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Abstract Background Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks’ gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. Methods Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals (n = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals (n = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals (n = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals (n = 8). Lambs were surgically delivered 48hr after first maternal injection at 122–125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. Results Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR

The discovery of gene fusions involving Neuregulin-1 (NRG1) within solid tumors has important therapeutic implications, as they are being actively explored as targets for emerging ERBB/ERBB2/ERBB3-directed anti-cancer agents. NRG1 fusions are very uncommon across all tumor types and are infrequently documented in the medical literature. We report a female patient presenting with widespread peritoneal carcinomatosis diagnosed as high grade serous fallopian tube carcinoma, which harbored a previously undescribed MYH10::NRG1 fusion. Moreover, we queried the whole transcriptome sequencing results of neoplasms analyzed by a commercial laboratory (Caris Life Sciences) to determine the overall incidence of NRG1 fusions in carcinomas of the ovary, fallopian tube, and peritoneum (0.18%). Twenty-five additional tumors were found to demonstrate NRG1 fusions, including 20 new genes partners that had not been previously identified in gynecologic carcinomas. Overall, NRG1 fusion events are rare in ovarian, fallopian tube, and primary peritoneal carcinomas, but they may carry diagnostic significance in the context of borderline/low grade serous tumors, which demonstrated exclusively CLU::NRG1 fusions, and could have important predictive implications for response to ERBB/ERBB2/ERBB3-directed therapies.

IntroductionPreclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization of a high-throughput screening hit. The aim of this study was to characterize the pharmacology, absorption, distribution, metabolism, elimination, and toxicity (ADMET) profile of RG7774, and to explore its potential for managing the key pathological features associated with retinal disease in rodents.MethodsThe in vitro pharmacology of RG7774 was investigated for CB2R binding and receptor activation using recombinant human and mouse CB2R expression in Chinese hamster ovary cells, and endogenous CB2R expression in human Jurkat cells, and rat and mouse spleen cells. The ADMET profile was evaluated and the effects of RG7774 on retinal permeability, leukocyte adhesion, and choroidal neovascularization (CNV) were investigated in rodent models of retinal disease. Pharmacokinetic (PK) parameters and the exposure-response relationship were characterized in healthy animals and in animals with laser-induced CNV.ResultsRG7774 was found to be a potent (EC50: 2.8 nM and Ki: 51.3 nM), selective, and full CB2R agonist with no signs of cannabinoid receptor type 1 (CB1R) binding or activation. The ligand showed a favorable ADMET profile and exhibited systemic and ocular exposure after oral delivery. Functional potency in vitro translated from recombinant to endogenous expression systems. In vivo, orally administered RG7774 reduced retinal permeability and leukocyte adhesion in rodents with lipopolysaccharide (LPS)-induced uveitis and streptozotocin (STZ)-induced DR, and reduced lesion areas in rats with laser-induced CNV with an ED50 of 0.32 mg/kg. Anatomically, RG7774 reduced the migration of retinal microglia to retinal lesions.DiscussionRG7774 is a novel, highly selective, and orally bioavailable CB2R agonist, with an acceptable systemic and ocular PK profile, and beneficial effects on retinal vascular permeability, leukocyte adhesion, and ocular inflammation in rodent animal models. Results support the development of RG7774 as a potential treatment for retinal diseases with similar pathophysiologies as addressed by the animal models.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by peripheral blood monocytosis and bone marrow dysplasia. In approximately one-fourth of cases, CMML can demonstrate progression to acute myeloid leukemia (AML), referred to as AML ex CMML. We present a 58-year-old woman with a past medical history of idiopathic thrombocytopenic purpura (ITP) who demonstrated 24% bone marrow blasts on a repeat biopsy obtained two years after being diagnosed with CMML. By the flow cytometric analysis, the blasts expressed partial CD34, CD13, CD117, partial MPO, and partial CD123 with coexpression of the T-lymphoid markers CD2, CD5, CD7, partial CD4, cytoplasmic CD3, partial cytoplasmic TDT, and CD38, suggestive of AML with rare mixed myeloid/T-cell phenotype. Treatment with various agents including decitabine, cytarabine, daunorubicin, etoposide, and venetoclax, and two experimental bromodomain and extraterminal (BET) inhibitors did not produce sustained remissions, and the patient eventually succumbed to her disease. T-cell phenotype is an exceedingly rare feature of AML ex CMML, and whether this unique differentiation pathway contributed to the aggressive disease course remains unclear.

