Publications by authors named "Paul Goldberg"

65 Publications

Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency.

Genet Med 2021 Mar 17. Epub 2021 Mar 17.

Greenwood Genetic Center, Greenwood, SC, USA.

Purpose: Variants in NUS1 are associated with a congenital disorder of glycosylation, developmental and epileptic encephalopathies, and are possible contributors to Parkinson disease pathogenesis. How the diverse functions of the NUS1-encoded Nogo B receptor (NgBR) relate to these different phenotypes is largely unknown. We present three patients with de novo heterozygous variants in NUS1 that cause a complex movement disorder, define pathogenic mechanisms in cells and zebrafish, and identify possible therapy.

Methods: Comprehensive functional studies were performed using patient fibroblasts, and a zebrafish model mimicking NUS1 haploinsufficiency.

Results: We show that de novo NUS1 variants reduce NgBR and Niemann-Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation. Reducing nus1 expression 50% in zebrafish embryos causes abnormal swim behaviors, cholesterol accumulation in the nervous system, and impaired turnover of lysosomal membrane proteins. Reduction of cholesterol buildup with 2-hydroxypropyl-ß-cyclodextrin significantly alleviates lysosomal proteolysis and motility defects.

Conclusion: Our results demonstrate that these NUS1 variants cause multiple lysosomal phenotypes in cells. We show that the movement deficits associated with nus1 reduction in zebrafish arise in part from defective efflux of cholesterol from lysosomes, suggesting that treatments targeting cholesterol accumulation could be therapeutic.
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http://dx.doi.org/10.1038/s41436-021-01137-6DOI Listing
March 2021

Reconstructing Late Pleistocene paleoclimate at the scale of human behavior: an example from the Neandertal occupation of La Ferrassie (France).

Sci Rep 2021 Jan 14;11(1):1419. Epub 2021 Jan 14.

Department of Human Evolution, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.

Exploring the role of changing climates in human evolution is currently impeded by a scarcity of climatic information at the same temporal scale as the human behaviors documented in archaeological sites. This is mainly caused by high uncertainties in the chronometric dates used to correlate long-term climatic records with archaeological deposits. One solution is to generate climatic data directly from archaeological materials representing human behavior. Here we use oxygen isotope measurements of Bos/Bison tooth enamel to reconstruct summer and winter temperatures in the Late Pleistocene when Neandertals were using the site of La Ferrassie. Our results indicate that, despite the generally cold conditions of the broader period and despite direct evidence for cold features in certain sediments at the site, Neandertals used the site predominantly when climatic conditions were mild, similar to conditions in modern day France. We suggest that due to millennial scale climate variability, the periods of human activity and their climatic characteristics may not be representative of average conditions inferred from chronological correlations with long-term climatic records. These results highlight the importance of using direct routes, such as the high-resolution archives in tooth enamel from anthropogenically accumulated faunal assemblages, to establish climatic conditions at a human scale.
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http://dx.doi.org/10.1038/s41598-020-80777-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809458PMC
January 2021

Issues of theory and method in the analysis of Paleolithic mortuary behavior: A view from Shanidar Cave.

Evol Anthropol 2020 Sep 11;29(5):263-279. Epub 2020 Jul 11.

McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK.

Mortuary behavior (activities concerning dead conspecifics) is one of many traits that were previously widely considered to have been uniquely human, but on which perspectives have changed markedly in recent years. Theoretical approaches to hominin mortuary activity and its evolution have undergone major revision, and advances in diverse archeological and paleoanthropological methods have brought new ways of identifying behaviors such as intentional burial. Despite these advances, debates concerning the nature of hominin mortuary activity, particularly among the Neanderthals, rely heavily on the rereading of old excavations as new finds are relatively rare, limiting the extent to which such debates can benefit from advances in the field. The recent discovery of in situ articulated Neanderthal remains at Shanidar Cave offers a rare opportunity to take full advantage of these methodological and theoretical developments to understand Neanderthal mortuary activity, making a review of these advances relevant and timely.
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http://dx.doi.org/10.1002/evan.21854DOI Listing
September 2020

The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic.

