP). DATA SOURCES: The databases MEDLINE (1946 to March 2016), PubMed, and International Pharmaceutical Abstracts were searched using the terms epoprostenol, Flolan, Raynaud's disease, and CREST syndrome. Further literature sources were identified by reviewing article citations. STUDY SELECTION AND DATA EXTRACTION: All English-language, clinical trials and case series evaluating IV epoprostenol for the management or treatment of RP were included. Lower-quality evidence were incorporated due to limited information. DATA SYNTHESIS: Seven small uncontrolled studies/case series, 1 small placebo controlled study, and 1 larger randomized trial were identified and included. There was no consistent measurement of efficacy utilized, but improvements in hand temperature, RP attack duration and frequency were commonly associated with IV epoprostenol treatment (5 trials). There were conflicting data regarding effect sustainability, with 5 trials showing long-term effects and 3 showing immediate effects. Fewer ischemic ulcers developed during treatment with IV epoprostenol in 1 trial compared to conventional treatment. Ulcer healing ocurred in 2 trials. Common adverse effects included hypotension, headache, flushing, gastrointestinal symptoms, and jaw pain. CONCLUSIONS: Available evidence supports the use of IV epoprostenol for treatment of severe RP in patients refractory or intolerant to standard therapies. The dose, titration schedule, and duration of IV epoprostenol utilized in studies varied, but a conservative approach to initiation should be considered. Patients who do not respond to intermittent infusions and have severe digital ischemia may require more aggressive regimens.

Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo.

Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T-lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing PTEN. T-ALL cell lines lacking PTEN had elevated levels of phosphorylated Akt, a gene expression pattern similar to human early T-cell precursor ALL, and were resistant to the potent and selective MEK inhibitor PD0325901. Our data, which demonstrate strong selective pressure to overcome the defective activation of PI3 kinase/Akt and Raf/MEK/ERK, implicate both Ras effector pathways as drivers of aberrant growth in T-ALL and further suggest that leukemia cells will deploy multiple mechanisms to develop resistance to targeted inhibitors in vivo.

Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group.

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML. PROCEDURE: Eighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial. RESULTS: Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib. CONCLUSIONS: Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival.

Personality affects the foraging response of a mammalian herbivore to the dual costs of food and fear.

Predators attack and plants defend, so herbivores face the dilemma of how to eat enough without being eaten. But do differences in the personality of herbivores affect the foraging choices of individuals? We explored the ecological impact of personality in a generalist herbivore, the brushtail possum (Trichosurus vulpecula). After quantifying personality traits in wild individuals brought temporarily into captivity, we tested how these traits altered foraging by individuals when free-ranging in their natural habitat. To measure their responses to the dual costs of predation risk and plant toxin, we varied the toxin concentration of food in safe foraging patches against paired, non-toxic risky patches, and used a novel synthesis of a manipulative Giving-Up-Density (GUD) experiment and video behavioural analysis. At the population level, the cost of safe patches pivoted around that of risky patches depending on food toxin concentration. At the individual level, boldness affected foraging at risky high-quality food patches (as behavioural differences between bold and shy), and at safe patches only when food toxin concentration was low (as differences in foraging outcome). Our results ecologically validate the personality trait of boldness, in brushtail possums. They also reveal, for the first time, a nuanced link between personality and the way in which individuals balance the costs of food and fear. Importantly, they suggest that high plant defence effectively attenuates differences in foraging behaviour arising from variation in personality, but poorly defended plants in safe areas should be differentially subject to herbivory depending on the personality of the herbivore.

Targeting oncogenic Ras signaling in hematologic malignancies.

Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer.

Multi-scale inference of interaction rules in animal groups using Bayesian model selection.

Inference of interaction rules of animals moving in groups usually relies on an analysis of large scale system behaviour. Models are tuned through repeated simulation until they match the observed behaviour. More recent work has used the fine scale motions of animals to validate and fit the rules of interaction of animals in groups. Here, we use a Bayesian methodology to compare a variety of models to the collective motion of glass prawns (Paratya australiensis). We show that these exhibit a stereotypical 'phase transition', whereby an increase in density leads to the onset of collective motion in one direction. We fit models to this data, which range from: a mean-field model where all prawns interact globally; to a spatial Markovian model where prawns are self-propelled particles influenced only by the current positions and directions of their neighbours; up to non-Markovian models where prawns have 'memory' of previous interactions, integrating their experiences over time when deciding to change behaviour. We show that the mean-field model fits the large scale behaviour of the system, but does not capture the observed locality of interactions. Traditional self-propelled particle models fail to capture the fine scale dynamics of the system. The most sophisticated model, the non-Markovian model, provides a good match to the data at both the fine scale and in terms of reproducing global dynamics, while maintaining a biologically plausible perceptual range. We conclude that prawns' movements are influenced by not just the current direction of nearby conspecifics, but also those encountered in the recent past. Given the simplicity of prawns as a study system our research suggests that self-propelled particle models of collective motion should, if they are to be realistic at multiple biological scales, include memory of previous interactions and other non-Markovian effects.

Fast and accurate decisions through collective vigilance in fish shoals.

Although it has been suggested that large animal groups should make better decisions than smaller groups, there are few empirical demonstrations of this phenomenon and still fewer explanations of the how these improvements may be made. Here we show that both speed and accuracy of decision making increase with group size in fish shoals under predation threat. We examined two plausible mechanisms for this improvement: first, that groups are guided by a small proportion of high-quality decision makers and, second, that group members use self-organized division of vigilance. Repeated testing of individuals showed no evidence of different decision-making abilities between individual fish. Instead, we suggest that shoals achieve greater decision-making efficiencies through division of labor combined with social information transfer. Our results should prompt reconsideration of how we view cooperation in animal groups with fluid membership.