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Single neutral pion production via muon antineutrino charged-current interactions in plastic scintillator (CH) is studied using the MINERvA detector exposed to the NuMI low-energy, wideband antineutrino beam at Fermilab. Measurement of this process constrains models of neutral pion production in nuclei, which is important because the neutral-current analog is a background for ν¯e appearance oscillation experiments. The differential cross sections for π0 momentum and production angle, for events with a single observed π0 and no charged pions, are presented and compared to model predictions. These results comprise the first measurement of the π0 kinematics for this process.

Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC) n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC) n , which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.

Here, the authors track the evolution of mass distribution through bird evolution challenging suggested coupling between body shape and centre-of-mass position, and instead showing that crouched bipedalism evolved after powered flight.

Here, the authors examine how body size, shape, and segment proportions correspond to ecology in models of 410 tetrapods. They find variable allometric relationships, differential scaling in small and large animals, and body proportions as a potential niche occupation mechanism.

IntroductionThe visual signals evoked at the retinal ganglion cells are modified and modulated by various synaptic inputs that impinge on lateral geniculate nucleus cells before they are sent to the cortex. The selectivity of geniculate inputs for clustering or forming microcircuits on discrete dendritic segments of geniculate cell types may provide the structural basis for network properties of the geniculate circuitry and differential signal processing through the parallel pathways of vision. In our study, we aimed to reveal the patterns of input selectivity on morphologically discernable relay cell types and interneurons in the mouse lateral geniculate nucleus.MethodsWe used two sets of Scanning Blockface Electron Microscopy (SBEM) image stacks and Reconstruct software to manually reconstruct of terminal boutons and dendrite segments. First, using an unbiased terminal sampling (UTS) approach and statistical modeling, we identified the criteria for volume-based sorting of geniculate boutons into their putative origins. Geniculate terminal boutons that were sorted in retinal and non-retinal categories based on previously described mitochondrial morphology, could further be sorted into multiple subpopulations based on their bouton volume distributions. Terminals deemed non-retinal based on the morphological criteria consisted of five distinct subpopulations, including small-sized putative corticothalamic and cholinergic boutons, two medium-sized putative GABAergic inputs, and a large-sized bouton type that contains dark mitochondria. Retinal terminals also consisted of four distinct subpopulations. The cutoff criteria for these subpopulations were then applied to datasets of terminals that synapse on reconstructed dendrite segments of relay cells or interneurons.ResultsUsing a network analysis approach, we found an almost complete segregation of retinal and cortical terminals on putative X-type cell dendrite segments characterized by grape-like appendages and triads. On these cells, interneuron appendages intermingle with retinal and other medium size terminals to form triads within glomeruli. In contrast, a second, presumed Y-type cell displayed dendrodendritic puncta adherentia and received all terminal types without a selectivity for synapse location; these were not engaged in triads. Furthermore, the contribution of retinal and cortical synapses received by X-, Y- and interneuron dendrites differed such that over 60% of inputs to interneuron dendrites were from the retina, as opposed to 20% and 7% to X- and Y-type cells, respectively.ConclusionThe results underlie differences in network properties of synaptic inputs from distinct origins on geniculate cell types.

Abstract Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

Abstract Koala Retrovirus (KoRV) has been widely speculated to cause immune suppression in koalas (Phascolarctos cinereus) and to underlie the koala’s susceptibility to infectious disease, however evidence for immunomodulation is limited. The aim of this study is to determine whether immunophenotypic changes are associated with KoRV infection in free ranging Victorian koalas. qPCR was used to examine mRNA expression for Th1 (IFNγ), Th2-promoting (IL6, IL10) and Th17 (IL17A) cytokines, along with CD4 and CD8 in whole blood of koalas (n = 74) from Mt Eccles and Raymond Island in Victoria, Australia, with and without natural chlamydial infection. KoRV positive koalas had significantly lower levels of IL17A (p`0.023) and IFNγ (p = 0.044) gene expression along with a decreased CD4:CD8 gene expression ratio (p = 0.025) compared to negative koalas. No effect of chlamydial infection or combined effect of KoRV and chlamydial infection was detected in these populations. The decreased expression of IFNγ could make KoRV infected koalas more susceptible to persistent chlamydial infection, and a decrease in IL17A could make them more susceptible to gram negative bacterial, fungal and mycobacterial infection; but more tolerant of chlamydial infection.

Summary: Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of DKK2 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including LGR5 in a model of colitis-associated cancer. Sequential mutations in APC, KRAS, TP53, and SMAD4 genes in colonic organoids revealed a significant increase of DKK2 expression by APC knockout and further increased by additional KRAS and TP53 mutations. Moreover, DKK2 activates proto-oncogene tyrosine-protein kinse Src followed by increased LGR5 expressing cells in colorectal cancer through degradation of HNF4α1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.

