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Purpose: Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution. Experimental Design: This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference. Results: Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data. Conclusions: AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.

Introduction Prostate artery embolization (PAE) is an effective in patients with benign prostatic hyperplasia (BPH) particularly. Balloon occlusion PAE (bPAE) is novel procedural adaption to the standard technique using a 2.2fr microcatheter with a compliant silicone balloon. Methods Retrospective single centre study of the first experience of balloon occlusion microcatheter for PAE in the UK. All patients undergoing PAE in the last 18 months were identified and those who had bPAE were included. Results 22 patients were included in the study mean age 72 (11 IQR, 67.25-78.2). Median prostate volume was 121g (86.75 IQR, 57.5- 144.25). Median IPSS, Qmax and PVR at base line were 19 (5.25 IQR, 16-21.25), 7.4 ml/s (4.27 IQR, 5-9.35), 188 mls (255 IQR, 42.5 - 298) respectively. Four patients had long term catheters pre-procedure. Patients were embolised with 45-150 µm Contour PVA particles (n=8) or 250 µm Embozene microspheres (n = 14) (Boston Scientific, MA, USA). At 3 months post bPAE, MRI demonstrated prostate volume reduction of 31% (37.5± IQR, 11-48.5) with a further infarct of a median of 5ml (9.6 IQR, 0.95-10.6). IPSS reduction of 11 points (8.5 IQR, 7-15.5), Qmax of 11.6 ml/s (13.4 IQR, 4.8-18.2) and PVR of 98 mls (161 IQR, 19-180). Conclusion Balloon occlusion PAE is effective in reducing lower urinary tract symptoms. It effectively reversed the penile and rectal shunts in 8/22 cases with no cases of non-target embolization.

Supplementary Figure S4

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor–normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers.Significance:Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers.This article is highlighted in the In This Issue feature, p. 2945

Supplementary Methods

Purpose:Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution.Experimental Design:This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference.Results:Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data.Conclusions:AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.

Supplementary Tables 1-6

Supplementary Figure 3. HRD Sum scores from ScarHRD analysis for biallelic, monoallelic, or no loss of HR genes in aoCPG and control samples.

Supplementary Figure 1. Signature exposures in 21 samples with aoCPG variants

Supplementary Figure 2. Molecular features of tumors harboring pathogenic aoCPG variants showing the full range of additional somatic second hits.

Substance P analogues, including [D-Arg1,D-Trp5,7,9,Leu11]SP (SPA) are broad-spectrum G protein–coupled receptor (GPCR) antagonists that have potential antitumorigenic activities, although the mechanism(s) are not completely understood. Here, we examined the effects of SPA in ductal pancreatic cancers that express multiple GPCRs for mitogenic agonists and also produce proangiogenic chemokines. Using HPAF-II, a well-differentiated pancreatic cancer cell line as our model system, we showed that SPA inhibited multiple neuropeptide-induced Ca2+ mobilization, DNA synthesis, and anchorage-independent growth in vitro. SPA also significantly attenuated the growth of HPAF-II tumor xenografts in nude mice beyond the treatment period. Interestingly, SPA markedly increased apoptosis but moderately decreased proliferation marker, Ki-67 in the tumor xenografts implying additional mechanism(s) for the significant growth inhibitory effect observed in vivo. HPAF-II cells express ELR+ CXC chemokines, including IL-8/CXCL8, which bind to CXCR2 (a member of GPCR superfamily) and promote angiogenesis in multiple cancers, including pancreatic cancer. SPA inhibited CXCR2-mediated Ca2+ mobilization and blocked specifically IL-8/CXCL8-induced angiogenesis in rat corneal micropocket assay in vivo. A salient feature of the results presented here is that SPA markedly reduced tumor-associated angiogenesis in the HPAF-II xenografts in vivo. Our results show that SPA, a broad-spectrum GPCR antagonist attenuates tumor growth in pancreatic cancer via a dual mechanism involving both the antiproliferative and antiangiogenic properties. We conclude that this novel dual-inhibitory property of SPA could be of significant therapeutic value in pancreatic cancer, when used in combination with other antiproliferative and/or antiangiogenic agents.

