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In 2018, the World Health Organization declared childhood cancer as a global disease burden, launching a Global Initiative to improve survival to 60% worldwide by 2030.[1] If achieved, it is estimated that an extra 1 million children's lives will be saved. Childhood bone tumours in primary care: helping GPs to identify "the needle in the haystack" THE CHALLENGES OF A BONE TUMOUR DIAGNOSIS Non-specificity of symptoms CYP with bone tumours present with non-specific symptoms that can be attributed to many other, more common illnesses and injuries. [Extracted from the article]

The impacts of the lack of skin tone diversity in medical education images on healthcare professionals (HCPs) and patients are not well studied. The aim of this study was to assess the diagnostic knowledge of HCPs and correlate this with confidence and training resources used. An online multiple choice quiz was developed. The participants' demographics, training resources and self-confidence in diagnosing skin conditions were collected. The differences in the results between the subgroups and the correlations between the respondents' experience, self-reported confidence and quiz results were assessed. The mean score of 432 international participants was 5.37 (SD 1.75) out of a maximum of 10 (highest score). Eleven percent (n = 47) reached the 80% pass mark. Subanalysis showed no difference by the continent (p = 0.270), ethnicity (p = 0.397), profession (p = 0.599), training resources (p = 0.198) or confidence (p = 0.400). A significance was observed in the specialty (p = 0.01). A weak correlation between experience and confidence (Spearman's ρ = 0.286), but no correlation between scores and confidence or experience (ρ = 0.087 and 0.076), was observed. Of diagnoses, eczema was recognised in 40% and meningococcal rash in 61%. This is the first study assessing the identification of paediatric skin conditions in different skin tones internationally. The correct identification of common/important paediatric conditions was poor, suggesting a possible difference in knowledge across skin tones. There is an urgent need to improve the representation of all skin tones to ensure equity in patient care. [ABSTRACT FROM AUTHOR]

When activated by thrombin, the platelets release their granular store of factors. These thrombin-activated platelets (TAPLT) have been shown to be capable of ameliorating pro-inflammatory processes. In this study, we tested if TAPLT could also protect the endothelium against tumor-related pro-inflammatory changes that promote angiogenesis and metastasis. Using endothelial cell (EC) models in vitro, we demonstrated that TAPLT protected EC against tumor conditioned medium (TCM)-induced increases of reactive oxygen species (ROS) production, EC permeability and angiogenesis, and inhibited transendothelial migration that was critical for cancer cell extravasation and metastasis. In vivo observations of TAPLT-mediated inhibition of angiogenesis and pulmonary colonization in a BALB/c nude mouse model were consistent with the in vitro findings. Neutralization of vascular cell adhesion molecule-1 (VCAM-1) binding significantly inhibited the ability of TAPLT to interact with EC and abrogated the TAPLT-mediated protection of EC against tumor angiogenesis and metastasis. Taken together, these findings suggest that VCAM-1-mediated linkage to EC is required for TAPLT to confer protection of EC against tumor-induced permeation and angiogenesis, thereby resisting tumor extravasation and metastasis. [ABSTRACT FROM AUTHOR]