To determine if infant vaccinations are associated with childhood asthma among full-term infants. The secondary objective was to describe relationships between characteristics of infant wheezing and childhood asthma. We used baseline data from a study of infant wheezing that selected full-term infants born into a health maintenance organization (HMO) during 1991–1994, continuously enrolled for at least 12 months and without perinatal pulmonary or other selected conditions. Information had been abstracted for infancy (0–18 months) regarding wheezing, vaccinations and asthma risk factors. Using automated data, we identified asthma cases in 1998 among those enrolled for at least 6 months during the year. A total of 1778 full-term infants met our study criterion and 9% had asthma in 1998. Childhood asthma was not significantly associated with having received Hepatitis B vaccine or age at first Hepatitis B vaccine; number of whole-cell pertussis, Haemophilis influenzae type b or oral polio vaccine doses; having received measles, mumps, rubella vaccine; or total number of vaccine doses combined. Childhood asthma was significantly associated with number of infant wheezing episodes. Our findings do not support concerns that vaccines are associated with increased risk of asthma but confirm that frequency of infant wheezing is associated with childhood asthma. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The transfer of technology from the foreign partner to the domestic partner has been a problem for international joint ventures throughout the world, but particularly in China. Because of the nature of organisational learning, especially in its tacit forms, such transfers can occur quite subtly without the foreign partner realising what has transpired until it is too late. The problem is complicated by the fact that technology is short-lived and must be exploited within narrow time frames, the fact that the Chinese partner's primary interest is in acquiring the foreign partner's technology, and the fact that the foreign partner typically shows little interest in obtaining the Chinese partner's unique non-technical knowledge as an offset. This article attempts to show how technology transfers can be controlled in the first place and how the foreign partner's competitive advantage can be preserved by acquiring the domestic partner's unique knowledge of host country circumstances. [ABSTRACT FROM AUTHOR]

The second of two articles on the transfer from foreign companies to affiliates in China. Addresses wholly owned subsidiaries. Tries to determine strategic management know-how and if it is currently being transferred. Attempts to forecast the likelihood of access to China's domestic market and if this will grow. [ABSTRACT FROM AUTHOR]

Looks at the problems of logistics in military operations and today’s commercial businesses. Traces the development of logistics management from a subordinate activity within a product producing entity to its performance by a separate entity which specializes in this area and requires a strategic alliance. Looks at this issue from the perspective of the outsourcing company and the logistical company. Considers what happens when this process is reversed and provides implications for the future. [ABSTRACT FROM AUTHOR]

Outlines the Japanese system of protectionism as a global barrier and focuses on the rice markets as one of the first markets to be opened up. Analyses the reasons for this and offers strategies for overseas companies to take advantage of this opportunity. Suggest that these examples can then be applied to other markets. [ABSTRACT FROM AUTHOR]

Abstract Background Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial fibrosing lung disease, manifesting as cough, exercise intolerance and ultimately, dyspnea and respiratory failure. It mainly affects West Highland white terriers (WHWTs), lacks curable treatment and has a poor prognosis. Aspiration of gastroesophageal refluxate may play a role in the development of CIPF. In the first part of this study, we completed label-free quantitative proteomic analysis of bronchoalveolar lavage fluid (BALF) from CIPF and healthy WHWTs. In the second part, we evaluated potential protein markers of reflux aspiration from canine gastric juice and vomitus and whether these were present in BALF from the two groups. Results Across all BALF samples, 417 proteins were identified, and of these, 265 proteins were identified by two or more unique tryptic peptides. Using the 265 high confidence assignments, the quantitative proteome profiles were very similar in the two cohorts, but they could be readily resolved by principal component analysis on the basis of differential protein expression. Of the proteins that were differentially abundant in the two groups, several (including inflammatory and fibrotic markers) were elevated in CIPF, and a smaller, more diverse group of proteins were diminished in CIPF. No protein markers indicative of reflux aspiration were identified. Conclusions Label-free proteomics allowed discrimination between CIPF and healthy WHWTs, consistent with fibrotic process but did not provide clear evidence for gastrointestinal aspiration. The measurement of proteins may provide a proteomics signature of CIPF that could be used to evaluate treatment options.

Background: Early diagnosis and treatment are important to reduce neonatal morbidity and mortality occurring from hypoxic ischemic encephalopathy (HIE). Objective: We aimed to correlate between urinary Activin-A and MRI (conventional and diffusion-weighted) and the degree of HIE according to Sarnat and Sarnat staging. Methods: Sixty full term neonates (37–42 weeks) selected from Minia University hospital for children from May 2014 to July 2016 were enrolled into the study. We measured urinary Activin-A using enzyme immunoassay and MRI using MRI scanner (Philips Achieva) and correlations between urinary Activin-A and MRI with the degree of HIE were done. Results: Neonates with HIE had higher levels of urinary Activin-A than controls (P

A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLB allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.

