Whittakermose0847

Cancer-associated fibroblasts (CAFs) play an important role in the initiation, metastasis, and invasion of breast cancer. However, whether autophagy acts as a tumor promotion mechanism by inducing epithelial-mesenchymal transition (EMT) is still controversial and remains undefined at the mechanistic levels. In this study, we investigated whether autophagy or FAP-α is required for the invasion, pulmonary metastasis and EMT of breast cancer cells and underlying mechanism. We employed an in vitro model of NIH3T3 fibroblasts treated with H2O2 and confirmed that TGF-β1 could convert fibroblasts into CAFs through autophagy under oxidative stress in the tumor microenvironment. Modulation of autophagy by rapamycin, 3-methyladenine or ATG-5 knockdown regulated the expression of CAFs markers, suggesting a role of autophagy in the tumor promotion mechanism of TGF-β1-induced CAFs activation. Furthermore, we established an indirect co-culture model and a mixed xenograft as a corresponding in vivo model. We demonstrated that TGF-β1-activated CAFs promote tumor invasion, pulmonary metastasis and EMT, which act through autophagy and overexpression of FAP-α in both models, while autophagy inhibitor 3-methyladenine blocked these effects induced by TGF-β1-activated CAFs. Moreover, the co-localization of LC3β and EMT marker vimentin in mixed xenograft also revealed that TGF-β1-activated CAFs promote tumor growth, pulmonary metastasis, and EMT program partly through autophagy. In addition, knockdown of FAP-α resulted in reversed EMT and abolished tumor invasion and pulmonary metastasis induced by TGF-β1-activated CAFs. Taken together, we conclude that both autophagy and FAP-α are required for breast cancer cell invasion and metastasis. Targeting autophagy or FAP-α rather than both can serve as a potential approach to improve the prognosis for human breast cancer.Transactivation of the epidermal growth factor receptor (EGFR) by the angiotensin II (AngII) type 1 (AT1) receptor is involved in AT1 receptor-dependent growth effects and cardiovascular pathologies, however the mechanisms underpinning this transactivation are yet to be fully elucidated. Recently, a potential intermediate of this process was identified following the discovery that a kinase called TRIO was involved in AngII/AT1 receptor-mediated transactivation of EGFR. BAY 11-7082 mouse To investigate the mechanisms by which TRIO acts as an intermediate in AngII/AT1 receptor-mediated EGFR transactivation we used bioluminescence resonance energy transfer (BRET) assays to investigate proximity between the AT1 receptor, EGFR, TRIO and other proteins of interest. We found that AngII/AT1 receptor activation caused a Gαq-dependent increase in proximity of TRIO with Gγ2 and the AT1-EGFR heteromer, as well as trafficking of TRIO towards the Kras plasma membrane marker and into early, late and recycling endosomes. In contrast, we found that AngII/AT1 receptor activation caused a Gαq-independent increase in proximity of TRIO with Grb2, GRK2 and PKCζ, as well as trafficking of TRIO up to the plasma membrane from the Golgi. link2 Furthermore, we confirmed the proximity between the AT1 receptor and the EGFR using the Receptor-Heteromer Investigation Technology, which showed AngII-induced recruitment of Grb2, GRK2, PKCζ, Gγ2 and TRIO to the EGFR upon AT1 coexpression. In summary, our results provide further evidence for the existence of the AT1-EGFR heteromer and reveal potential mechanisms by which TRIO contributes to the transactivation process.Abnormal outgrowth of sensory nerves is one of the important contributors to pain associated with cancer and its treatments. Primary neuronal cultures derived from dorsal root ganglia (DRG) have been widely used to study pain-associated signal transduction and electrical activity of sensory nerves. However, there are only a few studies using primary DRG neuronal culture to investigate neurite outgrowth alterations due to underlying cancer-related factors and chemotherapeutic agents. In this study, primary DRG sensory neurons derived from mouse, non-human primate, and human were established in serum and growth factor-free conditions. A bovine serum albumin gradient centrifugation method improved the separation of sensory neurons from satellite cells. The purified DRG neurons were able to maintain their heterogeneous subpopulations, and displayed an increase in neurite growth when exposed to cancer-derived conditioned medium, while they showed a reduction in neurite length when treated with a neurotoxic chemotherapeutic agent. Additionally, a semi-automated quantification method was developed to measure neurite length in an accurate and time-efficient manner. Finally, these exogenous factors altered the gene expression patterns of murine primary sensory neurons, which are related to nerve growth, and neuro-inflammatory pain and nociceptor development. Together, the primary DRG neuronal culture in combination with a semi-automated quantification method can be a useful tool for further understanding the impact of exogenous factors on the growth of sensory nerve fibers and gene expression changes in sensory neurons.We report a case of recurrent left atrial (LA) intimal sarcoma invading pulmonary veins (PV) which was treated by a novel surgical approach-resecting LA wall and PVs down to segmental levels, and then creating neo-LA using lung hilum and posterior mediastinal soft tissue without further reconstructive procedures. This surgical approach may be useful in selected cases with primary cardiac malignancy involving LA and PVs in the aim of achieving complete resection of the tumor. Left heart sarcoma is an extremely uncommon but lethal disease which poses challenges to physicians due to its equivocal presentation, limited treatment option and dismal prognosis. Although the mainstay of treatment is a complete resection, it is technically demanding due to a lack of extensive experience in cardiac malignancy surgery and its very location or involvement in vital structures. Therefore, establishing a creative surgical strategy to overcome aforementioned obstacles and to achieve complete resection with tumor-free resection margin is needed. Here in, we report a case of recurrent left atrial sarcoma which was removed by noteworthy surgical technique.Despite the emergent application of three-dimensional (3D) technology for thoracic reconstructions, reports regarding its use for the resolution of the heterogeneous subgroup of complex chest wall malformations are lacking. We aim to report a novel, standardized process of personalized repair of complex chest wall malformations comprising multidisciplinary, comprehensive surgical planning; surgical simulation on a 3D-printed scale model of the area of interest; manufacturing of customized prostheses; and surgical repair according to plan. We propose this therapeutic strategy for the resolution of such a wide variety of chest wall deformities to reduce improvisation and enhance outcomes.We report the case of a 23-year-old female with recurrent episodes of chest and back pain. A cardiac mass of uncertain etiology was discovered and she was referred to our multi-disciplinary cardiac tumor team. Pathological analysis from the surgical specimen confirmed this mass was a giant aneurysm of the left anterior descending artery. Giant coronary artery aneurysms (GCAAs) have been previously defined as localized coronary artery dilations greater than 20mm. While GCAAs are frequently found in pediatric populations, they are exceedingly rare in adults, with a reported incidence of 0.02-0.2%1, 2. link3 GCAAs can be caused by atherosclerosis, Takayasu arteritis, congenital coronary malformations, or Kawasaki disease3. While these aneurysms are often asymptomatic, they may induce ischemia or lead to an acute myocardial infarction due to disruption of coronary arterial flow from mass effect or luminal thrombosis. In this case, we describe a young woman who presented with chest pain and was found to have a cardiac mass identified pathologically as a GCAA.Oxidative stress-related ocular surface epithelial damage can be initiated by ambient oxygen, UV radiation, and chemical burns. The oxidative damage to cornea can lead to inflammation and even vision loss. Lingzhi (Ganoderma lucidum) is a Chinese herbal drug and has been shown to prevent chronic diseases in clinical practices and has been proven to possess anti-oxidative and anti-inflammatory properties. In the study, we prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) as a sustained drug release system of Lingzhi (LZH) to improve bioavailability. The particle size of developed NPs containing LZH (LZH-NPs) was ~184 nm with narrow size distribution. The results of cellular uptake revealed that using NPs as a drug delivery system could significantly increases the intracellular retention time. The results of the cell viability and chemiluminescence assay revealed that 5 μg/ml of LZH-NPs might be the threshold concentration for cultivation of corneal epithelial cells. After treating LZH-NPs in oxidative damaged cells, the results showed that the inflammation-related gene expression and DNA fragmentation level were both significantly decreased. Post-treatment of LZH-NPs in damaged corneal epithelial cells could increase the cell survival rate. In the rabbit corneal alkali burn model, topical instillation of LZH-NPs could promote corneal wound healing and decrease the inflammation. These results suggest that LZH-NPs may have the potential to treat ocular surface diseases caused by oxidative stress.