Epilepsy Behav 2020 02 10;103(Pt A):106839. Epub 2020 Jan 10.

Lafora Epilepsy Cure Initiative (LECI), USA; Laboratory of Neurology, IIS-Jimenez Diaz Foundation, UAM, 28045 Madrid, Spain; Biomedical Research Networking Center on Rare Diseases (CIBERER), 28029 Madrid, Spain.

Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.
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http://dx.doi.org/10.1016/j.yebeh.2019.106839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024738PMC
February 2020

TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.

Ann Clin Transl Neurol 2019 11 30;6(11):2164-2174. Epub 2019 Sep 30.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Objective: Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials.

Methods: TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers.

Results: Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration.

Interpretation: Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early-stage clinical trials.
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http://dx.doi.org/10.1002/acn3.50896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856596PMC
November 2019

Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).

Sci Rep 2019 09 26;9(1):13785. Epub 2019 Sep 26.

Centre for Archaeological Science, School of Earth, Atmospheric and Life Sciences, University of Wollongong, Wollongong, New South Wales, 2522, Australia.

Denisova Cave in southern Siberia uniquely contains evidence of occupation by a recently discovered group of archaic hominins, the Denisovans, starting from the middle of the Middle Pleistocene. Artefacts, ancient DNA and a range of animal and plant remains have been recovered from the sedimentary deposits, along with a few fragmentary fossils of Denisovans, Neanderthals and a first-generation Neanderthal-Denisovan offspring. The deposits also contain microscopic traces of hominin and animal activities that can provide insights into the use of the cave over the last 300,000 years. Here we report the results of a micromorphological study of intact sediment blocks collected from the Pleistocene deposits in the Main and East Chambers of Denisova Cave. The presence of charcoal attests to the use of fire by hominins, but other evidence of their activities preserved in the microstratigraphic record are few. The ubiquitous occurrence of coprolites, which we attribute primarily to hyenas, indicates that the site was visited for much of its depositional history by cave-dwelling carnivores. Microscopic traces of post-depositional diagenesis, bioturbation and incipient cryoturbation are observed in only a few regions of the deposit examined here. Micromorphology can help identify areas of sedimentary deposit that are most conducive to ancient DNA preservation and could be usefully integrated with DNA analyses of sediments at archaeological sites to illuminate features of their human and environmental history that are invisible to the naked eye.
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http://dx.doi.org/10.1038/s41598-019-49930-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763451PMC
September 2019

Named entity recognition in electronic health records using transfer learning bootstrapped Neural Networks.

Neural Netw 2020 Jan 6;121:132-139. Epub 2019 Sep 6.

University of Oxford, United Kingdom of Great Britain and Northern Ireland. Electronic address:

Neural networks (NNs) have become the state of the art in many machine learning applications, such as image, sound (LeCun et al., 2015) and natural language processing (Young et al., 2017; Linggard et al., 2012). However, the success of NNs remains dependent on the availability of large labelled datasets, such as in the case of electronic health records (EHRs). With scarce data, NNs are unlikely to be able to extract this hidden information with practical accuracy. In this study, we develop an approach that solves these problems for named entity recognition, obtaining 94.6 F1 score in I2B2 2009 Medical Extraction Challenge (Uzuner et al., 2010), 4.3 above the architecture that won the competition. To achieve this, we bootstrap our NN models through transfer learning by pretraining word embeddings on a secondary task performed on a large pool of unannotated EHRs and using the output embeddings as a foundation of a range of NN architectures. Beyond the official I2B2 challenge, we further achieve 82.4 F1 on extracting relationships between medical terms using attention-based seq2seq models bootstrapped in the same manner.
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http://dx.doi.org/10.1016/j.neunet.2019.08.032DOI Listing
January 2020

Differences in Stress Shoot Performance Among Special Forces Operators Who Participate in a Human Performance Program Versus Those Who Do Not.

J Spec Oper Med Winter 2018;18(4):64-68

Background: The purpose of this investigation was to determine if Army Special Operation Forces (ARSOF) Operators who participate in the Tactical Human Optimization, Rapid Rehabilitation and Reconditioning program perform significantly better on a simulated stress shoot scenario than ARSOF Operators who do not participate in the program.