Supplementary Table S1 from Broad-Spectrum G Protein–Coupled Receptor Antagonist, [D-Arg1,D-Trp5,7,9,Leu11]SP: A Dual Inhibitor of Growth and Angiogenesis in Pancreatic Cancer

Mutations of the RET proto-oncogene are responsible for several inherited human diseases and may function as genetic modifiers of the disease. However, the role of RET mutations in pancreatic cancer has not been studied. Expression of the glial cell line–derived neurotrophic factor (GDNF) receptors RET and GDNF family receptor α1 (GFRα1) in human pancreatic cancer cells was determined by Western blot, immunofluorescence, and flow cytometry. The effect of GDNF on cell proliferation and invasion was assessed. Small interfering RNA and antibodies were used to evaluate the involvement of RET. The G691S RET polymorphism was analyzed by sequencing and restriction analysis. The modifying effect of G691S RET on GDNF-induced invasion and mitogen-activated protein kinase (MAPK) signaling was evaluated. Transfection studies with wild-type and mutated RET determined the functional role of the G691S polymorphism. Pancreatic cancer specimens and matched tissues were analyzed for the presence of the G691S RET polymorphism. GDNF receptors were found on all cell lines. GDNF increased pancreatic cancer cell proliferation and invasion, which was mediated by RET. The effect of GDNF was more profound in cells with the G691S RET polymorphism (P < 0.01). G691S RET correlated with an enhanced activation of the downstream extracellular signal-regulated kinase pathway. Overexpression of G691S RET increased pancreatic cancer cell invasion. The G691S RET polymorphism was also detected in human pancreatic tumors and represented a somatic mutation in some patients. These findings indicate that the G691S RET single nucleotide polymorphism may directly correlate with the aggressive growth of pancreatic cancers and may function as a genetic modifier or even low-penetrance gene. (Cancer Res 2005; 65(24): 11536-44)

Supplementary Materials and Figure 1 from The G691S RET Polymorphism Increases Glial Cell Line–Derived Neurotrophic Factor–Induced Pancreatic Cancer Cell Invasion by Amplifying Mitogen-Activated Protein Kinase Signaling

Many early-career neuroscientists with diverse identities may not have mentors who are more advanced in the neuroscience pipeline and have a congruent identity due to historic biases, laws, and policies impacting access to education. Cross-identity mentoring relationships pose challenges and power imbalances that impact the retention of diverse early career neuroscientists, but also hold the potential for a mutually enriching and collaborative relationship that fosters the mentee’s success. Additionally, the barriers faced by diverse mentees and their mentorship needs may evolve with career progression and require developmental considerations. This article provides perspectives on factors that impact cross-identity mentorship from individuals participating in Diversifying the Community of Neuroscience (CNS)—a longitudinal, National Institute of Neurological Disorders and Stroke (NINDS) R25 neuroscience mentorship program developed to increase diversity in the neurosciences. Participants in Diversifying CNS were comprised of 14 graduate students, postdoctoral fellows, and early career faculty who completed an online qualitative survey on cross-identity mentorship practices that impact their experience in neuroscience fields. Qualitative survey data were analyzed using inductive thematic analysis and resulted in four themes across career levels: (1) approach to mentorship and interpersonal dynamics, (2) allyship and management of power imbalance, (3) academic sponsorship, and (4) institutional barriers impacting navigation of academia. These themes, along with identified mentorship needs by developmental stage, provide insights mentors can use to better support the success of their mentees with diverse intersectional identities. As highlighted in our discussion, a mentor’s awareness of systemic barriers along with active allyship are foundational for their role.

Background Hand dermatitis is a well-established occupational risk in nursing staff. Aims To explore skin health in nursing staff and to develop resources and recommendations to promote good skincare at work. Methods Cross-sectional survey. Results We analysed data from 1,545 surveys. Forty-six percent reported ‘poor’ skin health and the majority (93%) experienced at least one skin problem over the previous 12 months, with only 22% seeking help from their employer. Only 2% took time off work due to skin problems, with many expressing concerns that taking sick leave would be viewed negatively by others. Over half (53%) had reduced or stopped using antibacterial rubs and soap, and 18% had reduced the use of gloves. Most respondents used hand cream and over half used products they had purchased themselves. Only 42% received skin health care information from employers, with fewer (26%) receiving training on how to identify early signs of skin disease. Only 16% had access to skin surveillance in line with regulatory requirements. Only 26% of respondents were aware of the support offered by their professional nursing association. Suggestions for improving skin health included increasing publicity concerning the importance of skin health in healthcare settings, improving access to hand creams, better quality products, enhanced education and training and more involvement from Occupational Health (OH). Conclusions Results confirm that poor skin health remains a persistent problem for nurses. Employers could do more to promote skin health and nurses need to be made more aware of the support and guidance offered by professional bodies.