Background. Several studies have shown that Alaska Native people have higher smoking prevalence than non-Natives. However, no population-based studies have explored whether smoking-related knowledge, attitudes, and behaviours also differ among Alaska Native people and non-Natives. Objective. We compared current smoking prevalence and smoking-related knowledge, attitudes, and behaviour of Alaska Native adults living in the state of Alaska with non-Natives. Methods. We used Alaska Behavioral Risk Factor Surveillance System data for 1996 to 2010 to compare smoking prevalence, consumption, and cessation- and second-hand smoke-related knowledge, attitudes, and behaviours among self-identified Alaska Native people and non-Natives. Results. Current smoking prevalence was 41% (95% CI: 37.9%–44.4%) among Alaska Native people compared with 17.1% (95% CI: 15.9%–18.4%) among non-Natives. Among current every day smokers, Alaska Natives were much more likely to smoke less than 10 cigarettes per day (OR=5.0, 95% CI: 2.6–9.6) than non-Natives. Compared with non-Native smokers, Alaska Native smokers were as likely to have made a past year quit attempt (OR=1.4, 95% CI: 0.9–2.1), but the attempt was less likely to be successful (OR=0.5, 95% CI: 0.2–0.9). Among current smokers, Alaska Natives were more likely to believe second-hand smoke (SHS) was very harmful (OR=4.5, 95% CI: 2.8–7.2), to believe that smoking should not be allowed in indoor work areas (OR=1.9, 95% CI: 1.1–3.1) or in restaurants (OR=4.2, 95% CI: 2.5–6.9), to have a home smoking ban (OR=2.5, 95% CI: 1.6–3.9), and to have no home exposure to SHS in the past 30 days (OR=2.3, 95% CI: 1.5–3.6) than non-Natives. Conclusion. Although a disparity in current smoking exists, Alaska Native people have smoking-related knowledge, attitudes, and behaviours that are encouraging for reducing the burden of smoking in this population. Programs should support efforts to promote cessation, prevent relapse, and establish smoke-free environments.

Koala (Phascolarctos cinereus) populations are increasingly vulnerable and one of the main threats is chlamydial infection. Koala retrovirus (KoRV) has been proposed as an underlying cause of the koala's susceptibility to infection with Chlamydia and high rates of lymphoid neoplasia; however, the regionally ubiquitous, endogenous nature of this virus suggests that KoRV A infection is not sufficient for immune suppression to occur. A recently discovered exogenous variant of KoRV, KoRV B, has several structural elements that cause increased pathogenicity in related retroviruses and was associated with lymphoid neoplasia in one study. The present study assesses whether KoRV B infection is associated with alterations in immune function. Cytokine gene expression by mitogen stimulated lymphocytes of KoRV B positive (n = 5-6) and negative (n = 6-7) captive koalas was evaluated by qPCR four times (April 2014-February 2015) to control for seasonal variation. Key immune genes in the Th1 pathway (IFNγ, TNFα), Th2 pathway (IL 10, IL4, IL6) and Th17 pathway (IL17A), along with CD4:CD8 ratio, were assessed. KoRV B positive koalas showed significantly increased up-regulation of IL17A and IL10 in three out of four sampling periods and IFNγ, IL6, IL4 and TNFα in two out of four. IL17A is an immune marker for chlamydial pathogenesis in the koala; increased expression of IL17A in KoRV B positive koalas, and concurrent immune dysregulation, may explain the differences in susceptibility to chlamydial infection and severity of disease seen between individuals and populations. There was also marked seasonal variation in up-regulation for most of the cytokines and the CD4:CD8 ratio. The up-regulation in both Th1 and Th2 cytokines mirrors changes associated with immune dysregulation in humans and felids as a result of retroviral infections. This is the first report of altered immune expression in koalas infected by an exogenous variant of KoRV and also the first report of seasonal variation in cytokine up-regulation and CD4:CD8 ratio in marsupials.

Abstract We report a case of a cystic abdominal mass on ultrasound which presented a diagnostic dilemma at 32 weeks gestation. A presumptive antenatal diagnosis of a subcapsular liver hematoma (SCH) was made based on the location and ultrasound appearance similar to SCH seen in pediatric and adult patients. Sequential evaluation of the mass showed an evolving ultrasound appearance which reinforced our initial impression of a subcapsular hematoma of the fetal liver. Postnatal ultrasound confirmed the resolving SCH as well as a previously undetected echo bright lesion characteristic of an infantile focal hemangioma directly adjacent to the resolving SCH. A review of the literature is provided.

The nematode Angiostrongylus cantonensis is a rat lungworm, a zoonotic pathogen that causes human eosinophilic meningitis and ocular angiostrongyliasis characteristic of rat lungworm (RLW) disease. Definitive diagnosis is made by finding and identifying A. cantonensis larvae in the cerebral spinal fluid or by using a custom immunological or molecular test. This study was conducted to determine if genomic DNA from A. cantonensis is detectable by qPCR in the blood or tissues of experimentally infected rats. F1 offspring from wild rats were subjected to experimental infection with RLW larvae isolated from slugs, then blood or tissue samples were collected over multiple time points. Blood samples were collected from 21 rats throughout the course of two trials (15 rats in Trial I, and 6 rats in Trial II). In addition to a control group, each trial had two treatment groups: the rats in the low dose (LD) group were infected by approximately 10 larvae and the rats in the high dose (HD) group were infected with approximately 50 larvae. In Trial I, parasite DNA was detected in cardiac bleed samples from five of five LD rats and five of five HD rats at six weeks post-infection (PI), and three of five LD rats and five of five HD rats from tail tissue. In Trial II, parasite DNA was detected in peripheral blood samples from one of two HD rats at 53 minutes PI, one of two LD rats at 1.5 hours PI, one of two HD rats at 18 hours PI, one of two LD rats at five weeks PI and two of two at six weeks PI, and two of two HD rats at weeks five and six PI. These data demonstrate that parasite DNA can be detected in peripheral blood at various time points throughout RLW infection in rats.

