Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed ...to validate the concept of LND in OSCC.
The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis.
The OS was 49% for patients with LND0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures.
This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.
Abstract Background Mesenchymal stem cells (MSCs) show differentiation capacity along mesenchymal lineages and have the potential to aid tissue regeneration. MSC transplantation strategies are ...therefore currently being assessed following injury to various organs. However, potential MSC migration to these organs after intravenous (IV) MSC injection continues to be impeded by cell trapping within the lung. Methods Mouse MSCs were isolated, purified, transfected with firefly luciferase, and labeled with CSFE. Their size was assessed in vitro. To estimate the diameter of mouse pulmonary capillaries, fluorescence-labeled microspheres of different sizes were injected with or without sodium nitroprusside (SN) pretreatment. The lungs were harvested after 30 seconds and mean numbers of trapped microspheres per high-power field (HPF) were calculated. After IV injection of MSC suspensions (with or without SN), their dynamic distribution was monitored by in vivo luciferine imaging as well as by histopathology. Results The diameter of suspended MSCs in vitro was 15 to 19 μm. Whereas nearly no 4-μm microspheres could be detected in lung sections, the numbers of trapped 10- and 15-μm microspheres could be significantly decreased by prior SN injection from 19.3 ± 11.1 to 6.0 ± 1.6 cells/HPF ( P = .004) and from 34.9 ± 11.9 to 25.6 ± 8.1 cells/HPF ( P = .028), respectively. Within seconds after MSC IV injection, the vast majority of cells was found in the lungs. However, cell trapping in the pulmonary microvasculature was significantly reduced by pre-treatment with SN. Conclusions We demonstrate that cell trapping in lungs can be reduced with IV SN pretreatment, increasing MSC passage through the lung capillaries, and potentially facilitating cell access to injured organs.
Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting ...that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.
Background: Mutations of the transforming growth factor β (TGFβ) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). ...Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. Objective: To investigate kindreds presenting with both pulmonary hypertension and HHT. Methods: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. Results: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. Conclusions: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.
Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream ...effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation.
Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand-daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance.
Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR-181a, a marker of human PTB.
The findings indicate that a family history of stress may program central and peripheral pathways regulating gestational length and maternal and newborn health outcomes in the maternal lineage. This new paradigm may model the origin of many human PTB causes.
Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of ...former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19-3.91; MI, 2.10,1.17-3.76; CES-D, 3.08,1.65-5.76; AES, 2.39,1.32-4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76-0.97) and CES-D (OR, 95% CI: 0.85, 0.74-0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.
Sirolimus was introduced in de novo immunosuppression at Stanford University in view of its favorable effects on reduced rejection and cardiac allograft vasculopathy. After an apparent increase in ...the incidence of post‐surgical wound complications as well as symptomatic pleural and pericardial effusions, we reverted to a mycophenolate mofetil (MMF)‐based regimen. This retrospective study compared the outcome in heart transplant recipients on sirolimus (48 patients) with those on MMF (46 patients) in de novo immunosuppressive regimen. The incidence of any post‐surgical wound complication (52% vs. 28%, p = 0.019) and deep surgical wound complication (35% vs. 13%, p = 0.012) was significantly higher in patients on sirolimus than on MMF. More patients on sirolimus also had symptomatic pleural (p = 0.035) and large pericardial effusions (p = 0.033) requiring intervention. Logistic regression analysis showed sirolimus (p = 0.027) and longer cardiac bypass time (OR = 1.011; p = 0.048) as risk factors for any wound complication. Sirolimus in de novo immunosuppression after cardiac transplantation was associated with a significant increase in the incidence of post‐surgical wound healing complications as well as symptomatic pleural and pericardial effusions.
There is a crucial need for alternatives to native vein or artery for vascular surgery. The clinical efficacy of synthetic, allogeneic or xenogeneic vessels has been limited by thrombosis, rejection, ...chronic inflammation and poor mechanical properties. Using adult human fibroblasts extracted from skin biopsies harvested from individuals with advanced cardiovascular disease, we constructed tissue-engineered blood vessels (TEBVs) that serve as arterial bypass grafts in long-term animal models. These TEBVs have mechanical properties similar to human blood vessels, without relying upon synthetic or exogenous scaffolding. The TEBVs are antithrombogenic and mechanically stable for 8 months in vivo. Histological analysis showed complete tissue integration and formation of vasa vasorum. The endothelium was confluent and positive for von Willebrand factor. A smooth muscle-specific alpha-actin-positive cell population developed within the TEBV, suggesting regeneration of a vascular media. Electron microscopy showed an endothelial basement membrane, elastogenesis and a complex collagen network. These results indicate that a completely biological and clinically relevant TEBV can be assembled exclusively from an individual's own cells.
The aim of this paper was to study the auditory phenotype of three related children with sensorineural hearing loss (2 sisters and their cousin) following genetic analysis revealing mutations in ...LOXHD1.
Genetic testing was conducted on three related children. They were assessed with a standard clinical test battery including distortion otoacoustic emissions, auditory brainstem responses and audiometry.
We identified heterozygous variants in LOXHD1 in a family of Irish/German and Italian/Irish ancestry with autosomal recessive auditory neuropathy spectrum disorder (ANSD). Mutations in LOXHD1 (MIM #613072) have been linked to an autosomal recessive nonsyndromic hearing loss (DFNB77), mapped to the locus 18q12-q21. All three subjects had evidence of some, albeit few, functioning cochlear hair cells as revealed by the presence of a cochlear microphonic and/or partial otoacoustic emissions early in life.
To our knowledge, this is the first association between LOXHD1 mutations and ANSD in two patients who have been successfully managed with cochlear implants.
Bluebunch wheatgrass (referred to as BBWG) Pseudoroegneria spicata (Pursh) Á. Löve is an important rangeland Triticeae grass used for forage, conservation, and restoration. This diploid has the basic
...St
genome that occurs also in many polyploid Triticeae species, which serve as a gene reservoir for wheat improvement. Until now, the
St
genome in diploid species of Pseudoroegneria has not been mapped. Using a double-cross mapping populations, we mapped 230 expressed sequence tag derived simple sequence repeat (EST-SSR) and 3468 genotyping-by-sequencing (GBS) markers to 14 linkage groups (LGs), two each for the seven homologous groups of the
St
genome. The 227 GBS markers of BBWG that matched those in a previous study helped identify the unclassified seven LGs of the
St
sub-genome among 21 LGs of Thinopyrum intermedium (Host) Barkworth & D.R. Dewey. Comparisons of GBS sequences in BBWG to whole-genome sequences in bread wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) revealed that the
St
genome shared a homology of 35% and 24%, a synteny of 86% and 84%, and a collinearity of 0.85 and 0.86, with
ABD
and
H
, respectively. This first-draft molecular map of the
St
genome will be useful in breeding cereal and forage crops.
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