Methods: Deidentified archival data from 64 male ARSOF Operators (mean ± standard deviation: age, 31.1 ± 4.96 years; SOF experience, 3.44 ± 4.10 years) who participated in the Special Forces Advanced Urban Combat stress shoot were assessed to determine if differences in performance existed between program users (n = 25) and nonusers (n = 39). A series of bootstrapped analyses of variance in conjunction with effect-size calculations was conducted to determine if significant mean score differences existed between users and nonusers on raw and total course completion times, high-value target acquisition (positive identification time), and penalties accrued.

Results: Small to medium effect sizes were observed between users and nonusers in raw time, penalties, and total time. Although there were no significant differences between users and nonusers, there was less variation in raw time and total time in users compared with nonusers.

Conclusion: Our findings becomes a question of practical versus statistical significance, because less performance variability while under physical and psychological duress could be life saving for ARSOF Operators.
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June 2019

The 4th International Lafora Epilepsy Workshop: Shifting paradigms, paths to treatment, and hope for patients.

Epilepsy Behav 2019 01 6;90:284-286. Epub 2018 Dec 6.

Department of Molecular and Cellular Biochemistry, Epilepsy and Brain Metabolism Alliance, Lafora Epilepsy Cure Initiative, Epilepsy Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA. Electronic address:

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http://dx.doi.org/10.1016/j.yebeh.2018.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457339PMC
January 2019

Harold L. Dibble (1951-2018).

Nat Ecol Evol 2018 10;2(10):1521-1522

Universidade do Algarve, Faro, Portugal.

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http://dx.doi.org/10.1038/s41559-018-0665-5DOI Listing
October 2018

Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability.

J Clin Invest 2017 Jun 22;127(7):2805-2814. Epub 2017 May 22.

Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.
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http://dx.doi.org/10.1172/JCI92373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490760PMC
June 2017

Perianal synovial sarcoma treated postoperatively with Iodine-125 brachytherapy: Technical details.

Brachytherapy 2017 May - Jun;16(3):565-571. Epub 2017 Mar 30.

Department of Surgery, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.

Purpose: A 23-year-old lady had an incompletely excised perianal sarcoma. Brachytherapy as the sole treatment, rather than further surgery or external beam radiotherapy, was considered to be the best option with the least morbidity.

Methods And Materials: Although brachytherapy techniques with iridium-192 for anal and rectal carcinoma are well described using a perianal template, the size of the template was not suitable for a two-plane implant that needed to be in situ for about 4 days. An anal canal applicator was designed, which carried three templates about 15 mm apart inside it, to ensure accurate alignment of the tubes, and an inferior template that was 90 mm from the perianal skin. Three inner and three outer tubes of iodine-125 seeds were designed to treat a 2 o'clock h wedge of perianal tissue as a temporary implant. A thin metal shield was placed around a hole to protect the uninvolved anal canal. The tubes were inserted under general anesthetic and delivered a dose of 59 Gy at 0.8 Gy/h over 75 h. A spinal anesthetic was maintained for the duration of the insertion.

Results: The treatment was well tolerated, and the patient is well and clear of disease 6 years later with minimal morbidity.

Conclusions: Iodine-125 is a low-energy isotope, readily available in our unit, that can be easily screened to reduce morbidity to surrounding normal tissues. In the form of seeds, it provides a flexible system that can be adapted to different tumor sites as required, as illustrated in this case.
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http://dx.doi.org/10.1016/j.brachy.2017.02.007DOI Listing
December 2017

The age of three Middle Palaeolithic sites: Single-grain optically stimulated luminescence chronologies for Pech de l'Azé I, II and IV in France.

J Hum Evol 2016 06 20;95:80-103. Epub 2016 May 20.

Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany; Faculty of Archaeology, Leiden University, PO Box 9514, 2300, RA Leiden, The Netherlands.

