The prescribed mean curvature equation in weakly regular domains

We show that the characterization of existence and uniqueness up to vertical translations of solutions to the prescribed mean curvature equation, originally proved by Giusti in the smooth case, holds true for domains satisfying very mild regularity assumptions. Our results apply in particular to the non-parametric solutions of the capillary problem for perfectly wetting fluids in zero gravity. Among the essential tools used in the proofs, we mention a \textit{generalized Gauss-Green theorem} based on the construction of the weak normal trace of a vector field with bounded divergence, in the spirit of classical results due to Anzellotti, and a \textit{weak Young's law} for $(\Lambda,r_{0})$-minimizers of the perimeter.Comment: 23 pages, 1 figure --- The results on the weak normal trace of vector fields have been now extended and moved in a self-contained paper available at: arXiv:1708.0139

Polymorphism rs4919510:C>G in Mature Sequence of Human MicroRNA-608 Contributes to the Risk of HER2-Positive Breast Cancer but Not Other Subtypes

BACKGROUND: A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility. METHODS: The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism. RESULTS: In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34-2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.23-2.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43-2.72) for GG genotype (corrected P = 1.1 × 10(-4)). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is -35.9 kcal/mol, while that of variant-form (G-allele) is -31.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA. CONCLUSION: rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation

Effectiveness evaluation of an integrated automatic termomechanic massage system (SMATH® system) in non-specific sub-acute and chronic low back pain - a randomized double-blinded controlled trial, comparing SMATH therapy versus sham therapy: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) is a major health problem in modern society, with 70-85% of the population experiencing LBP at some time in their lives. Each year, 5-10% of the workforce misses work due to LBP, most for less than 7 days. Almost 10% of all patients are at risk of developing chronic pain and disability. Little clinical evidence is available for the majority of treatments used in LBP therapy. However, moderate evidence exists for interdisciplinary rehabilitation, exercise, acupuncture, spinal manipulation, and cognitive behavioral therapy for subacute and chronic LBP. The SMATH^®system (system for automatic thermomechanic massage in health) is a new medical device (MD) that combines basic principles of mechanical massage, thermotherapy, acupressure, infrared therapy, and moxibustion. SMATH^®is suitable for automatic multidisciplinary treatment on patients with non-specific sub-acute and chronic LBP.</p> <p>Methods/design</p> <p>This paper describes the protocol for a double-blinded, sham-controlled, randomized, single-center short term clinical trial in patients with non-specific sub-acute and chronic LBP aged 18 to 70 years. The primary outcome will be the effectiveness of SMATH^®versus sham therapy (medical device without active principles) determined by evaluating self perceived physical function with Roland Morris Disability Questionnaire (RMDQ) scores after 4 weeks of treatment (end of treatment). Major secondary outcome will be effectiveness of SMATH^®determined by evaluating self perceived physical function comparing RMDQ scores between end of treatment and baseline. The trial part of the study will take 7 months while observational follow-up will take 11 months. The sample size will be 72 participants (36 for each arm). The project has been approved by the Ethical Committee of Cremona Hospital, Italy on 29 November 2010.</p> <p>Discussion</p> <p>Compared to other medical specialties, physical and rehabilitation medicine (PRM) has not yet received the deserved recognition from clinicians and researchers in the scientific community, especially for medical devices. The best way to change this disadvantage is through well-conducted clinical research in sham-controlled randomized trials. Sham treatment groups are essential for improving the level of evidence-based practice in PRM. The present trial will counter the general lack of evidence concerning medical devices used in LBP therapy.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN08714168">ISRCTN08714168</a></p

