bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis
Authors: Bhangu Jagdeep Singh , Beer Andrea , Mittlböck Martina , Tamandl Dietmar , Pulverer Walter , Schönthaler Silvia , Taghizadeh Hossein , Stremitzer Stefan , Kaczirek Klaus , Gruenberger Thomas , Gnant Michael , Bergmann Michael , Mannhalter Christine , Weinhäusel Andreas , Oehler Rudolf , Bachleitner-Hofmann Thomas 
Published: August 2018

Background:
Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC.

Patients and Methods:
Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9.

Results:
The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response.

Conclusion:
Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.
A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma
Authors: Tsai Susan , Christians Kathleen K. , George Ben , Ritch Paul S. , Dua Kulwinder , Khan Abdul , Mackinnon A. Craig , Tolat Parag , Ahmad Syed A. , Hall William A. , Erickson Beth A. , Evans Douglas B. 
Published: August 2018

Objectives:
One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery.

Methods:
In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery.

Results:
The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC.

Conclusions:
We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.
Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD)
Authors: de Rooij Thijs , van Hilst Jony , van Santvoort Hjalmar , Boerma Djamila , van den Boezem Peter , Daams Freek , van Dam Ronald , Dejong Cees , van Duyn Eino , Dijkgraaf Marcel , van Eijck Casper , Festen Sebastiaan , Gerhards Michael , Groot Koerkamp Bas , de Hingh Ignace , Kazemier Geert , Klaase Joost , de Kleine Ruben , van Laarhoven Cornelis , Luyer Misha , Patijn Gijs , Steenvoorde Pascal , Suker Mustafa , Abu Hilal Moh’d , Busch Olivier , Besselink Marc 
Published: August 2018

Objective:
This trial followed a structured nationwide training program in minimally invasive distal pancreatectomy (MIDP), according to the IDEAL framework for surgical innovation, and aimed to compare time to functional recovery after minimally invasive and open distal pancreatectomy (ODP).

Background:
MIDP is increasingly used and may enhance postoperative recovery as compared with ODP, but randomized studies are lacking.

Methods:
A multicenter patient-blinded randomized controlled superiority trial was performed in 14 centers between April 2015 and March 2017. Adult patients with left-sided pancreatic tumors confined to the pancreas without vascular involvement were randomly assigned (1:1) to undergo MIDP or ODP. Patients were blinded for type of surgery using a large abdominal dressing. The primary endpoint was time to functional recovery. Analysis was by intention to treat. This trial was registered with the Netherlands Trial Register (NTR5689).

Results:
Time to functional recovery was 4 days [interquartile range (IQR) 3–6) in 51 patients after MIDP versus 6 days (IQR 5–8) in 57 patients after ODP (P < 0.001). The conversion rate of MIDP was 8%. Operative blood loss was less after MIDP (150 vs 400 mL; P < 0.001), whereas operative time was longer (217 vs 179 minutes; P = 0.005). The Clavien–Dindo grade ≥III complication rate was 25% versus 38% (P = 0.21). Delayed gastric emptying grade B/C was seen less often after MIDP (6% vs 20%; P = 0.04). Postoperative pancreatic fistulas grade B/C were seen in 39% after MIDP versus 23% after ODP (P = 0.07), without difference in percutaneous catheter drainage (22% vs 20%; P = 0.77). Quality of life (day 3–30) was better after MIDP as compared with ODP, and overall costs were non-significantly less after MIDP. No 90-day mortality was seen after MIDP versus 2% (n = 1) after ODP.

Conclusions:
In patients with left-sided pancreatic tumors confined to the pancreas, MIDP reduces time to functional recovery compared with ODP. Although the overall rate of complications was not reduced, MIDP was associated with less delayed gastric emptying and better quality of life without increasing costs.
Corrigendum to: T cell apoptosis at the maternal-fetal interface in early human pregnancy, involvement of galectin-1.- A correction with an important twist
Authors: Kopcow Hernan 
Published: August 2018

AbstractWe previously published a paper reporting the apoptotic nature of first trimester human decidual T cells (Kopcow et al 2008). New experiments and data re-analysis produced confirmatory, negative and contradictory results. We had previously shown by TUNEL and sub diploid DNA content analysis (SD) that ex-vivo decidual T cells, isolated either as CD3+ cells or as CD4+/8+ cells, are apoptotic and that the level of apoptosis differs significantly from peripheral blood T cells isolated in a similar way. Data re-examination including data points previously unintentionally ignored results in indetermination in the dataset structure with contradictory statistical significance results between TUNEL and SD and the two isolation approaches. Furthermore, data disaggregation and granular examination reveals discrepant TUNEL and SD readings within individual samples. We have previously shown that decidual CD3+ lymphocytes stain brighter with AnnexinV -Fitc than peripheral blood T cells and other decidual lympohocyte populations. Independent repetitions with modified and alternative isolation protocols using different flow cytometry equipment in the hands of another researcher failed to reproduce those results, while side by side repetition under the published conditions as well as under the alternative isolation protocol reproduced the published pattern when samples were ran in the same equipment used for the publication. A reflection on these results proposes to understand the scientific paper as one among other possible constructed narratives.
Cancer cell lipid class homeostasis is altered under nutrient-deprivation but stable under hypoxia
Authors: Lisec Jan , Jaeger Carsten , Zaidi Nousheen 
Published: August 2018