Lipotoxicity (LTx) leads to cellular dysfunction and cell death and has been proposed to be an underlying process during traumatic and hypoxic injuries and neurodegenerative conditions in the nervous system. This study examines cellular mechanisms responsible for docosahexaenoic acid (DHA 22:6 n‐3) protection in nerve growth factor‐differentiated pheochromocytoma (NGFDPC12) cells from palmitic acid (PAM)‐mediated lipotoxicity (PAM‐LTx). NGFDPC12 cells exposed to PAM show a significant lipotoxicity demonstrated by a robust loss of cell viability, apoptosis, and increased HIF‐1α and BCL2/adenovirus E1B 19 kDa protein‐interacting protein 3 gene expression. Treatment of NGFDPC12 cells undergoing PAM‐LTx with the pan‐caspase inhibitor ZVAD did not protect, but shifted the process from apoptosis to necroptosis. This shift in cell death mechanism was evident by the appearance of the signature necroptotic Topo I protein cleavage fragments, phosphorylation of mixed lineage kinase domain‐like, and inhibition with necrostatin‐1. Cultures exposed to PAM and co‐treated with necrostatin‐1 (necroptosis inhibitor) and rapamycin (autophagy promoter), showed a significant protection against PAM‐LTx compared to necrostatin‐1 alone. In addition, co‐treatment with DHA, as well as 20:5 n‐3, 20:4 n‐6, and 22:5 n‐3, in the presence of PAM protected NGFDPC12 cells against LTx. DHA‐induced neuroprotection includes restoring normal levels of HIF‐1α and BCL2/adenovirus E1B 19 kDa protein‐interacting protein 3 transcripts and caspase 8 and caspase 3 activity, phosphorylation of beclin‐1, de‐phosphorylation of mixed lineage kinase domain‐like, increase in LC3‐II, and up‐regulation of Atg7 and Atg12 genes, suggesting activation of autophagy and inhibition of necroptosis. Furthermore, DHA‐induced protection was suppressed by the lysosomotropic agent chloroquine, an inhibitor of autophagy. We conclude that DHA elicits neuroprotection by regulating multiple cell death pathways including enhancement of autophagy and inhibiting apoptosis and necroptosis. [ABSTRACT FROM AUTHOR]

Background: HeadSmart, a public and professional awareness campaign, was launched to enhance awareness of brain tumour symptomatology identified in the Royal College of Paediatrics and Child Health, National Institute for Health and Care Excellence-accredited guideline. Quality improvement data showed a reduction in diagnostic interval nationally. To reach the government target of 4 weeks, we need to identify subgroups with ongoing delays.Methods: Incident cases of brain tumours (0-18) diagnosed between January 2011 and May 2013 across 18 UK centres were included. Anonymised data including demographics, diagnosis and date of symptom onset/presentation were collected. Key outcome measures, total diagnostic interval (TDI), patient interval (PI) and system interval (SI) were calculated. Subanalysis by age, tumour grade and location was also performed.Results: Young children (0-5 years) accounted for 38% of cases, with a peak age at diagnosis of 2 years. Central tumours experienced longest intervals with a median TDI of 10.5 weeks, PI of 3.2 weeks and SI of 2.9 weeks. Craniopharyngioma, low-grade glioma and optic pathway gliomas had the longest TDIs with a median of 15.1, 11.9 and 10.4 weeks, respectively. The greatest proportion of delay was in the SI. The 12-18 age group had a median TDI of 12.1 weeks, compared with 8 weeks for the 5-11 age group and 6 weeks for the 0-5 age group (p<0.001).Conclusions: Clear patterns of intervals for different age groups and anatomical locations have been demonstrated. Tailoring education and awareness strategies to ensure earlier diagnosis for central tumours and young people is crucial to minimise brain injury, subsequent disability and late effects of treatment for 70% of survivors. [ABSTRACT FROM AUTHOR]

Background: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk. Methods: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2-23yrs; gender 28 M, 61 F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post-operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores. Results: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3-52%) and high-risk (34/89, predicted CMS probability ≥52%). Conclusions: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process. [ABSTRACT FROM AUTHOR]