Low-dose interleukin-2 is showing promise in the treatment of several autoimmune inflammatory diseases. Here authors map the trajectory of cellular and transcriptional changes in type 1 diabetes patients receiving an interval dosing interleukin-2 regimen, which shows an anti-inflammatory gene expression signature shared by all immune cell types analysed, persisting for at least a month after ending treatment.

Soft tissue sarcomas harboring EWSR1::CREM fusion are rare and challenging to treat. Pazopanib, a multi-tyrosine kinase inhibitor, is FDA-approved for advanced soft tissue sarcomas, but predictive biomarkers for its efficacy remain unidentified. We conducted a study on > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ) to detect rearrangements using whole transcriptome sequencing. Two sarcoma-experienced, board-certified pathologists performed histological reviews, and treatment/outcome information was collected. Among the identified cases (n = 18), we observed a diverse range of sarcoma and other cancers, including an intracranial myxoid mesenchymal tumor, mesothelioma, hyalinizing clear cell carcinomas of the head and neck, clear cell sarcomas, and undifferentiated round cell sarcomas, as well as histologically malignant tumors with epithelioid morphology. Notably, two undifferentiated, metastatic, abdominal round cell sarcoma cases treated with pazopanib demonstrated significant sustained partial response and clinical benefit. To explore the genetic factors associated with the efficacy of pazopanib in these cases, next-generation sequencing and fluorescence in situ hybridization were analyzed for alterations in the tumors. The genomic analysis provided compelling evidence confirming the presence of EWSR1::CREM fusion in both cases, with no other pathogenic gene variants or copy number alterations detected. These cases demonstrate the potential of Pazopanib as a promising therapeutic option for patients with EWSR1::CREM fusion-positive soft tissue sarcomas, including metastatic undifferentiated round cell sarcomas. The sustained clinical benefit and partial responses observed in these cases warrant further research to validate these findings and explore the wider utility of Pazopanib in this rare and challenging subset of soft tissue sarcomas. Case studies: Case 1: A 49-year-old man presented with abdominal pain, weight loss, and chronic cough. A computed tomography (CT) of the chest, abdomen, and pelvis showed multiple lung nodules and masses and a right rectus mass that was biopsied and revealed an undifferentiated round cell sarcoma with a rare fusion EWSR1-CREM. No additional pathogenic gene variants or copy number alterations were detected. He received neoadjuvant chemotherapy with three cycles of Vincristine, Adriamycin, and Ifosfamide (VAI) and seven cycles of Vincristine/Irinotecan and Temodar (VIT). After cycle 7 of VIT, he had surgical resection of the abdominal mass and received radiation for lung metastasis. He completed 13 cycles of VIT after which he presented with progression of disease and switched to monotherapy with Pazopanib. At the time of this analysis he had stable disease for 28 months. Case 2: A 75-year-old woman presented with pelvic pain and new onset constipation. CT abdomen showed a large pelvic mass and intraperitoneal tumor spread. Exploratory laparotomy revealed a ruptured pelvic mass and a small bowel tumor. Both tumors were proved to be high-grade, poorly differentiated sarcoma. Genomic analysis demonstrated an EWSR1::CREM fusion but no other pathogenic gene variants or copy number alterations. She was treated initially for a primitive neuroectodermal tumor (PNET) with four cycles of Vincristine/Adriamycin/Cytoxan/Olaratumab but declined additional chemotherapy after progression. Two years later, she presented with recurrent abdominal mass and received one cycle of Temodar/Irinotecan, then she began Pozapanib and underwent palliative radiation to the entire pelvis. She has been on Pazopanib for 23 months with stable disease.

Summary: DISC1 is a genetic risk factor for multiple psychiatric disorders. Compared to the dozens of murine Disc1 models, there is a paucity of zebrafish disc1 models—an organism amenable to high-throughput experimentation. We conducted the longitudinal neurobehavioral analysis of disc1 mutant zebrafish across key stages of life. During early developmental stages, disc1 mutants exhibited abrogated behavioral responses to sensory stimuli across multiple testing platforms. Moreover, during exposure to an acoustic sensory stimulus, loss of disc1 resulted in the abnormal activation of neurons in the pallium, cerebellum, and tectum—anatomical sites involved in the integration of sensory perception and motor control. In adulthood, disc1 mutants exhibited sexually dimorphic reduction in anxiogenic behavior in novel paradigms. Together, these findings implicate disc1 in sensorimotor processes and the genesis of anxiogenic behaviors, which could be exploited for the development of novel treatments in addition to investigating the biology of sensorimotor transformation in the context of disc1 deletion.