Optically stimulated luminescence (OSL) measurements were made on individual, sand-sized grains of quartz from Middle Palaeolithic deposits at three sites (Pech de l'Azé I, II and IV) located close to one another in the Dordogne region of southwest France. We were able to calculate OSL ages for 69 samples collected from these three sites. These ages reveal periods of occupation between about 180 and 50 thousand years ago. Our single-grain OSL chronologies largely support previous age estimates obtained by thermoluminescence dating of burnt flints at Pech IV, electron spin resonance dating of tooth enamel at Pech I, II and IV and radiocarbon dating of bone at Pech I and IV, but provide a more complete picture due to the ubiquitous presence of sand-sized quartz grains used in OSL dating. These complete chronologies for the three sites have allowed us to compare the single-grain ages for similar lithic assemblages among the three sites, to test the correlations among them previously proposed by Bordes in the 1970s, and to construct our own correlative chronological framework for the three sites. This shows that similar lithic assemblages occur at around the same time, and that where a lithic assemblage is unique to one or found at two of the Pech sites, there are no deposits of chronologically equivalent age at the other Pech site(s). We interpret this to mean that, at least for these Pech de l'Azé sites, the Mousterian variants show temporal ordering. Whether or not this conclusion applies to the wider region and beyond, the hypothesis that Mousterian industrial variation is temporally ordered cannot be refuted at this time.
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http://dx.doi.org/10.1016/j.jhevol.2016.03.010DOI Listing
June 2016

Driving physician adoption of mHeath solutions.

Healthc Financ Manage 2015 Feb;69(2):36-9

A well-executed mobile health (mHealth) solution can help a hospital with its population health and readmission reduction initiatives. Successful implementation of an mHealth solution requires a campaign to persuade physicians to use it. Orchestrating physician adoption includes educating physicians about benefits such as easy access to lab results, enhanced caregiver communications, and better access to consult requests.
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February 2015

BMPER variants associated with a novel, attenuated subtype of diaphanospondylodysostosis.

J Hum Genet 2015 Dec 15;60(12):743-7. Epub 2015 Oct 15.

Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

Diaphanospondylodysostosis (DSD), caused by loss of bone morphogenetic protein-binding endothelial regulator (BMPER), has been considered a lethal skeletal dysplasia characterized by severe deficiency of vertebral body and sacral ossification, reduced rib number and cystic kidneys. In this study, however, we have demonstrated that variants in BMPER may cause a milder disorder, without renal anomalies, that is compatible with long-term survival. Four siblings, three males and one female, presented with severe congenital scoliosis associated with rib and vertebral malformations as well as strikingly delayed ossification of the pedicles. The female was stillborn from an unrelated cause. Stabilization of the scoliosis with expandable titanium rods was successful in the three boys, all of whom have short stature. An autosomal recessive mode of inheritance was hypothesized. Single nucleotide polymorphism microarray analysis was performed for three of the siblings to identify autosomal genes with shared allele patterns, suggesting possible linkage. Exome sequencing of one sibling was then performed. Rare variants were identified in 347 genes with shared alleles. Only one of these genes had bi-allelic variants in a gene strongly expressed in paraxial mesenchyme: BMPER, which is the cause of DSD, an autosomal recessive disorder. The disorder described herein could represent an attenuated form of DSD or could be designated a separate entity such as spondylopedicular dysplasia.
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http://dx.doi.org/10.1038/jhg.2015.116DOI Listing
December 2015

The depositional environments of Schöningen 13 II-4 and their archaeological implications.

J Hum Evol 2015 Dec 2;89:71-91. Epub 2015 Sep 2.

Senckenberg Centre for Human Evolution and Palaeoecology, University of Tübingen, Rümelinstr. 23, 72070 Tübingen, Germany; Department of Early Prehistory and Quaternary Ecology, University of Tübingen, Schloss Hohentübingen, 72070 Tübingen, Germany.