AbstractUnder oxygen/nutrient deprivation cancer cells modify the balance between fatty acid (FA) synthesis and uptake, which alters the levels of individual triglyceride or phospholipid sub-species. These modifications may affect survival and drug-uptake in cancer cells. Here, we aimed to attain a more holistic overview of the lipidomic profiles of cancer cells under stress and assess the changes in major lipid-classes. First, expressions of markers of FA synthesis/uptake in cancer cells were assessed and found to be differentially regulated under metabolic stress. Next, we performed a broad lipidomics assay, comprising 244 lipids from six major classes, which allowed us to investigate robust stress induced changes in median levels of different lipid classes -additionally stratified by fatty acid side chain saturation status. The lipidomic profiles of cancer cells were predominantly affected by nutrient-deprivation. Neutral lipid compositions were markedly modified under serum-deprivation and, strikingly, the cellular level of triglyceride subspecies decreased with increasing number of double bonds in their fatty acyl chains. In contrast, cancer cells maintained lipid class homeostasis under hypoxic stress. We conclude that although the levels of individual lipid moieties alter under hypoxia, the robust averages of broader lipid class remain unchanged.
Static Kinks or Flexible Hinges: Conformational Distributions of Bent DNA Bound to Integration Host Factor Mapped by Fluorescence Lifetime Measurements
Authors: Connolly Mitchell , Arra Aline , Zvoda Viktoriya , Steinbach Peter J. , Rice Phoebe A. , Ansari Anjum 
Published: August 2018

AbstractGene regulation depends on proteins that bind to specific DNA sites. Such specific recognition often involves severe DNA deformations including sharp kinks. It has been unclear how rigid or flexible these protein-induced kinks are. Here, we investigated the dynamic nature of DNA in complex with integration host factor (IHF), a nucleoid-associated architectural protein known to bend one of its cognate sites (35 base pair H’) into a U-turn by kinking DNA at two sites. We utilized fluorescence lifetime based FRET spectroscopy to map the distribution of bent conformations in various IHF-DNA complexes. Our results reveal a surprisingly dynamic specific complex: while 80% of the IHF-H’ population exhibited FRET efficiency consistent with the crystal structure, 20% exhibited FRET efficiency indicative of unbent or partially bent DNA. This conformational flexibility is modulated by sequence variations in the cognate site. In another site (H1) that lacks an A-tract of H’ on one side of the binding site, the population in the fully U-bent conformation decreased to 36%, as did the extent of bending. A similar decrease in the U-bent population was observed with a single base mutation in H’ in a consensus region on the other side. Taken together, these results provide important insights into the finely tuned interactions between IHF and its cognate sites that keep the DNA bent (or not), and yield quantitative data on the dynamic equilibrium between different DNA conformations (kinked or not kinked) that depend sensitively on DNA sequence and deformability. Notably, the difference in dynamics between IHF-H’ and IHF-H1 reflects the different roles of these complexes in their natural context, in the phage lambda “intasome” (the complex that integrates phage lambda into theE. colichromosome).
Macrophage-induced rifampin tolerance across Mycobacterium tuberculosis lineages is Rv1258c-dependent
Authors: Adams Kristin N. , Verma Amit Kumar , Gopalaswamy Radha , Adikesavalu Harresh , Singhal Dinesh Kumar , Tripathy Srikanth , Ranganathan Uma Devi , Sherman David R. , Urdahl Kevin B. , Ramakrishnan Lalita , Hernandez Rafael E. 
Published: August 2018

ABSTRACTThe Mycobacterium tuberculosis (Mtb) Lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. Genetic mutation of the efflux pump Rv1258c in CDC1551 abolishes rifampin tolerance but not isoniazid tolerance. Here we show that clinical isolates from the other predominant Mtb lineages developed macrophage-induced isoniazid tolerance. Furthermore, all lineages developed rifampin tolerance except Lineage 2 Beijing strains, which are natural Rv1258c mutants. Thus macrophage-induced antibiotic tolerance is featured across the majority of Mtb lineages. Our findings further link Rv1258c to rifampin tolerance among clinical isolates.
The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls
Authors: Coleman Jonathan R. I. , Gaspar Héléna A. , Bryois Julien ,   Bipolar Disorder Working Group of the Psychiatric Genomics Consortium,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Breen Gerome 
Published: August 2018

AbstractBackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.
Ending AIDS: trends in the incidence of HIV in eastern and southern Africa
Authors: Williams Brian G. , Granich Reuben 
Published: August 2018

AbstractWhile great progress has been made in the control and management of the HIV epidemic there is still much to be done. Using trends in the rate of new HIV infections in eastern and southern Africa we assess the current state of the epidemic and evaluate the future prospects for controlling it. If we let an incidence of 1 per 1,000 people represent a control threshold then this has been reached, or will probably be reached by 2020, in eastern Africa and is reachable by 2020 in those southern African countries that do not have particularly strong social and economic ties to South Africa if they continue to scale up their treatment programmes. In South Africa and its immediate neighbours Lesotho, Mozambique and Swaziland, the prospects are less certain. These countries are unlikely to reach the control threshold by 2020 but with sufficient political will and commitment to ‘treatment for all’ could do so by 2030.There are two important caveats. First, reaching the control threshold still leaves 35 thousand new infections a year. As the lessons of polio remind us, finding the last few, hard to reach cases will demand more focussed strategies. Second, ending AIDS will not end HIV and about 35 million people will have to be kept on ART for the next 30 to 40 years unless and until a cure is discovered. Even if we assume a modest cost of, say, US$100 per person per year for ART treatment and support, this corresponds to a continuing financial commitment of US$3.5 Bn per year although this is substantially less than the approximately US$ 40 Bn per year currently committed to HIV and AIDS.
Long-read amplicon denoising
Authors: Kumar Venkatesh , Vollbrecht Thomas , Chernyshev Mark , Mohan Sanjay , Hanst Brian , Bavafa Nicholas , Lorenzo Antonia , Ketteringham Robert , Eren Kemal , Golden Michael , Oliveira Michelli Faria , Murrell Ben 
Published: August 2018

Long-read next generation amplicon sequencing shows promise for studying complete genes or genomes from complex and diverse populations. Current long-read sequencing technologies have challenging error profiles, hindering data processing and incorporation into downstream analyses. Here we consider the problem of how to reconstruct, free of sequencing error, the true sequence variants and their associated frequencies. Called “amplicon denoising”, this problem has been extensively studied for short-read sequencing technologies, but current solutions do not appear to generalize well to long reads with high indel error rates. We introduce two methods: one that runs nearly instantly and is very accurate for medium length reads (here ~2.6kb) and high template coverage, and another, slower method that is more robust when reads are very long or coverage is lower.On one real dataset with ground truth, and on a number of simulated datasets, we compare our two approaches to each other and to existing algorithms. We outperform all tested methods in accuracy, with competitive run times even for our slower method.Fast Amplicon Denoising (FAD) and Robust Amplicon Denoising (RAD) are implemented purely in the Julia scientific computing language, and are hereby released along with a complete toolkit of functions that allow long-read amplicon sequence analysis pipelines to be constructed in pure Julia. Further, we make available a webserver to dramatically simplify the processing of long-read PacBio sequences.
Kinetic Pathways of Topology Simplification by Type-II Topoisomerases in Knotted Supercoiled DNA
Authors: Ziraldo Riccardo , Hanke Andreas , Levene Stephen D. 
Published: August 2018

ABSTRACTThe topological state of covalently closed, double-stranded DNA is defined by the knot typeKand the linking-number difference ΔLkrelative to unknotted relaxed DNA. DNA topoisomerases are essential enzymes that control the topology of DNA in all cells. In particular, type-II topoisomerases change bothKand ΔLkby a duplex-strand-passage mechanism and have been shown to simplify the topology of DNA to levels below thermal equilibrium at the expense of ATP hydrolysis. It remains a puzzle how small enzymes are able to preferentially select strand passages that result in topology simplification in much larger DNA molecules. Using numerical simulations, we consider the non-equilibrium dynamics of transitions between topological states (K, ΔLk) in DNA induced by type-II topoisomerases. For a biological process that delivers DNA molecules in a given topological state (K,ΔLk) at a constant rate we fully characterize the pathways of topology simplification by type-II topoisomerases in terms of stationary probability distributions and probability currents on the network of topological states (K,ΔLk). In particular, we observe that type-II topoisomerase activity is significantly enhanced in DNA molecules that maintain a supercoiled state with constant torsional tension. This is relevant for bacterial cells in which torsional tension is maintained by enzyme-dependent homeostatic mechanisms such as DNA-gyrase activity.
Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals
Authors: Freidin Maxim B , Tsepilov Yakov A , Palmer Melody , Karssen Lennart C ,   CHARGE Musculoskeletal Working Group, Suri Pradeep , Aulchenko Yurii S , Williams Frances MK 
Published: August 2018

ABSTRACTBack pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large GWAS (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated three BP associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disc problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least two strong molecular axes of BP genesis, one related to structural/anatomic factors such as intervertebral disk problems and anthropometrics; and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of LBP.