Individuals with Down syndrome are at decreased risk of developing most types of solid tumors, including central nervous system malignancies. Several mechanisms have been proposed to explain how additional genetic material on chromosome 21 may confer this increased protection. Only two individuals with Down syndrome and meningioma have been described in the medical literature, whose tumors were both World Health Organization (WHO) grade 1. Here, we report the first individual with Down syndrome to our knowledge who developed an atypical meningioma, WHO grade 2. We also provide a hypothesis for how this tumor could have arisen in the setting of trisomy 21.

Abstract Microenvironmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological, and microenvironmental landscape across 85 multiple microdissected regions from 39 cases. Most somatic alterations, including whole-genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity was frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified three immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.

The tumor microenvironment is a complex mixture of cell types that bi-directionally interact and influence tumor initiation, progression, recurrence, and patient survival. Mesenchymal stromal cells (MSCs) of the tumor microenvironment engage in crosstalk with cancer cells to mediate epigenetic control of gene expression. We identified CD90+ MSCs residing in the tumor microenvironment of patients with invasive breast cancer that exhibit a unique gene expression signature. Single-cell transcriptional analysis of these MSCs in tumor-associated stroma identified a distinct subpopulation characterized by increased expression of genes functionally related to extracellular matrix signaling. Blocking the TGFβ pathway reveals that these cells directly contribute to cancer cell proliferation. Our findings provide novel insight into communication between breast cancer cells and MSCs that are consistent with an epithelial to mesenchymal transition and acquisition of competency for compromised control of proliferation, mobility, motility, and phenotype.

Collagenous gastritis has been reported as a rare cause of nausea, diarrhea, weight changes, and early satiety in female patients. Here, we describe two women aged 43 and 71 years who presented with similar symptoms. Gastric biopsies from both individuals showed thickened, irregular subepithelial collagen bands (>10 μm). The pathogenesis of collagenous gastritis is poorly understood, but it may be the presenting symptom for many underlying autoimmune conditions. In particular, there is a well-established connection between collagenous disorders of the gastrointestinal tract and celiac sprue, Sjögren syndrome, and lymphocytic colitis; however, none of these conditions had been diagnosed in our patients. The older woman had incidentally discovered hypogammaglobinemia and IgA deficiency, whereas the younger woman suffered from fibromyalgia. Although a gluten-free diet and budesonide have been effective in some cases, there is no standardized therapy for collagenous gastritis. Our patients trialed diet modification and have required no additional medical interventions.

Omega-3 long-chain polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are poorly synthesised in the human body and are substantially lower in Western diets compared with their shorter-chain omega-3 essential fatty acid precursors, α-linolenic acid (18:3n-3; ALA). We assessed their intake among 111 (20.45 years old; 78 females) De Montfort University (DMU, England) students. The dietary intakes of total fat (100.55 vs. 81.72; p-value = 0.032), PUFA (14.61 vs. 12.91; NS), linoleic acid (LA; 3.893 vs. 2.787; p-value = 0.0019), ALA (0.925 vs. 0.613; p-value = 0.00008), arachidonic acid (AA; 0.109 vs. 0.082; p-value = 0.0303), EPA (0.088 vs. 0.075; NS), DHA (0.153 vs. 0.121; NS), and docosapentaenoic acid (DPA; 0.043 vs. 0.032 all in g/day; NS) were significantly higher or higher in male participants, respectively. The dietary intakes of DHA + EPA in the whole group monitored (0.130 + 0.079 = 0.209 g/day) were lower than the RDI of 0.5 g/day, which considers the intake of one to two portions of fish per week. Our results highlight that some DMU students did not meet the nutritional goals for ALA, EPA, and DHA. DMU students should specifically enhance the intake of oily fish (12.422, 13.406, and 10.054 g/day for the overall, female, and male population, respectively), as these intakes only provide around 0.228, 0.246, and 0.184 g of DHA + EPA/day. Education would be required to increase awareness of the importance of consuming more fish among these young adults. Another option would be to encourage the intake of dietary fish oil supplements or the enrichment of food items largely consumed by young British adults with these long-chain PUFAs.