Geoarchaeological research at the Middle Pleistocene site of Schöningen 13 II-4, often referred to as the Speerhorizont, has focused on describing and evaluating the depositional contexts of the well-known wooden spears, butchered horses, and stone tools. These finds were recovered from the transitional contact between a lacustrine marl and an overlying organic mud, originally thought to be a peat that accumulated in place under variable moisture conditions. The original excavators proposed that hominin activity, including hunting and butchery, occurred on a dry lake shore and was followed by a rapid sedimentation of organic deposits that embedded and preserved the artifacts. Our geoarchaeological analysis challenges this model. Here, we present evidence that the sediments of Schöningen 13 II-4 were deposited in a constantly submerged area of a paleolake. Although we cannot exclude the possibility that the artifacts were deposited during a short, extreme drying event, there are no sedimentary features indicative of surface exposure in the sediments. Accordingly, this paper explores three main alternative models of site formation: anthropogenic disposal of materials into the lake, a geological relocation of the artifacts, and hunting or caching on lake-ice. These models have different behavioral ramifications concerning hominin knowledge and exploitation of the landscape and their subsistence strategies.
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http://dx.doi.org/10.1016/j.jhevol.2015.07.008DOI Listing
December 2015

On the evidence for human use and control of fire at Schöningen.

J Hum Evol 2015 Dec 16;89:181-201. Epub 2015 Jun 16.

Department of Early Prehistory and Quaternary Ecology, University of Tübingen, Schloss Hohentübingen, 72070 Tübingen, Germany; Senckenberg Centre for Human Evolution and Palaeoecology, University of Tübingen, Schloss Hohentübingen, 72070 Tübingen, Germany.

When and how humans began to control fire has been a central debate in Paleolithic archaeology for decades. Fire plays an important role in technology, social organization, subsistence, and manipulation of the environment and is widely seen as a necessary adaptation for the colonization of northern latitudes. Many researchers view purported hearths, burnt wooden implements, and heated flints from Schöningen as providing the best evidence for the control of fire in the Lower Paleolithic of Northern Europe. Here we present results of a multianalytical study of the purported hearths along with a critical examination of other possible evidence of human use or control of fire at Schöningen. We conclude that the analyzed features and artifacts present no convincing evidence for human use or control of fire. Our study also shows that a multianalytical, micro-contextual approach is the best methodology for evaluating claims of early evidence of human-controlled fire. We advise caution with macroscopic, qualitative identification of combustion features, burnt flint, and burnt wood without the application of such techniques as micromorphology, Fourier transform infrared (FTIR) spectroscopy, organic petrology, luminescence, and analysis of mineral magnetic parameters. The lack of evidence for the human control of fire at Schöningen raises the possibility that fire control was not a necessary adaptation for the human settlement of northern latitudes in the Lower Paleolithic.
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http://dx.doi.org/10.1016/j.jhevol.2015.04.004DOI Listing
December 2015

Quantitative profiling of colorectal cancer-associated bacteria reveals associations between fusobacterium spp., enterotoxigenic Bacteroides fragilis (ETBF) and clinicopathological features of colorectal cancer.

PLoS One 2015 9;10(3):e0119462. Epub 2015 Mar 9.

Institute of Infectious Disease & Molecular Medicine, Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Various studies have presented clinical or in vitro evidence linking bacteria to colorectal cancer, but these bacteria have not previously been concurrently quantified by qPCR in a single cohort. We quantify these bacteria (Fusobacterium spp., Streptococcus gallolyticus, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Enteropathogenic Escherichia coli (EPEC), and afaC- or pks-positive E. coli) in paired tumour and normal tissue samples from 55 colorectal cancer patients. We further investigate the relationship between a) the presence and b) the level of colonisation of each bacterial species with site and stage of disease, age, gender, ethnicity and MSI-status. With the exception of S. gallolyticus, we detected all bacteria profiled here in both tumour and normal samples at varying frequencies. ETBF (FDR = 0.001 and 0.002 for normal and tumour samples) and afaC-positive E. coli (FDR = 0.03, normal samples) were significantly enriched in the colon compared to the rectum. ETBF (FDR = 0.04 and 0.002 for normal and tumour samples, respectively) and Fusobacterium spp. (FDR = 0.03 tumour samples) levels were significantly higher in late stage (III/IV) colorectal cancers. Fusobacterium was by far the most common bacteria detected, occurring in 82% and 81% of paired tumour and normal samples. Fusobacterium was also the only bacterium that was significantly higher in tumour compared to normal samples (p = 6e-5). We also identified significant associations between high-level colonisation by Fusobacterium and MSI-H (FDR = 0.05), age (FDR = 0.03) or pks-positive E. coli (FDR = 0.01). Furthermore, we exclusively identified atypical EPEC in our cohort, which has not been previously reported in association with colorectal cancer. By quantifying colorectal cancer-associated bacteria across a single cohort, we uncovered inter- and intra-individual patterns of colonization not previously recognized, as well as important associations with clinicopathological features, especially in the case of Fusobacterium and ETBF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119462PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353626PMC
January 2016

What is the role of journalists in distinguishing hype from reality?

