👤 William G Harrison

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of The online version contains supplementary material available at 10.1186/s12974-026-03698-2. Show less

The spatial progression of longitudinal tau pathology has been inferred using cross-sectional data, but longitudinal voxel-wise analyses allow these patterns to be established without inference. We pooled 1426 flortaucipir (FTP) positron emission tomography (PET) scans from 583 participants across the aging and Alzheimer's disease (AD) spectrum from four studies. Using longitudinal tau-PET slope maps, we examined tau accumulation by clinical group and its associations with participant characteristics, baseline beta-amyloid (Aβ), and tau. Tau accumulation was limited to temporoparietal cortices in unimpaired participants but widespread in patients. Baseline Aβ, entorhinal, and inferior temporal tau predicted progressively more severe tau accumulation patterns. Age, sex, and apolipoprotein E (APOE) ε4 had modest moderating effects. Aβ and early tau interactions showed synergistic effects. Greater tau accumulation was linked to worse follow-up cognition than baseline. While Aβ influences early tau progression, baseline tau drives later progression. These results may guide future trials targeting tau accumulation at different disease stages. Faster tau spread from temporal to frontal lobes was linked to clinical impairment. Global beta-amyloid (Aβ), entorhinal, and inferior temporal gyrus (ITG) tau predicted progressively worse tau accumulation. Age, sex, and apolipoprotein E (APOE) had minimal effects on tau accumulation. Aβ and early tau burden interact synergistically to drive tau accumulation. More severe tau accumulation was linked to worse cognition at follow-up than baseline. Show less

The importance of advance care planning in parkinsonism is increasingly recognised. Existing evidence shows plans are infrequent in this population. Little is known about the details of the plans themselves and whether patient factors predict advance care planning practices. This study aimed to describe advance care planning in people with parkinsonism enrolled in the PRoactive Integrated Management and Empowerment (PRIME-UK) trial, and identify factors associated with advance care planning. This is a cross-sectional substudy of 211 participants within the PRIME-UK randomised controlled trial, a single-centre trial that randomised 214 people with parkinsonism to receive either a novel model of care (PRIME-Parkinson care) or usual care (ISRCTN trial ID 16783200). The presence of a treatment escalation plan was used as a measure of advance care planning. At the time of this study, a quarter (n=53, 25%) of participants had a treatment escalation plan. 45% of plans were created during an emergency hospital admission. 100 participants had appointed a lasting power of attorney (LPA). In adjusted regression models, increasing parkinsonism severity (OR 2.2, 95% CI 1.55 to 3.12), increasing frailty (OR 3.69, 95% CI 1.42 to 9.63) and increasing comorbidity (OR 2.51, 95% CI 1.53 to 4.14) were associated with having a treatment escalation plan. Treatment escalation plans for people with parkinsonism are frequently completed in advanced disease during emergency hospital admission. Many individuals are appointing LPAs, suggesting an interest in future planning that could be further supported by clinicians. Future research should explore interventions to improve proactive outpatient advance care planning. 16783200. Show less

Canine Cognitive Dysfunction (CCD) is an increasingly prevalent naturally occurring neurodegenerative condition in senescent dogs that share neuropathological and clinical features with human Alzheimer's disease (AD). Metabolic profiling allows for identification of new candidates for AD biomarkers, diagnostics, and therapeutics. Despite its translational potential, plasma metabolomic profiling of dogs with CDD has not been previously characterized. This case-control study analyzed plasma samples from ten client-owned geriatric dogs, including five with severe CCD and five age-matched, clinically healthy controls. Untargeted plasma metabolomics was performed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Multivariate and univariate statistical analyses identified significant metabolic differences between the groups. Metabolites were considered significant based on a variable importance in projection (VIP) score > 1.5, fold change (FC) > 2.0, and adjusted Fifteen metabolites across seven chemical classes were significantly altered in CCD dogs compared to controls, including glycerophospholipids, steroid derivatives, indoles, and mitochondrial-related compounds. Notably, elevated lysophosphatidic acid (LPA 20:2/0:0) and reduced ubiquinone-2 levels suggest dysregulation in neuroinflammatory and oxidative stress pathways. Cholesterol exhibited the highest FC and VIP scores, further reinforcing its role in AD pathogenesis. Hierarchical clustering and pathway enrichment analyses supported distinct metabolic signatures in CCD that mirror those observed in human AD. This is the first untargeted plasma metabolomic profiling of dogs with CCD, revealing systemic metabolic disturbances that align with AD pathophysiology. Data was collected from senescent community-dwelling companion dogs, which enhances the study's ecological and translational relevance. It supports the utility of CCD as an AD model and highlight candidate plasma biomarkers that warrant further investigation. Future longitudinal studies integrating metabolomics with neuroimaging, histopathology, and behavioral assessments are required to validate these findings and contribute to AD biomarker discovery and therapeutic development. Show less