The aim was two-fold: to characterise the risks of lead (Pb) in Agaricus bitorquis collected in the city of Leicester (England), and to evaluate its presence in urban topsoils. Pb was monitored by ICP-MS in twenty-two homogenised mushroom samples (caps and stipes) mineralised with HNO3/H2O2 [LoD = 0.872 mg/kg dry weight (dw)]. Moreover, 450 topsoil samples were collected from 18 urban parks across Leicester; Pb was also measured by ICP-MS after appropriate digestion (LoD = 0.698 mg/kg). Levels were significantly higher in the mushroom caps (p-value = 3 × 10−5); median and ranges are provided in mg/kg dw: 2.461 (1.806–6.664) vs. 1.579 (0.988–4.223). Concentrations were much higher than those reported in sixteen A. bisporus (median < 1.0 mg/kg DW) specifically cultivated in high-traffic areas in the inner city of Berlin, suggesting some contamination by Pb. All caps monitored exceeded the established maximum concentration limit for Pb in cultivated mushrooms in the European Union (3 mg/kg dw), in line with the high accumulative metal capability described in the literature for Agaricus spp. Although non-carcinogenic risks characterised for Pb were negligible in the monitored mushrooms, a high consumption of wild green edibles in Leicester’s city should be limited as there are multiple additional sources of Pb and other metals, and they should be substituted by cultivated edibles where possible.

The aims were: (a) to biomonitor vanadium (V) in wild edible mushrooms collected from urban/rural areas across Leicestershire (England); (b) to characterise the risk to humans caused by its content in topsoils. Thirty-four mushrooms were collected: twenty-two Agaricus bitorquis from a green area close to a busy traffic area; four Marasmius oreades from the NE; and eight Coprinus atramentarius from Bradgate Park, which is northwest of Leicester city. Moreover, 850 topsoil samples were collected and processed as composite samples (eighteen urban and eight rural), which were further processed in duplicate. The level of V was measured twice in each of the 52 composite samples and in the cleaned, dried and homogenised mushrooms by ICP-MS. Significant higher levels of V were found in C. atramentarius (0.856 (0.175–4.338)) than in the edible mushrooms collected in the urban areas (M. oreades, 0.305 (A. bitorquis, 0.078 (

A diversified energy portfolio may include marine energy in the form of current energy converters (CECs) such as tidal or in-river turbines. New technology development in the research stage typically requires monitoring for environmental effects. A significant environmental effect of concern for CECs is the risk of moving parts (e.g., turbine blades) colliding with animals such as fishes. CECs are installed in energetic locations in which it is difficult to operate sensors to fulfill monitoring requirements for informing collision risk. Collecting data (i.e., about blade strikes or near-misses) that inform interactions of fishes with CECs is usually attempted using active acoustic sensors or video cameras (VCs). Limitations of low-light conditions or water turbidity that preclude effective use of VCs are overcome by using high-resolution multibeam echosounders (or acoustic cameras (ACs)). We used an AC at two sites to test its ability to detect artificial and real fish targets and determine if strike, near-miss, and near-field behavior could be observed. Interactions with fish and artificial targets with turbines have been documented but strike confirmation with an AC is novel. The first site was in a tidal estuary with a 25 kW turbine and water clarity sufficient to allow VC data to be collected concurrently with AC data showing turbine blade strike on tethered artificial fish targets. The second site was a turbid, debris-laden river with a 5 kW turbine where only AC data were collected due to high water turbidity. Data collection at the second site coincided with downstream Pacific salmon (Oncorhynchus spp.) smolt migration. Physical fish capture downstream of the turbine was performed with an incline plane trap (IPT) to provide context for the AC observations, by comparing fish catches. Discrimination between debris and fishes in the AC data was not possible, because active movement of fishes was not discernable. Nineteen fishes were released upstream of the turbine to provide known times of possible fish/turbine interactions, but detection was difficult to confirm in the AC data. ACs have been used extensively in past studies to count large migratory fish such as Pacific salmon, but their application for small fish targets has been limited. The results from these two field campaigns demonstrate the ability of ACs to detect targets in turbid water and observe blade strikes, as well as their limitations such as the difficulty of distinguishing small fishes from debris in a high-energy turbid river. Recommendations are presented for future applications associated with CEC device testing.