Abstract: Lipotoxicity, which is triggered when cells are exposed to elevated levels of free fatty acids, involves cell dysfunction and apoptosis and is emerging as an underlying factor contributing to various pathological conditions including disorders of the central nervous system and diabetes. We have shown that palmitic acid (PA)-induced lipotoxicity (PA-LTx) in nerve growth factor-differentiated PC12 (NGFDPC12) cells is linked to an augmented state of cellular oxidative stress (ASCOS) and apoptosis and that these events are inhibited by docosahexanoic acid (DHA). The mechanisms of PA-LTx in nerve cells are not well understood, but our previous findings indicate that it involves ROS generation, mitochondrial membrane permeabilization (MMP), and caspase activation. The present study used nerve growth factor differentiated PC12 cells (NGFDPC12 cells) and found that lysosomal membrane permeabilization (LMP) is an early event during PA-induced lipotoxicity that precedes MMP and apoptosis. Cathepsin L, but not cathepsin B, is an important contributor in this process since its pharmacological inhibition significantly attenuated LMP, MMP, and apoptosis. In addition, co-treatment of NGFDPC12 cells undergoing lipotoxicity with DHA significantly reduced LMP, suggesting that DHA acts by antagonizing upstream signals leading to lysosomal dysfunction. These results suggest that LMP is a key early mediator of lipotoxicity and underscore the value of interventions targeting upstream signals leading to LMP for the treatment of pathological conditions associated with lipotoxicity. [Copyright &y& Elsevier]

Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p [ABSTRACT FROM AUTHOR]

Several reports describe regulatory interactions between NK cells and CTLs. We addressed the issue of NK participation in the early anti-tumor defense by inoculating α-ASGM-1 treated mice with BW-Sp3 T lymphoma. Rejection of BW-Sp3 depends on strong CTL responses. Our results demonstrated that (i) NK cells are a prerequisite for efficient CTL generation and (ii) the absence of NK cells favors the outgrowth of alternatively activated macrophages that can suppress CTL restimulation. In vitro studies demonstrate that in splenic cultures from NK-deficient, tumor-bearing mice, the presence of alternatively activated macrophages correlates with a lack of Type 1 cytokines, while the production of Type 2 cytokines is promoted. Provision of the Type 1 cytokine, IFN-γ can boost overall CTL activity but does not revert the dominance of arginase producing adherent cells in the NK-deficient CTL cultures. The role of NK effector functions in the efficient switch of the immune system towards Type 1 activation was evaluated in cytotoxicity assays. The results indicate that the accessory function of NK can depend at least partially on their ability to preferentially engage arginase-producing cells, suggesting that NK/macrophage lytic interactions might be involved in the switch from Type 2 to Type 1-dependent immune responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Ependymomas are the second most common paediatric brain tumour, and the 5-year survival rate remains no higher than 50%. Identifying new prognostic markers and targets for therapy in ependymoma is an important area of research. In this study, we demonstrate that brain lipid binding protein (BLBP, FABP7) is expressed in a sub-population of cells in ependymoma patient samples, consistent with it being a cancer stem cell marker. BLBP expression was associated with both significantly reduced event free survival and overall survival. BLBP can be functionally inhibited by PPAR antagonists, and we demonstrated that these antagonists can reduce ependymoma cell migration, invasion and chemo-resistance. The BLBP ligand docosohexanoic acid also attenuated these three hallmark characteristics of ependymomas, leading us to conclude that BLBP is not just a prognostic marker for poor ependymoma survival, but that it represents a druggable target in ependymoma therapy. Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial—5 y OS 45% vs. 80%, p = 0.011—and CNS9904, a radiotherapy-led trial—OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP's fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients. [ABSTRACT FROM AUTHOR]

Snake envenomation is a serious public health issue in many tropical and subtropical countries. Accurate diagnosis and immediate antivenom treatment are critical for effective management. However, the venom concentration in the victims' plasma is usually low, representing one of the bottlenecks in developing clinically applicable assays for venom detection and snakebite diagnosis. In this study, we attempted to develop a simple method for rapid enrichment of venom proteins from human plasma to facilitate detection. Our experiments showed that several major protein components of both Naja atra (N. atra) and Bungarus multicinctus (B. multicinctus) venoms have higher isoelectric point (pI) values relative to high-abundance human plasma proteins and could be separated via strong cation exchange–high-performance liquid chromatography (SCX-HPLC). Based on this principle, we developed an SCX tip column-based protocol for rapid enrichment of N. atra and B. multicinctus venom proteins from human plasma. Application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) led to the identification of cytotoxin and beta-bungarotoxin as the major proteins enriched by the SCX tip column in each venom sample. The entire process of venom enrichment could be completed within 10–15 min. Combination of this method with our previously developed lateral flow strip assays (rapid test) significantly enhanced the sensitivity of the rapid test, mainly via depletion of the plasma protein background, as well as increase in venom protein concentration. Notably, the SCX tip column-based enrichment method has the potential to efficiently enrich other Elapidae snake venoms containing proteins with higher pI values, thereby facilitating venom detection with other assays. This simple and rapid sample preparation method should aid in improving the clinical utility of diagnostic assays for snakebite. [ABSTRACT FROM AUTHOR]