New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses. Show less

Myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 rearrangements (MLN- We assigned eligible patients to receive oral pemigatinib 13.5 mg once daily (2 weeks on followed by 1 week off or continuously). End points included complete response rate (primary) and complete cytogenetic response rate. Responses were assessed locally by investigators per protocol-defined criteria and were retrospectively adjudicated by a central review committee using criteria defined by the committee. Of 47 treated patients (safety population), 45 had confirmed In our study, pemigatinib manifested near complete efficacy in chronic-phase patients with MLN- Show less

Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field. Show less

Lipoprotein(a) (Lp[a]) is an established predictor of cardiovascular risk but associations with secondary events are less certain, and data on understudied ethnic groups are scarce. This study aimed to assess the association between Lp(a) and secondary events and explore variation in Lp(a) levels by ethnicity in first-time acute coronary syndrome (ACS) patients, to inform future risk prediction models. The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a longitudinal multi-centre cohort study of 1900 patients enrolled during their ACS admission. Baseline plasma Lp(a) concentrations were measured using an isoform-insensitive assay measured in nmol/L. The primary outcome was a composite of all-cause mortality or cardiovascular readmission, ascertained through national health datasets. Cox regression models were used to assess the association between Lp(a) levels and outcomes, adjusted for clinical risk factors. The mean age was 61 years, 20 % were female, and 73 % were European, 14 % Māori, 5 % Pacific peoples, 4 % Indian and 3 % other ethnicities. Of 1890 alive at discharge, 493 (26 %) experienced the primary outcome over a median follow-up of 4.9 years. Higher Lp(a) levels were associated with increased risk of secondary events. Compared to the lowest quartile (≤7 nmol/L), the adjusted hazard ratio for the highest quartile (>92 nmol/L) was 1.46 (95 %CI 1.12-1.89, p = 0.004). In this ACS cohort, Lp(a) concentrations varied by ethnicity, being highest amongst Indian participants (median 27 nmol/L) and lowest amongst Māori participants (median 12 nmol/L). Elevated Lp(a) concentrations are associated with secondary events following ACS. Further research is needed to define optimal thresholds for increased risk and explore ethnic-specific implications for secondary prevention. Show less

This brief report details the initial findings from a Phase 1b/2 trial of TN-201, an adeno-associated virus serotype 9 (AAV9) gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), a condition with significant morbidity, increased risk of mortality, and no approved therapy for the majority of patients. TN-201 was well tolerated, and changes to the management of potential immune responses resulted in a shorter period of immunosuppression. These results show consistent transduction and expression of TN-201 in cardiomyocytes, corresponding with increases in MyBP-C levels, reductions or stabilization of cardiac biomarkers, and reductions in key measures of left ventricular (LV) hypertrophy. Show less

The genetic etiology of hypertrophic cardiomyopathy (HCM) and the critical role of sarcomeric variants in its pathogenesis are well recognized (1). Among these, loss-of-function variants in the myosin binding protein C gene ( This was a prospective, cross-sectional study of 100 adults (aged 18-65 years) with symptomatic Pre-existing anti-AAV9 NAb were undetectable in 50% of patients. Among those with detectable titers (range: 1:10-1:720), only 16% exceeded 1:40. TAb were undetectable in 53%; titers ranged from 1:10 to 1:65,600. A strong correlation was observed between NAb and TAb titers (r = 0.671, Pre-existing immunity to AAV9 was absent or low in most Show less

Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of Show less

A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs. Show less

The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted. Show less

Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations. A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource. Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association. The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families. Show less

Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA. Show less

Streptococcus pneumoniae's polysaccharide capsule is an important virulence factor; vaccine-induced immunity to specific capsular polysaccharide effectively prevents disease. Serotype 1 S. pneumoniae is rarely found in healthy persons, but is highly invasive and a common cause of meningitis outbreaks and invasive disease outside of the United States. Here we show that genes for polysaccharide capsule similar to those expressed by pneumococci were commonly detected by polymerase chain reaction among upper respiratory tract samples from older US adults not carrying pneumococci. Serotype 1-specific genes were predominantly detected. In five oropharyngeal samples tested, serotype 1 gene belonging to S. mitis expressed capsules immunologically indistinct from pneumococcal capsules. Whole genome sequencing revealed three distinct S. mitis clones, each representing a cps1 operon highly similar to the pneumococcal cps1 reference operon. These findings raise important questions about the contribution of commensal streptococci to natural immunity against pneumococci, a leading cause of mortality worldwide. Show less

Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Māori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout. Show less

The gel-mediated syntheses and crystal structures of [N'-(pyridin-2-ylmethylidene-κN)benzohydrazide-κ(2) N',O]tris(thiocyanato-κN)praseodymium(III) mono-hydrate, [Pr(NCS)3(C13H11N3O)2]·H2O, (I), and aqua(nitrato-κ(2) O,O')[N'-(pyri-din-2-ylmethylidene-κN)benzohydrazide-κ(2) N',O](thiocyanato-κN)neo-dym-ium(III) nitrate 2.33-hydrate, [Nd(NCS)(NO3)(C13H11N3O)2(H2O)]NO3·2.33H2O, (II), are reported. The Pr(3+) ion in (I) is coordinated by two N,N,O-tridentate N'-(pyridin-2-ylmethylidene)benzohydrazide (pbh) ligands and three N-bonded thio-cyanate ions to generate an irregular PrN7O2 coordination polyhedron. The Nd(3+) ion in (II) is coordinated by two N,N,O-tridentate pbh ligands, an N-bonded thio-cyanate ion, a bidentate nitrate ion and a water mol-ecule to generate a distorted NdN5O5 bicapped square anti-prism. The crystal structures of (I) and (II) feature numerous hydrogen bonds, which lead to the formation of three-dimensional networks in each case. Show less

Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships. Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene. Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM₀₀₂₄₇₈.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype. We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme. Show less

The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor type and potential proteins that can be the target of antibody-mediated therapy. We have used next-generation deep RNA sequencing (RNA-seq) coupled to an in-house database of genes encoding cell surface proteins (herein referred to as the surfaceome) as a tool to define a cell surface proteome of Ewing sarcoma compared with progenitor mesenchymal stem cells. This subtractive RNA-seq analysis revealed a specific surfaceome of Ewing and showed unexpectedly that the leucine-rich repeat and Ig domain protein 1 (LINGO1) is expressed in over 90% of Ewing sarcoma tumors, but not expressed in any other somatic tissue apart from the brain. We found that the LINGO1 protein acts as a gateway protein internalizing into the tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a new, unique, and specific biomarker and drug target for the treatment of Ewing sarcoma. Show less

Carcinoids are slow-growing neuroendocrine tumors (NETs) that are characterized by hormone overproduction; surgery is currently the only option for treatment. Activation of the Notch pathway has previously been shown to have a role in tumor suppression in NETs. The marine-derived thiodepsipeptide thiocoraline was investigated in vitro in two carcinoid cell lines (BON and H727). Carcinoid cells treated with nanomolar concentrations of thiocoraline resulted in a decrease in cell proliferation and an alteration of malignant phenotype evidenced by decrease of NET markers, achaete-scute complex like-1, chromogranin A and neurospecific enolase. Western blotting analysis demonstrated the activation of Notch1 on the protein level in BON cells. Additionally, thiocoraline activated downstream Notch targets HES1, HES5 and HEY2. Thiocoraline effectively suppressed carcinoid cell growth by promoting cell cycle arrest in BON and H727 cells. An in vivo study demonstrated that thiocoraline, formulated with polymeric micelles, slowed carcinoid tumor progression. Thus the therapeutic potential of thiocoraline, which induced activation of the Notch pathway, in carcinoid tumors was demonstrated. Show less

Amyloidosis is caused by extracellular deposition of proteins in an insoluble manner within tissues. In hereditary forms of amyloidosis, transthyretin, fibrinogen A-α, lysozyme, gelsolin, apolipoprotein A-I, and A-II accumulate in the tissue plaques. Here we describe a 52-year-old man with no family history of renal disease who presented with increased urinary frequency, gradual loss of renal function but no significant proteinuria. Renal biopsy found large amounts of amyloid restricted to the medulla with no involvement of glomeruli or vessels. Immunohistochemical analysis for transthyretin or serum amyloid A and tests for an underlying monoclonal gammopathy were negative. Although initially suspected to be amyloid light chain amyloidosis, laser microdissection and mass spectrometry showed that the amyloid was composed of large amounts of apolipoprotein A-IV. This was based on mass spectrometry studies that showed 100, 96, and 73 spectra in three microdissected samples that matched to apolipoprotein A-IV with 100% probability. DNA analyses detected three sequence variants representing common polymorphisms of the apolipoprotein A-IV gene. Thus, in this case, apolipoprotein A-IV deposition and renal involvement appear to be restricted to the medulla. A high degree of suspicion is required for the diagnosis of apolipoprotein A-IV amyloidosis as it may be missed if a renal biopsy consists only of cortex. Show less

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents. Show less

Fetal akinesia deformation sequence syndrome (FADS) is a heterogeneous disorder characterised by fetal akinesia and developmental defects including, in some case, pterygia. Multiple pterygium syndromes (MPS) are traditionally divided into prenatally lethal and non-lethal (such as Escobar) types. Previously, we and others reported that homozygous mutations in the fetal acetylcholine receptor gamma subunit (CHRNG) can cause both lethal and non-lethal MPS, demonstrating that pterygia resulted from fetal akinesia, and that mutations in the acetylcholine receptor subunits CHRNA1, CHRND, and Rapsyn (RAPSN) can also result in a MPS/FADS phenotype. We hypothesised that mutations in other acetylcholine receptor related genes may interfere with neurotransmission at the neuromuscular junction and so we analysed 14 cases of lethal MPS/FADS without CHRNG, CHRNA1, CHRNB1, CHRND, or RAPSN mutations for mutations in DOK7. A homozygous DOK7 splice site mutation, c.331+1G>T, was identified in a family with three children affected with lethal FADS. Previously DOK7 mutations have been reported to underlie a congenital myaesthenic syndrome with a characteristic "limb girdle" pattern of muscle weakness. This finding is consistent with the hypothesis that whereas incomplete loss of DOK7 function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype. Show less

Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype. Show less

Several murine models demonstrate that mammalian longevity can be increased by single gene mutations affecting endocrine signalling, particularly via the GH/IGF-1 axis. In this study, we identify age-independent patterns of hepatic gene expression characteristic of long-lived Snell (Pit1(dw/dwJ)) dwarf mice. Comparative microarray analysis of young and aged male livers was performed to discover specific genes differentially expressed between Pit1(dw/dwJ) and control mice. Further examination by real-time RT-PCR confirmed that transcripts encoding HMG-CoA synthase-1, HMG-CoA reductase, farnesyl diphosphate synthase, isopentenyl pyrophosphate isomerase, mevalonate decarboxylase, squalene epoxidase, lanosterol demethylase, malic enzyme and apolipoprotein A-IV were significantly decreased in both male and female Pit1(dw/dwJ) livers at 3-5 and 24-28 months of age. In contrast, transcripts encoding the beta(3)-adrenergic receptor, lipoprotein lipase, PPAR gamma and a very low-density lipoprotein receptor homologue were increased significantly in dwarf livers relative to age-matched controls. These studies reveal enduring transcriptional changes characteristic of Pit1(dw/dwJ) dwarf mice that involve genes regulating cholesterol biosynthesis, fatty acid metabolism and lipoprotein homeostasis. Linked to global energy metabolism, this stable shift in hepatic gene expression may contribute to longevity determination by influencing particular metabolic functions often compartmentalized within the mitochondrion and peroxisome; further this metabolic shift may also parallel many transcriptional changes induced by caloric restriction. Show less

Recently a novel subfamily of closely related orphan G protein-coupled receptors (GPCRs) was identified, called GPRC5A, GPRC5B, GPRC5C and GPRC5D. Based on sequence homology, these receptors were classified as family C GPCRs, which include metabotropic GABA(B) receptors, metabotropic glutamate receptors, the calcium sensing receptor and a number of pheromone receptors. GPRC5 receptors share approximately 30-40% sequence homology to each other and 25% homology to the other family C members. It has been shown human GPRC5B mRNA is predominantly expressed in the central nervous system. In order to further characterise this receptor, we investigated both the mRNA and protein expression profiles in rodent tissues. Western blot analysis, using affinity-purified antisera specific to GPRC5B, identified a protein migrating at approximately 68 kDa, close to the predicted molecular weight for GPRC5B. Immunocytochemical analysis of GPRC5B-transfected cells revealed a cell surface localisation. In addition, immunohistochemical analysis of GPRC5B in rat brain and spinal cord demonstrated receptor expression in many areas, with highest levels of immunoreactivity in the neocortex, all subfields of the hippocampus, the granule cell layer of the cerebellum and throughout the spinal cord. Show less