Investigation of the immune response of the koala (Phascolarctos cinereus) is needed urgently, but has been limited by scarcity of species-specific reagents and methods for this unique and divergent marsupial. Infectious disease is an important threat to wild populations of koalas; the most widespread and important of these is Chlamydial disease, caused by Chlamydia pecorum and Chlamydia pneumoniae. In addition, koala retrovirus (KoRV), which is of 100% prevalence in northern Australia, has been proposed as an important agent of immune suppression that could explain the koala’s susceptibility to disease. The correct balance of T regulatory, T helper 1 (Th1) and Th2 lymphocyte responses are important to an individual’s susceptibility or resistance to chlamydial infection. The ability to study chlamydial or KoRV pathogenesis, effects of environmental stressors on immunity, and the response of koalas to vaccines under development, by examining the koala’s adaptive response to natural infection or in-vitro stimulation, has been limited to date by a paucity of species- specific reagents. In this study we have used cytokine sequences from four marsupial genomes to identify mRNA sequences for key T regulatory, Th1 and Th2 cytokines interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10) and interferon gamma (IFNγ) along with CD4 and CD8β. The koala sequences used for primer design showed >58% homology with grey short-tailed opossum, >71% with tammar wallaby and 78% with Tasmanian devil amino acid sequences. We report the development of real-time RT-PCR assays to measure the expression of these genes in unstimulated cells and after three common mitogen stimulation protocols (phorbol myristate acetate/ionomycin, phorbol myristate acetate/phytohemagglutinin and concanavalin A). Phorbol myristate acetate/ionomycin was found to be the most effective mitogen to up-regulate the production of IL-4, IL-10 and IFNγ. IL-6 production was not consistently up-regulated by any of the protocols. Expression of CD4 and CD8β was down-regulated by mitogen stimulation. We found that the reference genes GAPDH and 28s are valid for normalising cytokine expression by koala lymphocytes after mitogen stimulation.

The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease.

Purpose: High-grade gliomas in infants and very young children (less than 3 to 5 years old) pose significant challenges due to the limited scientific literature available and high risks associated with treatments. This study aims to investigate their characteristics, treatment, and outcomes., Methods: A cohort study was conducted at Children's Cancer Hospital, Egypt. Cases included children aged < 5 years old with confirmed CNS high-grade glioma. Baseline clinical and radiological characteristics, besides potential prognostic factors were assessed., Results: In total, 76 cases were identified, 7 of them were < 1 year old. Gross- or near-total resection (GTR/NTR) was achieved in 32.9% of all cases. Of the tested cases, H3K27M-alteration was present in 5 subjects only. The 3-year OS and EFS for all cases were 26.9% and 15.4%, respectively. Extent of resection was the most important prognostic factor, as those achieving GTR/NTR experienced more than double the survival compared to those who do not (p = 0.05). Age had a "bimodal" effect on EFS, with those aged 1 to 3 years old faring better than younger and older age groups. Subjects with midline tumors had worse survival compared to non-midline tumors (1-year EFS = 18.5% vs 35%, respectively, p = 0.02)., Conclusion: This study in a large cohort of HGG in infants and very young children offers insights into the characteristics and treatment challenges. Extent of resection, age group, and tumor localization are important prognostic factors. Further research with larger sample size is warranted to refine treatment approaches and improve outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Delayed healing of chronic wounds results in amputation and mortality rates in serious cases. The present study examines the merged wound-restorative efficacy of injectable bone marrow-derived mesenchymal stem cells (BMMSCs) and topical Callyspongia sp. extract in immunocompromised rats. HR-LC-MS analysis of Callyspongia sp. extract tentatively identified twenty-nine compounds (1-29) and highlighted its richness in fatty acids and terpenoids, known for their wound regenerating efficacies. The wound closure was greatly prominent in the BMMSCs/Callyspongia sp. group in contrast to the control group (p<0.001). The RT-PCR gene expression emphasized these results by attenuating the oxidative, inflammatory, and immunity markers, further confirmed by histopathological findings. Additionally, in silico modeling was particularly targeting matrix metalloproteinase-9 (MMP9), a key player in wound healing processes. Computational analysis revealed that compounds 18 and 19 potentially modulate MMP9 activity. The combination of BMMSCs and topical Callyspongia sp. extract holds a promise for regenerative therapy constituting a drastic advance in the wound cure of immunocompromised patients, eventually further safety assessments and clinical trials are required., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background and Objective: PD-1 inhibitors have revolutionized cancer therapies and are being used to treat an expanding array of cancers. To best serve patients, clinicians should be familiar with the spectrum of skin manifestations associated with PD-1 inhibitor therapy. Here, we report a unique case of hypertrophic lichen planus (HLP) in a 64-year-old man treated with pembrolizumab; the presentation initially suggested a squamous cell carcinoma (SCC) morphology, then evolved into a morphology more typical of hypertrophic lichen planus. This case underscores the need for caution in diagnosing eruptive SCCs associated with PD-1 inhibitor therapy. In such instances, maintaining a high suspicion for lichenoid reactions as sequelae of PD-1 inhibitor treatment and starting an empiric trial of therapy for lichenoid dermatitis may be warranted to ensure timely management of lesions., Methods: We describe a case of hypertrophic lichen planus mimicking squamous cell carcinoma in the setting of PD-1 inhibitory therapy with pembrolizumab. A PubMed literature review was conducted to identify other cases and determine the incidence of lichenoid reactions imitating squamous cell carcinoma in the setting of PD-1 inhibitor use., Results: Our case is one of the few available pieces of literature describing eruptive hypertrophic lichen planus imitating SCC in the setting of PD-1 inhibitor use. Initial skin nodule biopsy appeared histologically compatible with squamous cell carcinoma. Repeat biopsy of the skin lesions revealed histological features consistent with hypertrophic lichen planus. Over time, lower extremity lesions evolved into a more typical appearance of hypertrophic lichen planus. Treatment with topical 0.05% clobetasol ointment and oral acitretin 25 mg led to complete resolution of lesions within 2-3 months., Conclusions: This case underscores the significance of maintaining vigilance for lichenoid reactions as potential sequelae of PD-1 inhibitor therapy. It highlights the variability in initial presentation and the potential for lesions to transform over time. Timely recognition and appropriate management, including high-potency topical corticosteroids and oral acitretin, are crucial for achieving favorable outcomes in patients experiencing such reactions. More studies are necessary to fully analyze the rate of HLP occurrence as a consequence of PD-1 inhibitor use., (© 2024. The Author(s).)