A homemade Bonner cylinder spectrometer was used to determine the neutron spectrum from thermal energy up to several GeV at a heavily-shielded light source facility. The spectrometer, similar to the design of Bonner spheres, features high sensitivity of neutron detection because of using a long cylindrical 3He proportional counter. The spectrum measurement was performed during the facility commissioning by intentionally parking the injected electrons at the septum of the storage ring. Based on a high-fidelity FLUKA simulation, the predicted neutron spectrum at the location of measurement was adopted as the initial guess of spectrum unfolding. The unfolded result indicated an underestimation of the calculated neutron spectrum in the high-energy portion, leading to a substantial revision of the neutron dose rate at the location.

Abstract Background To explore any gender-related differences in the prevalence of conditions-associated with non-alcoholic fatty liver disease (NAFLD) among Taiwanese taxi drivers in Taipei, Taiwan. Methods We studied 1635 healthy taxi drivers (1541 males and 94 females) who volunteered for physical check-ups in 2006. Blood samples and ultrasound fatty liver sonography results were collected. Results The prevalence of NAFLD was 66.4% and revealed no statistically significant decrease with increasing age (p = 0.58). Males exhibited a greater prevalence of NAFLD than did females (67.5% vs 47.9%, p < 0.0001). Gender-related differences for associated factors were found. For males, hypertension, hyperuricemia, higher AST, higher ALT, hypertriglyceridemia, and higher fasting plasma glucose were significantly related to NAFLD. These conditions were not sigfinicantly related to NAFLD in females. Conclusion Several gender-related differences were noted for NAFLD among Taiwanese taxi drivers.

Abstract Background ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinum-induced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or drug vehicle twice weekly for 8 weeks. Results In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them. Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals. Conclusions In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. The neuron subtype-specific and largely non-overlapping distribution of ATP7A and CTR1 within rat DRG tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin.

Abstract Background Oxaliplatin and related chemotherapeutic drugs cause painful chronic peripheral neuropathies in cancer patients. We investigated changes in neuronal size profiles and neurofilament immunoreactivity in L5 dorsal root ganglion (DRG) tissue of adult female Wistar rats after multiple-dose treatment with oxaliplatin, cisplatin, carboplatin or paclitaxel. Results After treatment with oxaliplatin, phosphorylated neurofilament heavy subunit (pNF-H) immunoreactivity was reduced in neuronal cell bodies, but unchanged in nerve fibres, of the L5 DRG. Morphometric analysis confirmed significant changes in the number (-75%; P < 0.0002) and size (-45%; P < 0.0001) of pNF-H-immunoreactive neurons after oxaliplatin treatment. pNF-H-immunoreactive neurons had overlapping size profiles and co-localisation with neurons displaying cell body immunoreactivity for parvalbumin, non-phospho-specific neurofilament medium subunit (NF-M) and non-phospho-specific neurofilament heavy subunit (NF-H), in control DRG. However, there were no significant changes in the numbers of neurons with immunoreactivity for parvalbumin (4.6%, P = 0.82), NF-M (-1%, P = 0.96) or NF-H (0%; P = 0.93) after oxaliplatin treatment, although the sizes of parvalbumin (-29%, P = 0.047), NF-M (-11%, P = 0.038) and NF-H (-28%; P = 0.0033) immunoreactive neurons were reduced. In an independent comparison of different chemotherapeutic agents, the number of pNF-H-immunoreactive neurons was significantly altered by oxaliplatin (-77.2%; P < 0.0001) and cisplatin (-35.2%; P = 0.03) but not by carboplatin or paclitaxel, and their mean cell body area was significantly changed by oxaliplatin (-31.1%; P = 0.008) but not by cisplatin, carboplatin or paclitaxel. Conclusion This study has demonstrated a specific pattern of loss of pNF-H immunoreactivity in rat DRG tissue that corresponds with the relative neurotoxicity of oxaliplatin, cisplatin and carboplatin. Loss of pNF-H may be mechanistically linked to oxaliplatin-induced neuronal atrophy, and serves as a readily measureable endpoint of its neurotoxicity in the rat model.