Bardet-Biedl syndrome is an autosomal recessive disease characterized by rod-cone dystrophy, postaxial polydactyly, kidney defects, obesity, mental retardation and hypogonadism. Here, we report different genotypes in two Bardet-Biedl syndrome affected sisters with a different clinical phenotype regarding severity.

The proband of the family was examined by Next Generation Sequencing (NGS) using clinical exome and filtering by syndromic and non-syndromic genes associated with retinal dystrophies.

Targeted NGS revealed two novel variants in the MKKS and CEP290 genes in homozygosis state in the proband. Segregation analysis revealed the presence of the same MKKS homozygous variant in her younger affected sister but not the CEP290 variant. Both sisters presented different clinical manifestation, at different ages, with a more severe renal and retinal defect in the case of the sister carrying mutations in both genes. Another unaffected sister showed only homozygosity for the CEP290 variant, thus supporting thnt different genotypes and clinical manifestation, suggesting that the novel CEP290 variant could be acting as a modifier, making the phenotype more severe in the sister homozygote for MKKS and CEP290 genes. On the other hand, the difference in the age of both sisters highlight the important role of monitoring disease progression also to confirm the modifier role of genetic variants.

We examined the most important correlates to sleep duration and efficiency from a comprehensive array of multilevel factors.

Baseline data from a cohort of 216 Black/African American smokers aged 40-65 years were examined. The binary outcomes of healthy sleep duration (6-8 h/night) and efficiency (≥85%) were ascertained from 14 consecutive days of actigraphy. Seventy-three independent variables from socio-demographic, individual behavioral, individual physiological, interpersonal, and community domains were assessed. Random survival forest decision trees were generated for each outcome, and variable importance metrics used to rank the predictive abilities of exposure variables. The 5 most predictive exposure variables for each outcome were entered into a regression model of the respective outcome (with age and sex).

Study participants (N=216) had a mean age of 54.57 years (SD=6.17) and 57% were male. Healthy sleep duration was achieved by 56.5% and healthy sleep efficiency by 13.6% of the sample. Regression models showed every additional minute of light physical activity was associated with 1% increased odds, while every unit decrease in the inflammation marker of interleukin-8 was associated with 12% increased odds, of achieving a healthy sleep duration.