Background: Pure germinomas account for 40% of pineal tumors and are characterized by the lack of appreciable tumor markers, thus requiring a tumor biopsy for diagnosis. MicroRNAs (miRNA) have emerged as potential non-invasive biomarkers for germ cell tumors and may facilitate the non-invasive diagnosis of pure pineal germinomas., Material and Methods: A retrospective chart review was performed on all patients treated at the Children's Cancer Hospital Egypt diagnosed with a pineal region tumor between June 2013 and March 2021 for whom a research blood sample was available. Plasma samples were profiled for miRNA expression, and DESeq2 was used to compare between pure germinoma and other tumor types. Differentially expressed miRNAs were identified. The area under the curve of the receive;r operating characteristic curve was constructed to evaluate diagnostic performance., Results: Samples from 39 pediatric patients were available consisting of 12 pure germinomas and 27 pineal region tumors of other pathologies, including pineal origin tumors [ n = 17; pineoblastoma ( n = 13) and pineal parenchymal tumors of intermediate differentiation ( n = 4)] and others [ n = 10; low-grade glioma ( n = 6) and atypical teratoid rhabdoid tumor ( n = 4)]. Using an adjusted p -value <0.05, three miRNAs showed differential expression (miR-143-3p, miR-320c, miR-320d; adjusted p = 0.0058, p = 0.0478, and p = 0.0366, respectively) and good discriminatory power between the two groups (AUC 90.7%, p < 0.001) with a sensitivity of 25% and a specificity of 100%., Conclusion: Our results suggest that a three-plasma miRNA signature has the potential to non-invasively identify pineal body pure germinomas which may allow selected patients to avoid the potential surgical complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fakhry, Elayadi, Elzayat, Samir, Maher, Taha, El-Beltagy, Refaat, Zamzam, Abdelbaki, Sayed, Kieran and Elhaddad.)

This article focuses on bacterial infections that commonly affect geriatric patients. The elderly population is at a higher risk of contracting bacterial infections due to weakened immune systems and comorbidities. The article explores the cause, pathogenesis, clinical manifestations, and treatment options of these infections. Additionally, antibiotic resistance is a growing concern in the treatment of bacterial infections. The article highlights the importance of preventing these infections through proper hygiene and wound care. This article aims to provide an understanding of bacterial infections in geriatric patients and inform health-care providers on the most effective ways to manage and prevent these infections., Competing Interests: Disclosure No conflicts of interest for the authors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Atypical teratoid rhabdoid tumor (ATRT) is a rare type of potentially fatal childhood brain tumor. The present study aimed to examine the overall survival (OS) and event-free survival (EFS) outcomes of pediatric patients with ATRT and to analyze the impact of different prognostic factors, including age, sex, tumor site and size, metastatic disease, the extent of resection, radiotherapy, and chemotherapy, on survival. The present study included 47 patients with ATRT treated at the Children's Cancer Hospital of Egypt (Cairo, Egypt) between July 2007 and December 2017. These patients were treated according to the Dana-Farber Cancer Institute protocol 02-294 for 51 weeks. Various prognostic factors, including age, sex, tumor size and initial metastatic status, exhibited no impact on the radiological response measured at 6 weeks and at the end of treatment. The primary tumor site significantly affected the response to treatment at 6 weeks (P=0.008). Toxicity-related mortality occurred in 29.8% of patients. The median duration of the treatment protocol was 66.9 weeks. The duration of treatment was in the present cohort was longer than the actual 51 weeks of the protocol due to prolonged supportive care of the included patients. Patients who encountered toxicity received reduced dose of chemotherapy in the subsequent cycles in the protocol. Age, initial metastatic status, tumor site and resection extent did not significantly affect the patient outcomes. Preoperative tumor size significantly affected the EFS (P=0.03) and OS (P=0.04). Radiotherapy administration significantly affected the OS (P<0.001) and EFS (P<0.001). The median EFS and OS of patients were 9.3 and 10.3 months, respectively. A total of 24 (51.1%) patients exhibited disease progression or recurrence. The progression sites were local (n=6), metastatic (n=9) or both local and metastatic (n=9). The results of the present study demonstrated that the therapeutic regimen should be patient-adjusted to maintain the treatment intensity and avoid toxicity-related mortality. In lower middle-income countries, short and intensified induction followed by consolidation of treatment, either by single or tandem autologous stem cell transplant, is needed to avoid prolonged exposure to myelosuppression and toxicity-related mortality., Competing Interests: The authors declare that they have no competing interests., (Copyright: © El-Hemaly et al.)