Abstract Background Previous studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 (dimethyl-H3K9) and DNA methylation cooperate to maintain a repressive mode of inactive genes. Less clear is whether this cooperation is generalized in mammalian genomes, such as mouse genome. Here we use epigenomic tools to simultaneously interrogate chromatin modifications and DNA methylation in a mouse leukemia cell line, L1210. Results Histone modifications on H3K9 and DNA methylation in L1210 were profiled by both global CpG island array and custom mouse promoter array analysis. We used chromatin immunoprecipitation microarray (ChIP-chip) to examine acetyl-H3K9 and dimethyl-H3K9. We found that the relative level of acetyl-H3K9 at different chromatin positions has a wider range of distribution than that of dimethyl-H3K9. We then used differential methylation hybridization (DMH) and the restriction landmark genome scanning (RLGS) to analyze the DNA methylation status of the same targets investigated by ChIP-chip. The results of epigenomic profiling, which have been independently confirmed for individual loci, show an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing. In contrast to the previous notion, dimethyl-H3K9 seems to be less distinct in specifying silencing for the genes tested. Conclusion This study demonstrates in L1210 leukemia cells a diverse relationship between histone modifications and DNA methylation in the maintenance of gene silencing. Acetyl-H3K9 shows an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing as expected. However, dimethyl-H3K9 seems to be less distinct in relation to promoter methylation. Meanwhile, a combination of epigenomic tools is of help in understanding the heterogeneity of epigenetic regulation, which may further our vision accumulated from single-gene studies.

Abstract Background Systematic reviews or randomised-controlled trials usually help to establish the effectiveness of drugs and other health technologies, but are rarely sufficient by themselves to ensure actual clinical use of the technology. The process from innovation to routine clinical use is complex. Numerous computerised decision support systems (DSS) have been developed, but many fail to be taken up into actual use. Some developers construct technologically advanced systems with little relevance to the real world. Others did not determine whether a clinical need exists. With NHS investing £5 billion in computer systems, also occurring in other countries, there is an urgent need to shift from a technology-driven approach to one that identifies and employs the most cost-effective method to manage knowledge, regardless of the technology. The generic term, 'decision tool' (DT), is therefore suggested to demonstrate that these aids, which seem different technically, are conceptually the same from a clinical viewpoint. Discussion Many computerised DSSs failed for various reasons, for example, they were not based on best available knowledge; there was insufficient emphasis on their need for high quality clinical data; their development was technology-led; or evaluation methods were misapplied. We argue that DSSs and other computer-based, paper-based and even mechanical decision aids are members of a wider family of decision tools. A DT is an active knowledge resource that uses patient data to generate case specific advice, which supports decision making about individual patients by health professionals, the patients themselves or others concerned about them. The identification of DTs as a consistent and important category of health technology should encourage the sharing of lessons between DT developers and users and reduce the frequency of decision tool projects focusing only on technology. The focus of evaluation should become more clinical, with the impact of computer-based DTs being evaluated against other computer, paper- or mechanical tools, to identify the most cost effective tool for each clinical problem. Summary We suggested the generic term 'decision tool' to demonstrate that decision-making aids, such as computerised DSSs, paper algorithms, and reminders are conceptually the same, so the methods to evaluate them should be the same.