Authors:
Paul Goldberg

Clin Adv Hematol Oncol 2014 Dec;12(12):855-7

The Cancer Letter, Washington, DC.

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December 2014

Problems with public reporting of cancer quality outcomes data.

J Oncol Pract 2014 May;10(3):215-8

The Cancer Letter, Washington, DC; and University of Chicago, Chicago, IL.

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http://dx.doi.org/10.1200/JOP.2014.001405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795653PMC
May 2014

Fertility and apparent genetic anticipation in Lynch syndrome.

Fam Cancer 2014 Sep;13(3):369-74

Deakin University Department of Surgery, Geelong Hospital, Ryrie Street, Geelong, VIC, 3227, Australia,

Genetic anticipation is the phenomenon in which age of onset of an inherited disorder decreases in successive generations. Inconsistent evidence suggests that this occurs in Lynch syndrome. A possible cause for apparent anticipation is fecundity bias, which occurs if the disease adversely affects fertility. The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer (CRC) on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation. A computer model simulated age of diagnosis of CRC in hypothetical Lynch syndrome carriers and their offspring. The model assumed similar age distribution of CRC across generations (i.e. that there was no true anticipation). Age distribution of CRC diagnosis, and lifetime fertility rates (grouped by age of diagnosis of CRC) were determined from the Australasian Colorectal Cancer Family Registry (ACCFR). Apparent anticipation was calculated by comparing ages of diagnosis of CRC in affected parent-child pairs. A total of 1,088 patients with CRC were identified from the ACCFR. Total lifetime (cohort) fertility was related to age of diagnosis of CRC (correlation coefficient 0.13, P = 0.0001). In the simulation, apparent anticipation was 1.8 ± 0.54 years (P = 0.0044). Observed apparent anticipation in the ACCFR cohort was 4.8 ± 1.73 years (P = 0.0064). There was no difference in apparent anticipation between the simulate d and observed parent-child pairs (P = 0.89). The appearance of genetic anticipation in Lynch syndrome can be falsely created due to changes in fertility.
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http://dx.doi.org/10.1007/s10689-014-9714-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357528PMC
September 2014

Deciphering site formation processes through soil micromorphology at Contrebandiers Cave, Morocco.

J Hum Evol 2014 Apr 17;69:8-30. Epub 2014 Mar 17.

Institut National des Sciences de l'Archéologie et du Patrimoine, 10001 Rabat, Morocco.

Contrebandiers Cave preserves a Late Pleistocene sequence containing Middle Stone Age (MSA) so-called Maghrebian Mousterian and Aterian occupations, spanning from ∼126 to 95 ka (thousands of years ago), followed by spatially restricted Iberomaurusian industries. Micromorphological analyses, complemented by instrumental mineralogical identification and fabric orientation, allowed for the reconstruction of the main site formation processes at the site. Initial deposition is characterized by local reworking of marine shelly sands dating to Marine Isotopic Stage 5e (MIS5e). The subsequent stratification reveals sedimentary dynamics predominantly associated with gravity-driven inputs and contributions from weathering of the encasing bedrock, at the same time that anthropogenic sediments were being accumulated. The allochthonous components reflect soil degradation and vegetation changes around the cave during the last interglacial. Human occupations seems to be somewhat ephemeral in nature, with some stratigraphic units apparently lacking archaeological components, while in others the human-associated deposits (e.g., burned bones, charcoal, and ashes) can be substantial. Ephemeral breaks in sedimentation and/or erosion followed by stabilization are mainly discernible microscopically by the presence of phosphatic-rich laminae interpreted as short-lived surfaces, peaks of increased humidity and colonization by plants. More substantial erosion affects the uppermost Aterian layers, presumably due to localized reconfigurations of the cave's roof. The subsequent Iberomaurusian deposits are not in their primary position and are associated with well-sorted silts of aeolian origin. While the effects of chemical diagenesis are limited throughout the whole stratigraphic sequence, physical bioturbation (e.g., by wasps, rodents, and earthworms) is more pervasive and leads to localized movement of the original sedimentary particles.
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http://dx.doi.org/10.1016/j.jhevol.2013.12.016DOI Listing
April 2014

Overcoming barriers to physician adoption of EHRs.