Background and Objectives: Children and Youth with Special Health Care Needs have high healthcare utilization, fragmented care, and unmet health needs. Accountable Care Organizations (ACOs) increasingly use pediatric care management to improve quality and reduce unnecessary utilization. We evaluated effects of pediatric care management on total medical expense (TME) and utilization; perceived quality of care coordination, unmet needs, and patient and family experience; and differential impact by payor, risk score, care manager discipline, and behavioral health diagnosis., Methods: Mixed-methods analysis including claims using quasi-stepped-wedge design pre and postenrollment to estimate difference-in-differences, participant survey, and semistructured interviews. Participants included 1321 patients with medical, behavioral, or social needs, high utilization, in Medicaid or commercial ACOs, and enrolled in multidisciplinary, primary care-embedded care management., Results: TME significantly declined 1 to 6 months postenrollment and continued through 19 to 24 months (-$645.48 per member per month, P < .001). Emergency department and inpatient utilization significantly decreased 7 to 12 months post-enrollment and persisted through 19 to 24 months (-29% emergency department, P = .012; -82% inpatient, P < .001). Of respondents, 87.2% of survey respondents were somewhat or very satisfied with care coordination, 56.1% received education coordination when needed, and 81.5% had no unmet health needs. Emergency department or inpatient utilization decreases were consistent across payors and care manager disciplines, occurred sooner with behavioral health diagnoses, and were significant among children with above-median risk scores. Satisfaction and experience were equivalent across groups, with more unmet needs and frustration with above-median risk scores., Conclusions: Pediatric care management in multipayor ACOs may effectively reduce TME and utilization and clinically provide high-quality care coordination, including education and family stress, with high participant satisfaction., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: The pediatric pulmonary multisystem Langerhans cell histiocytosis (PPM LCH) is associated with either low risk or high risk organ(s). The nodulo-cystic lung lesions although pathognomonic, yet are very variable in severity and remain a source of controversy in certifying pulmonary LCH diagnosis. The study aimed to examine the prognostic value of clinical respiratory manifestations and radiological lung lesions severity. This is through associating a CT chest triad of bilateral, extensive and diffuse lesions. It is a retrospective study of 350 LCH patients who received systemic treatment at Children's Cancer Hospital Egypt during the period from 2007 to 2020., Results: Sixty-seven patients (67/350-19.1%) had PPM LCH at presentation. Severe lung lesions were present in 24 of them. The median follow-up period was 61 months (IQR: 3.4-8.3). The 5-year overall survival (OS) and event free survival (EFS) was 89% and 56.6% respectively. The EFS, for severe radiological lesions triad was 38% ± 20.7 versus 66% ± 16.2 for non-severe lesions triad p 0.002, while for presence of chest X-ray changes 27% ± 22.344 versus absence of chest X ray changes 66% ± 14.7 p 0.001, for clinical respiratory manifestations 13% ± 13.9 versus none 62% ± 22.9 p < 0.001, for RO- with severe lung lesions 47% ± 30.4 versus RO- without severe lung lesions 69% ± 5.9 p 0.04. There was a tendency for the independent prognostic impact of severe lung involvement; aHR = 1.7 (95% CI 0.92-3.13, p = 0.09)., Conclusion: Although the lung is a low -risk organ per se in LCH, our study demonstrates a non negligeable prognostic impact of severe lung involvement in the risk stratification of pediatric LCH. This warrants further study and external validation., (© 2023. The Author(s).)