Activin A can induce erythroid differentiation, whereas basic fibroblast growth factor (bFGF) can maintain the undifferentiated status of erythroid progenitors. How these two factors together can affect the regulation of erythroid differentiation in hematopoietic cells has not been elucidated. This study demonstrates that bFGF antagonizes activin A-mediated growth inhibition and hemoglobin (Hb) synthesis in K562 cells. Analyses of mitogen-activated protein kinases revealed that activin A-induced p38 phosphorylation and inhibited ERK1/2 phosphorylation. In contrast, bFGF worked antagonistically to induce ERK1/2 phosphorylation and inhibited p38 phosphorylation in K562 cells. Furthermore, co-treatment of cells with activin A and bFGF decreased p38 phosphorylation and increased ERK1/2 phosphorylation. SB203580 inhibition of p38 activity eliminated activin A-mediated growth inhibition and Hb synthesis, whereas U0126 inhibition of ERK1/2 activity augmented the effects of activin A on K562 cells. These results suggest that bFGF can negatively modulate p38 and positively modulate ERK1/2 to antagonize activin A-mediated growth inhibition and Hb synthesis in K562 cells. [Copyright &y& Elsevier]

Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens. [ABSTRACT FROM AUTHOR]

Better in vitro models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma., (© 2024. The Author(s).)