Animal data show that the presence of an oncogenic Kras mutation in pancreatic acinar cells leads to acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Inflammatory macrophages play an important role in the formation of ADMs and transition to PanINs. Epidemiologically, statins are associated with a reduced risk of PDAC. We investigated whether statins inhibit inflammatory cytokine production in macrophages and whether this leads to reduced ADM formation.The efficacy of statins on inflammatory cytokine production in 2 macrophage cell lines was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of macrophage-conditioned medium on ADM in primary pancreatic acinar cells was investigated. Mouse pancreatic tissue samples were analyzed for macrophage numbers, cytokine levels, and neoplastic/dysplastic area.Lipophilic statins prevented inflammatory cytokine production in Raw264.7 and J774A.1 cells stimulated by lipopolysaccharide. The inhibitory effect of statins was mediated by inhibition of mevalonate and geranylgeranyl pyrophosphate synthesis and disruption of the actin cytoskeleton but not by a reduction in intracellular cholesterol. Treatment of macrophages with lipophilic statins also blocked ADM formation of primary pancreatic acinar cells. Furthermore, oral administration of simvastatin was associated with a reduction in the number of intrapancreatic macrophages, decreased inflammatory cytokine levels in the pancreas, and attenuated ADM/PanIN formation in mice.Our data support the hypothesis that statins oppose early PDAC development by their effects on macrophages and ADM formation. The inhibitory actions of statins on macrophages may collaborate with direct inhibitory effects on transformed pancreatic epithelial cells, which cumulatively may reduce early PDAC development and progression.

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Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology of the human disease, and sometimes accurately recreate the genetic perturbations found in patients. Ideally, models achieve both, but this is not always possible; nonetheless, such models are informative. Here we describe two animal models of inherited peripheral neuropathy: mice with a mutation in tyrosyl tRNA-synthetase, YarssupE196K/sup, modeling dominant intermediate Charcot-Marie-Tooth disease type C (diCMTC), and mice with a mutation in serine palmitoyltransferase long chain 1, Sptlc1supC133W/sup, modeling hereditary sensory and autonomic neuropathy type 1 (HSAN1). YarssupE196K/supmice develop disease-relevant phenotypes including reduced motor performance and reduced nerve conduction velocities by 4 months of age. Peripheral motor axons are reduced in size, but there is no reduction in axon number and plasma neurofilament light chain levels are not increased. Unlike the dominant human mutations, the YarssupE196K/supmice only show these phenotypes as homozygotes, or as compound heterozygotes with a null allele, and no phenotype is observed in E196K or null heterozygotes. The Sptlc1supC133W/supmice carry a knockin allele and show the anticipated increase in 1-deoxysphingolipids in circulation and in a variety of tissues. They also have mild behavioral defects consistent with HSAN1, but do not show neurophysiological defects or axon loss in peripheral nerves or in the epidermis of the hind paw or tail. Thus, despite the biochemical phenotype, the Sptlc1supC133W/supmice do not show a strong neuropathy phenotype. Surprisingly, these mice were lethal as homozygotes, but the heterozygous genotype studied corresponds to the dominant genetics seen in humans. Thus, YarssupE196K/suphomozygous mice have a relevant phenotype, but imprecisely reproduce the human genetics, whereas the Sptlc1supC133W/supmice precisely reproduce the human genetics, but do not recreate the disease phenotype. Despite these shortcomings, both models are informative and will be useful for future research.

The implementation of 5G-and-beyond networks requires faster, high-performance, and power-efficient semiconductor devices, which are only possible with materials that can support higher frequencies. Gallium nitride (GaN) power amplifiers are essential for 5G-and-beyond technologies since they provide the desired combination of high frequency and high power. These applications along with terrestrial hub and backhaul communications at high power output can present severe heat removal challenges. The cooling of GaN devices with diamond as the heat spreader has gained significant momentum since device self-heating limits GaN's performance. However, one of the significant challenges in integrating polycrystalline diamond on GaN devices is maintaining the device performance while achieving a low diamond/GaN channel thermal boundary resistance. In this study, we achieved a record-low thermal boundary resistance of around 3.1 ± 0.7 m

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Highlights from the Science family of journals