Background: Skin lightening products (SLPs) are popular among women for medical and non-medical reasons. Therefore, this study aimed to determine the extent of SLP use among women, identify their sources of information, explore factors associated with SLP use and SLP related knowledge, attitudes, and practices (KAP) among women in the UAE., Methods: A structured questionnaire in English and Arabic was distributed to women in the UAE. The questionnaire included demographic characteristics, knowledge (10 items), attitudes (10 items), practices (9 items), and four additional questions on SLP use. Adequate KAP scores were defined as a score of ≥70% out of the maximum score for each KAP section. Chi-square tests were used to test associations between demographic characteristics, dichotomized KAP scores, and SLP use., Results: The study included 370 participants, 50% of the respondents were aged 18-24, and 40% were from the Middle East, 64.8% were unmarried, 91% had university degrees, and 50% had healthcare related profession. Among the respondents 25% use SLPs, the majority use SLPs for non-medical reasons. Employment status is significantly associated with SLP use. The percentage of participants with a knowledge, attitude, and practice score of ≥70% is 66.48%, 76.75%, and 74.72% respectively. Type of profession was significantly associated knowledge and practice. In addition, nationality was also associated with practice., Conclusion: This study highlighted knowledge, attitude and practice gaps and varied levels of SLP-related KAP among women in the UAE. To promote the rational use of SLPs, educational campaigns and stricter regulations are necessary., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The treatment of glioblastoma has limited clinical progress over the past decade, partly due to the lack of effective drug delivery strategies across the blood-brain-tumor barrier. Moreover, discrepancies between preclinical and clinical outcomes demand a reliable translational platform that can precisely recapitulate the characteristics of human glioblastoma. Here we analyze the intratumoral blood-brain-tumor barrier heterogeneity in human glioblastoma and characterize two genetically engineered models in female mice that recapitulate two important glioma phenotypes, including the diffusely infiltrative tumor margin and angiogenic core. We show that pulsed laser excitation of vascular-targeted gold nanoparticles non-invasively and reversibly modulates the blood-brain-tumor barrier permeability (optoBBTB) and enhances the delivery of paclitaxel in these two models. The treatment reduces the tumor volume by 6 and 2.4-fold and prolongs the survival by 50% and 33%, respectively. Since paclitaxel does not penetrate the blood-brain-tumor barrier and is abandoned for glioblastoma treatment following its failure in early-phase clinical trials, our results raise the possibility of reevaluating a number of potent anticancer drugs by combining them with strategies to increase blood-brain-tumor barrier permeability. Our study reveals that optoBBTB significantly improves therapeutic delivery and has the potential to facilitate future drug evaluation for cancers in the central nervous system., (© 2023. Springer Nature Limited.)

MINERvA has measured the ν&#95;{μ}-induced coherent π^{+} cross section simultaneously in hydrocarbon (CH), graphite (C), iron (Fe), and lead (Pb) targets using neutrinos from 2 to 20 GeV. The measurements exceed the predictions of the Rein-Sehgal and Berger-Sehgal PCAC based models at multi-GeV ν&#95;{μ} energies and at produced π^{+} energies and angles, E&#95;{π}>1  GeV and θ&#95;{π}<10°. Measurements of the cross-section ratios of Fe and Pb relative to CH reveal the effective A scaling to increase from an approximate A^{1/3} scaling at few GeV to an A^{2/3} scaling for E&#95;{ν}>10  GeV.

Background: Posterior fossa tumor is a type of brain tumor that is located at the borders of both the brain stem and cerebellum. The cerebellum is the brain region in charge of balance and coordination. Pediatric patients diagnosed with posterior fossa tumor have been reported to fall frequently., Objectives: The aim of this study is to investigate the effectiveness of balance and coordination training in these children., Methods: This randomized control clinical trial (ClinicalTrials.gov Identifier: NCT04528316) was carried out between September 2020 and April 2021 at Children's Cancer Hospital-57357. The inclusion criteria were patients with posterior fossa tumor in maintenance phase and, age between 5 and 12 years. The exclusion criteria were patients who had a genetic disorder or suffer from mental retardation, a chronic lung disease, severe cardiomyopathy, or a neuromuscular disease that does not relate to tumor. The study participants were randomly assigned into three groups: Group I/Control group: they received Pilates core stability exercises program, Group II/Postural stability group: they received the same program plus HUMAC balance program, and Group III/Coordination group: they received the same program plus coordination exercises of BOT-2. The semi-parametric proportional odds model was used to compare follow-up scores of the Postural stability group vs Control, and Coordination group vs Control, while adjusting for baseline values. All tests were two sided, with alpha set to 0.05., Results: Sixty children including 38 boys and 22 girls were enrolled in this study. In all three groups, postural stability and coordination improved significantly in terms of modified clinical test of sensory integration of balance, center of pressure, limits of stability, bilateral coordination, and upper-limb coordination., Conclusion: The current study supports the value of adding postural stability and coordination training to the physiotherapy plan for children with posterior fossa tumor., Trial Registration Number and Date of Registration: ClinicalTrials.gov Identifier: NCT04528316 on August 27, 2020., (© 2022. The Author(s).)

Neutrino-induced charged-current single π^{+} production in the Δ(1232) resonance region is of considerable interest to accelerator-based neutrino oscillation experiments. In this Letter, high statistic differential cross sections are reported for the semiexclusive reaction ν&#95;{μ}A→μ^{-}π^{+}+ nucleon(s) on scintillator, carbon, water, iron, and lead targets recorded by MINERvA using a wideband ν&#95;{μ} beam with ⟨E&#95;{ν}⟩≈6  GeV. Suppression of the cross section at low Q^{2} and enhancement of low T&#95;{π} are observed in both light and heavy nuclear targets compared with phenomenological models used in current neutrino interaction generators. The cross sections per nucleon for iron and lead compared with CH across the kinematic variables probed are 0.8 and 0.5 respectively, a scaling which is also not predicted by current generators.