ZJ-101, a structurally simplified analog of marine natural product superstolide A, was previously designed and synthesized in our laboratory. In the present study four new analogs of ZJ-101 were designed and synthesized to investigate the structure-activity relationship of the acetamide moiety of the molecule. The biological evaluation showed that the amide moiety is important for the molecule's anticancer activity. Replacing the amide with other functional groups such as a sulfonamide group, a carbamate group, and a urea group resulted in the decrease in anticancer activity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Zhendong Jin is the founder and a shareholder of InnoBioPharma, LLC that sponsored the project, “Development of novel anticancer agents based on natural products” at the University of Iowa., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Time to diagnosis (TTD) of childhood soft tissue sarcoma (STS) is significantly associated with survival. This review aims to identify pre-diagnostic symptoms/signs to inform earlier diagnosis interventions., Methods: Medline, Embase, Cochrane and Web-of-Science were searched between January 2010 and February 2021 for studies including children (<18 years) diagnosed with STS, with no language restrictions. Pooled proportions of symptoms/signs were calculated and subanalysed by tumour location and age., Results: Fifty-nine eligible studies were identified, totalling 2462 cases. The most frequent symptoms were lump/swelling (38%, 95% CI 27% to 51%), pain (6%, 95% CI 3% to 10%), cutaneous changes (4%, 95% CI 0 to 9%), localised eye swelling (3%, 95% CI 0 to 7%), cranial nerve deficits (2%, 95% CI 0 to 5%) and constitutional symptoms (2%, 95% CI 0 to 5%).Symptoms varied by location and age. Localised eye swelling (20%, 95% CI 3% to 45%), cranial nerve deficits (14%, 95% CI 4% to 28%) and impaired visual function (6%, 95% CI 0 to 17%) were frequent in head and neck tumours. For abdomen/pelvic tumours, urinary symptoms (24%, 95% CI 5% to 15%), abdominal distension/discomfort (22%, 95% CI 4% to 47%), genital lump/swelling (16%, 95% CI 1% to 42%), constitutional symptoms (9%, 95% CI 0%] to 23%), vaginal bleeding (7%, 95%C I 0 to 21%) and bowel habit changes (6%, 95% CI 0 to 17%) were frequent.In <5 years, consumptive coagulopathy (16%, 95% CI 0 to 48%), cutaneous changes (5%, 95% CI 0 to 40%), genital lump/swelling (4%, 95% CI 0 to 14%), reduced mobility (3%, 95% CI 0 to 11%), vaginal bleeding (2%, 95% CI 0 to 11%) and bleeding/bruising/petechiae (2%, 95% CI 0 to 20%) were frequent compared with lump/swelling, constitutional symptoms, pain and headaches which were frequent among >11 years., Conclusions: For STS, pre-diagnostic symptoms differ by age and location, highlighting the need to tailor early diagnosis interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess public awareness of the risks and symptoms of cancer in children, teenagers, and young adults (CTYA) aged <18 years in Great Britain., Methods: A face-to-face computer-assisted opinion survey was conducted by Ipsos MORI. Participants were a population-based sample of 1000 adults (475 men, 525 women) aged >18 years, with 26% having children aged 6-15 in their households. Questions covered perception about cumulative cancer risk, confidence in recognising signs and symptoms, recognition and perceived urgency of classical signs and symptoms., Results: Only 32% of respondents felt confident in recognising CTYA cancer signs and symptoms. Symptoms deemed to require medical assessment within 48 hours by over 50% of participants included seizures/fits, blood in urine or stool, and persistent vomiting. All symptoms except one were selected for assessment within 3 months. On average, respondents identified 10.6 out of 42 classical signs and symptoms. The most recognised symptoms included lump, swelling in pelvis, testicle or breast (46%), blood in urine or stool (44%), changes to moles (43%), lump/swelling in the chest wall or armpits (41%) and weight loss (40%). The least recognised symptoms were early/late puberty (10%), developmental delay in children aged <2 years (11%) and slow growth (13%), with 8%, 2% and 6%, respectively, perceiving no need to discuss them with a doctor., Conclusions: Public awareness of childhood cancer risks and symptoms is substantially lower compared with adult cancer awareness in Great Britain. These findings indicate knowledge and awareness gaps among the general public, highlighting the need for a child cancer awareness campaign., Competing Interests: Competing interests: DS is funded by the National Institute for Health Research (NIHR) Doctoral Fellowship. AG is the CEO of Children’s Cancer and Leukaemia Group (CCLG). J-FL is funded by CCLG., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sepsis is one of the most severe complications and causes of mortality in the clinic. It remains a great challenge with no effective treatment for clinicians worldwide. Inhibiting the release of proinflammatory cytokines during sepsis is considered as an important strategy for treating sepsis and improving survival. In the present study, we have observed the effect of dimethyl fumarate (DMF) on lipopolysaccharide- (LPS-) induced sepsis and investigated the possible mechanism. By screening a subset of the Johns Hopkins Drug Library, we identified DMF as a novel inhibitor of nitric oxide synthesis in LPS-stimulated RAW264.7 cells, suggesting that DMF could be a potential drug to treat sepsis. To further characterize the effect of DMF on LPS signaling, TNF- α , MCP-1, G-CMF, and IL-6 expression levels were determined by using cytokine array panels. In addition, an endotoxemia model with C57BL/6 mice was used to assess the in vivo efficacy of DMF on sepsis. The survival rate was assessed, and HE staining was performed to investigate histopathological damage to the organs. DMF was found to increase the survival of septic mice by 50% and attenuate organ damage, consistent with the reduction in IL-10, IL-6, and TNF- α (inflammatory cytokines) in serum. In vitro experiments revealed DMF's inhibitory effect on the phosphorylation of p65, I κ B, and IKK, suggesting that the primary inhibitory effects of DMF can be attributed, at least in part, to the inhibition of phosphorylation of I κ B α , IKK as well as nuclear factor- κ B (NF- κ B) upon LPS stimulation. The findings demonstrate that DMF dramatically inhibits NO and proinflammatory cytokine production in response to LPS and improves survival in septic mice, raising the possibility that DMF has the potential to be repurposed as a new treatment of sepsis., Competing Interests: The authors declare no conflicts of interests., (Copyright © 2023 He Fang et al.)

Molecular glues suppress the active form of the oncogenic protein KRAS.