Highlights from the Science family of journals

Highlights from the Science family of journals

Highlights from the Science family of journals

Highlights from the Science family of journals

Highlights from the Science family of journals

B lymphocytes play a central role in host immune defense. B cell receptor (BCR) signaling regulates survival, proliferation and differentiation of B lymphocytes. Signaling through the BCR signalosome is a multi-component cascade that is tightly regulated and is important in the coordination of B cell differentiation and function. At different stages of development, B cells that have BCRs recognizing self are eliminated to prevent autoimmunity. microRNAs (miRNAs) are small single-stranded non-coding RNAs that contribute to post-transcriptional regulation of gene expression and have been shown to orchestrate cell fate decisions through the regulation of lineage specific transcriptional profiles. Studies have identified miRNAs to be crucial for B cell development in the bone marrow and their subsequent population of the peripheral immune system. In this review, we focus on the role of miRNAs in the regulation of BCR signaling as it pertains to B lymphocyte development and function. In particular, we discuss the most recent studies describing the role of miRNAs in the regulation of both early B cell development and peripheral B cell responses and examine the ways by which miRNAs regulate signals downstream of B cell antigen receptor to prevent aberrant activation and autoimmunity.

Measuring the maximum operating temperature within the channel of ultrawide band-gap transistors is critically important since the temperature dependence of the device reliability sets operational limits such as maximum operational power. Thermoreflectance imaging (TTI) is an optimal choice to measure the junction temperature due to its submicrometer spatial resolution and submicrosecond temporal resolution. Since TTI is an imaging technique, data acquisition is orders of magnitude faster than point measurement techniques such as Raman thermometry. Unfortunately, commercially available LED light sources used in thermoreflectance systems are limited to energies less than ∼3.9 eV, which is below the band gap of many ultrawide band-gap semiconductors (>4.0 eV). Therefore, the semiconductors are transparent to the probing light sources, prohibiting the application of TTI. To address this thermal imaging challenge, we utilize an MoS2 coating as a thermoreflectance enhancement coating that allows for the measurement of the surface temperature of (ultra)wide band-gap materials. The coating consists of a network of MoS2 nanoflakes with the c axis aligned normal to the surface and is easily removable via sonication. The method is validated using electrical and thermal characterization of GaN and AlGaN devices. We demonstrate that this coating does not measurably influence the electrical performance or the measured operating temperature. A maximum temperature rise of 49 K at 0.59 W was measured within the channel of the AlGaN device, which is over double the maximum temperature rise obtained by measuring the thermoreflectance of the gate metal. The importance of accurately measuring the peak operational temperature is discussed in the context of accelerated stress testing.

Charcot–Marie–Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot–Marie–Tooth disease type 2S (CMT2S). Using CRISPR-cas9 mutagenesis, we developed the first mouse models of CMT2S [p.Glu365del (E365del) and p.Tyr918Cys (Y918C)]. E365del is the first CMT2S mouse model to be discovered and Y918C is the first human CMT2S allele knock-in model. Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration. Neuromuscular and locomotor assays indicate that both E365del and Y918C mice have motor deficits, while neurobehavioral characterization of sensory function found that E365del mutants have mechanical allodynia. Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but it does so in the Y918C model. Based on these results, the E365del mutant mouse, and the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2. These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.

Aim PAE (prostatic arterial embolisation) is a non-surgical, minimally invasive procedure used to treat symptoms of benign prostatic hyperplasia (BPH). It is used to treat patients with moderate to severe lower urinary tract symptoms including those requiring long term urinary catheter placement and intermittent self-catheterisation. The incidence of urinary tract infection is greater in this group at baseline and the risk of infection as a complication of PAE is recognised in the literature. This study aimed to compare the clinical outcomes of PAE to those of TURP (transurethral resection of the prostate), the reference standard for BPH treatment. Method All patients who underwent PAE between 2019 to 2021 at a single centre were included in this retrospective study. Clinical outcomes of patients were also recorded including international prostate symptom score (IPSS) and urodynamic results. These were compared to TURP results provided in the UK ROPE study. Results 82% of patients experienced an improved IPSS after PAE, with a median reduction of 15 points, compared with a median reduction of 17 points with TURP. PAE caused a greater reduction in median prostate volume but proved to be less effective in improving urodynamic test results when compared to TURP. Conclusion While still clinically effective, PAE is less effective for treatment of lower urinary tract symptoms from BPH when compared to TURP.

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Renal masses are commonly encountered on cross-sectional imaging examinations performed for nonrenal indications. Although most can be dismissed as benign cysts, a subset will be either indeterminate or suspicious; in many cases, imaging cannot be used to reliably differentiate between benign and malignant masses. On-going research in defining characteristics of common renal masses on advanced imaging shows promise in offering solutions to this issue. A recent update of the Bosniak classification (used to categorize cystic renal masses) was proposed with the goals of decreasing imaging follow-up in likely benign cystic masses, and therefore avoiding unnecessary surgical resection of such masses.

Highlights from the Science family of journals

Highlights from the Science family of journals

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