This Letter presents the first simultaneous measurement of the quasielasticlike neutrino-nucleus cross sections on C, water, Fe, Pb, and scintillator (hydrocarbon or CH) as a function of longitudinal and transverse muon momentum. The ratio of cross sections per nucleon between Pb and CH is always above unity and has a characteristic shape as a function of transverse muon momentum that evolves slowly as a function of longitudinal muon momentum. The ratio is constant versus longitudinal momentum within uncertainties above a longitudinal momentum of 4.5  GeV/c. The cross section ratios to CH for C, water, and Fe remain roughly constant with increasing longitudinal momentum, and the ratios between water or C to CH do not have any significant deviation from unity. Both the overall cross section level and the shape for Pb and Fe as a function of transverse muon momentum are not reproduced by current neutrino event generators. These measurements provide a direct test of nuclear effects in quasielasticlike interactions, which are major contributors to long-baseline neutrino oscillation data samples.

Background: F18-FET PET has an established diagnostic role in adult brain gliomas. In this study we analyzed image derived static and dynamic parameters with available conventional MRI, histological, clinical and follow-up data in assessment of pediatric brain tumor patients at different stages of the disease., Methods: Forty-four pediatric patients with median age 7 years, diagnosed with brain tumors and underwent forty-seven 18F-FET PET scans either initially (20 scans) or post-therapy (27 scans) were enrolled. Standardized analysis of summed FET PET images early from 10-20 min and late from 30-40 min post-injection were used for static (mean and maximum tumor to brain ratio [TBR] and biological tumor volume [BTV]) parameters evaluation as well as the time activity curve [TAC]., Results: Nineteen out of 20 initially assessed patients had pathologically and/or clinico-radiologically proven neoplastic lesions and one patient had pathologically proven abscess. Receiver operator curve (ROC) marked early TBR max 2.95, early TBR mean 1.76, late TBR max 2.5 and late TBR mean 1.74 as discriminator points with diagnostic accuracy reaching 90% when TBR max was combined with dynamic parameters. Significant association was found between initial FET scans, early and late BTV and event free survival (EFS) (P value=0.042 and 0.005 respectively). In post-therapy assessment, the diagnostic accuracy of conventional MRI was 81.48% when used alone and 96.30% when combined with F18-FET PET scan findings. A cutoff point of 3.2 cm 3 for late BTV, in post-therapy scans, was successfully marked as a predictor for therapy response (P value 0.042) and was significantly associated with EFS (P value 0.002). In FET-avid / MRI non-enhancing lesions, early TBR max was able to detect highly malignant processes (high-grade tumors in initial scans and residue/recurrence in post-therapy scans) with 80% sensitivity and 100% specificity when cutoff value of 2.25 was used (P value=0.024). In patients with FET-avid brainstem lesions, whether enhancing or non-enhancing in MRI scans, 81.8% were associated with high risk diagnoses and 68.2% of them were associated with poor therapy outcome. The degree of FET uptake matched tumor-grading, but did not show significant association with OS or EFS (P value>0.05)., Conclusions: F18-FET PET seems to be an evolving pediatric neuro-imaging technique with valuable diagnostic and prognostic information at initial and post-therapy evaluation.

Scattering of high energy particles from nucleons probes their structure, as was done in the experiments that established the non-zero size of the proton using electron beams 1 . The use of charged leptons as scattering probes enables measuring the distribution of electric charges, which is encoded in the vector form factors of the nucleon 2 . Scattering weakly interacting neutrinos gives the opportunity to measure both vector and axial vector form factors of the nucleon, providing an additional, complementary probe of their structure. The nucleon transition axial form factor, F A , can be measured from neutrino scattering from free nucleons, ν μ n → μ - p and [Formula: see text], as a function of the negative four-momentum transfer squared (Q 2 ). Up to now, F A (Q 2 ) has been extracted from the bound nucleons in neutrino-deuterium scattering 3-9 , which requires uncertain nuclear corrections 10 . Here we report the first high-statistics measurement, to our knowledge, of the [Formula: see text] cross-section from the hydrogen atom, using the plastic scintillator target of the MINERvA 11 experiment, extracting F A from free proton targets and measuring the nucleon axial charge radius, r A , to be 0.73 ± 0.17 fm. The antineutrino-hydrogen scattering presented here can access the axial form factor without the need for nuclear theory corrections, and enables direct comparisons with the increasingly precise lattice quantum chromodynamics computations 12-15 . Finally, the tools developed for this analysis and the result presented are substantial advancements in our capabilities to understand the nucleon structure in the weak sector, and also help the current and future neutrino oscillation experiments 16-20 to better constrain neutrino interaction models., (© 2023. The Author(s).)

Aims: To assess the clinical, pathological and molecular characteristics (Sonic hedgehog and group 3/4 molecular subtypes expression) and treatment modalities for infantile medulloblastoma in correlation with outcomes. Materials & methods: A retrospective study of 86 medulloblastoma patients (≤3 years) was conducted. M0 patients <2.5 years received four cycles of chemotherapy followed by focal radiotherapy (FRT) and chemotherapy. Between 2007 and 2015, Metastatic patients <2.5 years received craniospinal irradiation (CSI) after the end of chemotherapy. After 2015, metastatic patients <2.5 years received CSI postinduction. Results: The hazard ratio for death was significantly higher in the FRT (HR = 2.8) group compared with the CSI group (hazard ratio = 1). Metastatic disease significantly affected the overall survival of the Sonic hedgehog group and the overall survival and event-free survival of group 3/4. Conclusion: Metastatic disease had a significant impact on outcomes. FRT is not effective in treating infantile medulloblastoma.