Western Eurasia witnessed several large-scale human migrations during the Holocene
. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly ...from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
Purpose: A previous phase I trial of i.p. photodynamic therapy established the maximally tolerated dose of Photofrin (Axcan Pharma,
Birmingham, AL)-mediated photodynamic therapy and showed ...encouraging efficacy. The primary objectives of this phase II study
were to determine the efficacy and toxicities of i.p. photodynamic therapy in patients with peritoneal carcinomatosis and
sarcomatosis.
Experimental Design: Patients received Photofrin 2.5 mg/kg i.v. 48 hours before debulking surgery. Intraoperative laser light was delivered to
the peritoneal surfaces of the abdomen and pelvis. The outcomes of interest were ( a ) complete response, ( b ) failure-free survival time, and ( c ) overall survival time. Photosensitizer levels in tumor and normal tissues were measured.
Results: One hundred patients were enrolled into one of three strata (33 ovarian, 37 gastrointestinal, and 30 sarcoma). Twenty-nine
patients did not receive light treatment. All 100 patients had progressed by the time of statistical analysis. The median
failure-free survival and overall survival by strata were ovarian, 2.1 and 20.1 months; gastrointestinal cancers, 1.8 and
11.1 months; sarcoma, 3.7 and 21.9 months. Substantial fluid shifts were observed postoperatively, and the major toxicities
were related to volume overload. Two patients died in the immediate postoperative period from bleeding, sepsis, adult respiratory
distress syndrome, and cardiac ischemia.
Conclusions: Intraperitoneal Photofrin-mediated photodynamic therapy is feasible but does not lead to significant objective complete responses
or long-term tumor control. Heterogeneity in photosensitizer uptake and tumor oxygenation, lack of tumor specificity for photosensitizer
uptake, and the heterogeneity in tissue optical properties may account for the lack of efficacy observed.
Abstract only
Introduction:
Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF), with or without overt ventricular involvement. The ...efficacy of AF ablation in these patients is unknown.
Research Questions/Hypothesis:
To test the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have a higher risk of recurrence following AF ablation, and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM ALVC, arrhythmogenic right ventricular CM ARVC, dilated CM DCM, hypertrophic CM HCM, or a channelopathy) have a higher risk of recurrence.
Methods:
We performed a prospective observational cohort study in participants referred for AF catheter ablation who underwent whole exome sequencing. Our primary outcome was AF recurrence, defined as >30 seconds of AF, atrial flutter, or atrial tachycardia that occurred at least 90 days after AF ablation.
Results:
Among 1,366 participants, 109 (8.0%) had a pathogenic or likely-pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15 (0.84-1.60), p=0.53,
Figure 1A
). When analyzed according to gene group, P/LP variants in the ALVC gene group, predominantly
LMNA
, were associated with increased recurrence (N=10; HR 3.75 (1.84-7.63), p<0.001), compared to those in the ARVC gene group (N=6; HR 1.97 (0.62-6.27), p=0.25), DCM gene group (N=50; HR 0.98 (0.59-1.63), p=0.94), HCM gene group (N=33; HR 1.28 (0.76-2.17), p=0.35), and channelopathy gene group (N=17; HR 0.58 (0.21-1.56), p=0.28), as shown in
Figure 1B, 1C
.
Conclusions:
Our results support the continued use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including
TTN
. However, patients with ALVC variants, such as in
LMNA
, may be at a significantly higher risk for arrhythmia recurrence.
Nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) are increasingly being diagnosed but management, especially of small tumors, remains a clinical dilemma. Endoscopic ultrasound guided ...fine-needle aspiration (EUS-FNA) is now routinely used for diagnosis of pancreatic neuroendocrine tumors (pNETs) but has not been well studied as a tool for identifying aggressive disease.
A systematic search of the cytology database identified all patients at our center who underwent EUS-FNA from 1999 through 2011 and were diagnosed with NF-pNET.
A total of 50 patients were identified. Though patients with metastatic disease had a mean tumor size of 40 mm compared to 25 mm in patients without metastatic disease (P = 0.04), we also identified several patients with tumors <20 mm who presented with metastatic disease. Furthermore, we found no statistically significant difference in metastatic disease between tumors <20 mm and >20 mm (P = 0.13). Using receiver operating characteristic (ROC) analysis, we found that using a cutoff point of 20 mm only led to a sensitivity of 85% in screening for metastases, while lowering the cutoff point to 18 mm allowed for a sensitivity of 95%.
Currently, guidelines suggest that only patients with tumors greater than 20 mm undergo surgical resection, as tumors less than this size are thought to have low risk of metastases. Our analysis suggests that these recommendations could lead to undertreating patients with small tumors. Tumor size alone may be inadequate as a marker for aggressive NF-pNETs. Given this, other risk factors for aggressive pNETs should be studied to help identify the patients most likely to benefit from surgery.
Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and ...7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that ...displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases.
Top predators have cascading effects throughout the food web, but their impacts on scavenger abundance are largely unknown. Gray wolves (Canis lupus) provide carrion to a suite of scavenger species, ...including the common raven (Corvus corax). Ravens are wide‐ranging and intelligent omnivores that commonly take advantage of anthropogenic food resources. In areas where they overlap with wolves, however, ravens are numerous and ubiquitous scavengers of wolf‐acquired carrion. We aimed to determine whether subsidies provided through wolves are a limiting factor for raven populations in general and how the wolf reintroduction to Yellowstone National Park in 1995–1997 affected raven population abundance and distribution on the Yellowstone's Northern Range specifically. We counted ravens throughout Yellowstone's Northern Range in March from 2009 to 2017 in both human‐use areas and wolf habitat. We then used statistics related to the local wolf population and the winter weather conditions to model raven abundance during our study period and predict raven abundance on the Northern Range both before and after the wolf reintroduction. In relatively severe winters with greater snowpack, raven abundance increased in areas of human use and decreased in wolf habitat. When wolves were able to acquire more carrion, however, ravens increased in wolf habitat and decreased in areas with anthropogenic resources. Raven populations prior to the wolf reintroduction were likely more variable and heavily dependent on ungulate winter‐kill and hunter‐provided carcasses. The wolf recovery in Yellowstone helped stabilize raven populations by providing a regular food supply, regardless of winter severity. This stabilization has important implications for effective land management as wolves recolonize the west and global climate patterns change.
Grey wolves provide carrion to numerous scavenger species on the Northern Range of Yellowstone National Park, including common ravens. In the winter, common raven use of human‐use areas and wolf habitat depends on winter severity as well as the amount of carrion biomass supplied by wolves. Wolf recovery in Yellowstone helped stabilize local raven populations by providing a regular winter food supply that was not directly tied to winter severity and ungulate winter‐kill.
>Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is ...poorly understood. Here, we performed comprehensive lipidomics to create a lipid network map during ZIKV infection. We found that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein resulted in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocked ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.
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