Healthc Financ Manage 2014 Feb;68(2):48-52

Jersey City Medical Center, Jersey City, NJ, USA.

A hospital's success in implementing an electronic health record will depend largely on physicians' willingness to adopt the new technology. Therefore, before embarking on such an initiative, finance leaders should conduct a targeted survey to assess the likelihood that the initiative will meet with physician resistance. The survey results can provide a basis for developing an outreach program that will bring physicians on board by helping them understand the initiative's purpose and giving them a stake in its success.
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February 2014

Predictive genetic testing in children: constitutional mismatch repair deficiency cancer predisposing syndrome.

J Genet Couns 2014 Apr 15;23(2):147-55. Epub 2013 Oct 15.

Biallelic germline mutations in mismatch repair genes predispose to constitutional mismatch repair deficiency syndrome (CMMR-D). The condition is characterized by a broad spectrum of early-onset tumors, including hematological, brain and bowel and is frequently associated with features of Neurofibromatosis type 1. Few definitive screening recommendations have been suggested and no published reports have described predictive testing. We report on the first case of predictive testing for CMMR-D following the identification of two non-consanguineous parents, with the same heterozygous mutation in MLH1: c.1528C > T. The genetic counseling offered to the family, for their two at-risk daughters, is discussed with a focus on the ethical considerations of testing children for known cancer-causing variants. The challenges that are encountered when reporting on heterozygosity in a child younger than 18 years (disclosure of carrier status and risk for Lynch syndrome), when discovered during testing for homozygosity, are addressed. In addition, the identification of CMMR-D in a three year old, and the recommended clinical surveillance that was proposed for this individual is discussed. Despite predictive testing and presymptomatic screening, the sudden death of the child with CMMR-D syndrome occurred 6 months after her last surveillance MRI. This report further highlights the difficulty of developing guidelines, as a result of the rarity of cases and diversity of presentation.
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http://dx.doi.org/10.1007/s10897-013-9659-2DOI Listing
April 2014

Neandertals made the first specialized bone tools in Europe.

Proc Natl Acad Sci U S A 2013 Aug 12;110(35):14186-90. Epub 2013 Aug 12.

Faculty of Archaeology, Leiden University, 2300 RA Leiden, The Netherlands.

Modern humans replaced Neandertals ∼40,000 y ago. Close to the time of replacement, Neandertals show behaviors similar to those of the modern humans arriving into Europe, including the use of specialized bone tools, body ornaments, and small blades. It is highly debated whether these modern behaviors developed before or as a result of contact with modern humans. Here we report the identification of a type of specialized bone tool, lissoir, previously only associated with modern humans. The microwear preserved on one of these lissoir is consistent with the use of lissoir in modern times to obtain supple, lustrous, and more impermeable hides. These tools are from a Neandertal context proceeding the replacement period and are the oldest specialized bone tools in Europe. As such, they are either a demonstration of independent invention by Neandertals or an indication that modern humans started influencing European Neandertals much earlier than previously believed. Because these finds clearly predate the oldest known age for the use of similar objects in Europe by anatomically modern humans, they could also be evidence for cultural diffusion from Neandertals to modern humans.
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http://dx.doi.org/10.1073/pnas.1302730110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761603PMC
August 2013

CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease.

J Med Genet 2013 Oct 29;50(10):696-703. Epub 2013 Jul 29.

Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: New mutations for Huntington disease (HD) occur due to CAG repeat instability of intermediate alleles (IA). IAs have between 27 and 35 CAG repeats, a range just below the disease threshold of 36 repeats. While they usually do not confer the HD phenotype, IAs are prone to paternal germline CAG repeat instability. Consequently, they may expand into the HD range upon transmission to the next generation, producing a new mutation. Quantified risk estimates for IA repeat instability are extremely limited but needed to inform clinical practice.

Methods: Using small-pool PCR of sperm DNA from Caucasian men, we examined the frequency and magnitude of CAG repeat instability across the entire range of intermediate CAG sizes. The CAG size-specific risk estimates generated are based on the largest sample size ever examined, including 30 IAs and 18 198 sperm.

Results: Our findings demonstrate a significant risk of new mutations. While all intermediate CAG sizes demonstrated repeat expansion into the HD range, alleles with 34 and 35 CAG repeats were associated with the highest risk of a new mutation (2.4% and 21.0%, respectively). IAs with ≥33 CAG repeats showed a dramatic increase in the frequency of instability and a switch towards a preponderance of repeat expansions over contractions.

Conclusions: These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.
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http://dx.doi.org/10.1136/jmedgenet-2013-101796DOI Listing
October 2013

Self-Expanding Metal Stenting for Palliation of Patients with Malignant Colonic Obstruction: Effectiveness and Efficacy on 255 Patients with 12-Month's Follow-up.

Gastroenterol Res Pract 2012 11;2012:296347. Epub 2012 Jun 11.

Endoscopy Unit, Bispebjerg Hospital, Bispebjerg Bakke 23, Entrance 7B, 2400 Copenhagen NV, Denmark.

Background. Self-expanding metal stents can alleviate malignant colonic obstruction in incurable patients and avoid palliative stoma surgery. Objective. Evaluate stent effectiveness and safety on palliation of patients with malignant colorectal strictures. Design. Two prospective, one Spanish and one global, multicenter studies. Settings. 39 centers (22 academic, 17 community hospitals) from 13 countries. Patients. A total of 257 patients were enrolled, and 255 patients were treated with a WallFlex uncovered enteral colonic stent. Follow-up was up to 12 months or until death or retreatment. Interventions(s). Self-expanding metal stent placement. Main Outcome Measures. Procedural success, clinical success, and safety. Results. Procedural success was 98.4% (251). Clinical success rates were 87.8% at 30 days, 89.7% at 3 months, 92.8% at 6 months, and 96% at 12 months. Overall perforation rate was 5.1%. Overall migration rate was 5.5%. Overall death rate during follow-up was 48.6% (124), with 67.7% of deaths related to the patient's colorectal cancer, unrelated in 32.3%. Only 2 deaths were related to the stent or procedure. Limitations. No control group. Conclusions. The primary palliative option for patients with malignant colonic obstruction should be self-expanding metal stent placement due to high rates of technical success and efficacy in symptom palliation and few complications.
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http://dx.doi.org/10.1155/2012/296347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384950PMC
August 2012

Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors.

Bioorg Med Chem Lett 2012 Aug 15;22(15):5108-13. Epub 2012 Jun 15.

Department of Medicinal Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, Canada.

Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.
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http://dx.doi.org/10.1016/j.bmcl.2012.05.129DOI Listing
August 2012

Early pottery at 20,000 years ago in Xianrendong Cave, China.

Science 2012 Jun;336(6089):1696-700

School of Archaeology and Museology, Peking University, Beijing 100871, China.

The invention of pottery introduced fundamental shifts in human subsistence practices and sociosymbolic behaviors. Here, we describe the dating of the early pottery from Xianrendong Cave, Jiangxi Province, China, and the micromorphology of the stratigraphic contexts of the pottery sherds and radiocarbon samples. The radiocarbon ages of the archaeological contexts of the earliest sherds are 20,000 to 19,000 calendar years before the present, 2000 to 3000 years older than other pottery found in East Asia and elsewhere. The occupations in the cave demonstrate that pottery was produced by mobile foragers who hunted and gathered during the Late Glacial Maximum. These vessels may have served as cooking devices. The early date shows that pottery was first made and used 10 millennia or more before the emergence of agriculture.
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http://dx.doi.org/10.1126/science.1218643DOI Listing
June 2012