The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid

<p>Abstract</p> <p>Background</p> <p>Cerebrospinal fluid (CSF) contacts many brain regions and may mediate humoral signaling distinct from synaptic neurotransmission. However, synthesis and transport mechanisms for such signaling are not defined. The purpose of this study was to investigate whether human CSF contains discrete structures that may enable the regulation of humoral transmission.</p> <p>Methods</p> <p>Lumbar CSF was collected prospectively from 17 participants: with no neurological or psychiatric disease, with Alzheimer's disease, multiple sclerosis, or migraine; and ventricular CSF from two cognitively healthy participants with long-standing shunts for congenital hydrocephalus. Cell-free CSF was subjected to ultracentrifugation to yield supernatants and pellets that were examined by transmission electron microscopy, shotgun protein sequencing, electrophoresis, western blotting, lipid analysis, enzymatic activity assay, and immuno-electron microscopy.</p> <p>Results</p> <p>Over 3,600 CSF proteins were identified from repeated shotgun sequencing of cell-free CSF from two individuals with Alzheimer's disease: 25% of these proteins are normally present in membranes. Abundant nanometer-scaled structures were observed in ultracentrifuged pellets of CSF from all 16 participants examined. The most common structures included synaptic vesicle and exosome components in 30-200 nm spheres and irregular blobs. Much less abundant nanostructures were present that derived from cellular debris. Nanostructure fractions had a unique composition compared to CSF supernatant, richer in omega-3 and phosphoinositide lipids, active prostanoid enzymes, and fibronectin.</p> <p>Conclusion</p> <p>Unique morphology and biochemistry features of abundant and discrete membrane-bound CSF nanostructures are described. Prostaglandin H synthase activity, essential for prostanoid production and previously unknown in CSF, is localized to nanospheres. Considering CSF bulk flow and its circulatory dynamics, we propose that these nanostructures provide signaling mechanisms <it>via </it>volume transmission within the nervous system that are for slower, more diffuse, and of longer duration than synaptic transmission.</p

Dose-Dependent Onset of Regenerative Program in Neutron Irradiated Mouse Skin

Background: Tissue response to irradiation is not easily recapitulated by cell culture studies. The objective of this investigation was to characterize, the transcriptional response and the onset of regenerative processes in mouse skin irradiated with different doses of fast neutrons. Methodology/Principal Findings: To monitor general response to irradiation and individual animal to animal variation, we performed gene and protein expression analysis with both pooled and individual mouse samples. A high-throughput gene expression analysis, by DNA oligonucleotide microarray was done with three months old C57Bl/6 mice irradiated with 0.2 and 1 Gy of mono-energetic 14 MeV neutron compared to sham irradiated controls. The results on 440 irradiation modulated genes, partially validated by quantitative real time RT-PCR, showed a dose-dependent up-regulation of a subclass of keratin and keratin associated proteins, and members of the S100 family of Ca2+-binding proteins. Immunohistochemistry confirmed mRNA expression data enabled mapping of protein expression. Interestingly, proteins up-regulated in thickening epidermis: keratin 6 and S100A8 showed the most significant up-regulation and the least mouse-to-mouse variation following 0.2 Gy irradiation, in a concerted effort toward skin tissue regeneration. Conversely, mice irradiated at 1 Gy showed most evidence of apoptosis (Caspase-3 and TUNEL staining) and most 8-oxo-G accumulation at 24 h post-irradiation. Moreover, no cell proliferation accompanied 1 Gy exposure as shown by Ki67 immunohistochemistry. Conclusions/Significance: The dose-dependent differential gene expression at the tissue level following in vivo exposure to neutron radiation is reminiscent of the onset of re-epithelialization and wound healing and depends on the proportion of cells carrying multiple chromosomal lesions in the entire tissue. Thus, this study presents in vivo evidence of a skin regenerative program exerted independently from DNA repair-associated pathways

Matrix Metalloproteinase-8 Mediates the Unfavorable Systemic Impact of Local Irradiation on Pharmacokinetics of Anti-Cancer Drug 5-Fluorouracil

Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. Here, we evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats after computerized tomography-based planning. 5-FU at 100 mg/kg was prescribed 24 hours after radiation. A high-performance liquid chromatography system was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased in bile with a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Our findings first indicate that local irradiation modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. The pharmacokinetics of 5-FU during concurrent chemoradiaiton therapy should be rechecked and the optimal 5-FU dose should be reevaluated, and adjusted if necessary, during CCRT

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB

Resveratrol Acts Not through Anti-Aggregative Pathways but Mainly via Its Scavenging Properties against Aβ and Aβ-Metal Complexes Toxicity

It has been recently suggested that resveratrol can be effective in slowing down Alzheimer's disease (AD) development. As reported in many biochemical studies, resveratrol seems to exert its neuro-protective role through inhibition of β-amyloid aggregation (Aβ), by scavenging oxidants and exerting anti-inflammatory activities. In this paper, we demonstrate that resveratrol is cytoprotective in human neuroblastoma cells exposed to Aβ and or to Aβ-metal complex. Our findings suggest that resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties