Background and purpose
The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of ...frontotemporal dementia (FTD), including microtubule‐associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD.
Methods
In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor‐based morphometry. Sample size estimates were calculated.
Results
Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD.
Conclusion
These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.
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TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately one-fourth of subjects with pathologically ...confirmed Alzheimer disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine whether subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging, or pathologic features compared with subjects with AD without abTDP-43 immunoreactivity.
Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls.
Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity.
The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.
Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. ...Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.
A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral ...sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
To compare patterns of gray matter loss in subjects with mutations in the progranulin (PGRN) gene to subjects with mutations in the microtubule-associated protein tau (MAPT) gene.
We identified all ...subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group.
Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT. The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects.
These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers.
Electrosynthesis is a popular, green alternative to traditional organic methods. Understanding the mechanisms is not trivial yet is necessary to optimize reaction processes. To this end, a multitude ...of analytical tools is available to identify and quantitate reaction products and intermediates. The first portion of this review serves as a guide that underscores electrosynthesis fundamentals, including instrumentation, electrode selection, impacts of electrolyte and solvent, cell configuration, and methods of electrosynthesis. Next, the broad base of analytical techniques that aid in mechanism elucidation are covered in detail. These methods are divided into electrochemical, spectroscopic, chromatographic, microscopic, and computational. Technique selection is dependent on predicted reaction pathways and electrogenerated intermediates. Often, a combination of techniques must be utilized to ensure accuracy of the proposed model. To conclude, future prospects that aim to enhance the field are discussed.
There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is ...lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma.
Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index.
In total, 17,930 LNs from 763 patients were examined. LN response classified as
(LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%),
(LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%),
(LNRS 4-5; n = 303, 39.7%), or
(no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio HR, 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%).
Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.
Background
The aim was to define the pathological response in lymph nodes following neoadjuvant chemotherapy for oesophageal adenocarcinoma and to quantify any associated survival benefit.
Methods
...Lymph nodes retrieved at oesophagectomy were examined retrospectively by two pathologists for evidence of a response to chemotherapy. Patients were classified as lymph node‐negative (either negative nodes with no evidence of previous tumour involvement or negative with evidence of complete regression) or positive (allocated a lymph node regression score based on the proportion of fibrosis to residual tumour). Lymph node responders (score 1, complete response; 2, less than 10 per cent remaining tumour; 3, 10–50 per cent remaining tumour) and non‐responders (score 4, more than 50 per cent viable tumour; 5, no response) were compared in survival analyses using Kaplan–Meier and Cox regression analysis.
Results
Among 377 patients, 256 had neoadjuvant chemotherapy. Overall, 68 of 256 patients (26·6 per cent) had a lymph node response and 115 (44·9 per cent) did not. The remaining 73 patients (28·5 per cent) had negative lymph nodes with no evidence of regression. Some patients had a lymph node response in the absence of a response in the primary tumour (27 of 99, 27 per cent). Lymph node responders had a significant survival benefit (P < 0·001), even when stratified by patients with or without a response in the primary tumour. On multivariable analysis, lymph node responders had decreased overall (hazard ratio 0·53, 95 per cent c.i. 0·36 to 0·78) and disease‐specific (HR 0·42, 0·27 to 0·66) mortality, and experienced reduced local and systemic recurrence.
Conclusion
Lymph node regression is a strong prognostic factor and may be more important than response in the primary tumour.
Nodal response predicts survival
Inertial confinement fusion implosions must achieve high in-flight shell velocity, sufficient energy coupling between the hot spot and imploding shell, and high areal density (ρR=∫ρdr) at stagnation. ...Asymmetries in ρR degrade the coupling of shell kinetic energy to the hot spot and reduce the confinement of that energy. We present the first evidence that nonuniformity in the ablator shell thickness (∼0.5% of the total thickness) in high-density carbon experiments is a significant cause for observed 3D ρR asymmetries at the National Ignition Facility. These shell-thickness nonuniformities have significantly impacted some recent experiments leading to ρR asymmetries on the order of ∼25% of the average ρR and hot spot velocities of ∼100 km/s. This work reveals the origin of a significant implosion performance degradation in ignition experiments and places stringent new requirements on capsule thickness metrology and symmetry.
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