Search

Based on the well-known principle of selective photothermolysis, laser has been a promising way for the treatment of port wine stains (PWSs). The laser wavelengths used for PWS’s clinical treatment include but are not limited to pulsed dye laser (PDL) in 585–600 nm, long-pulse 755-nm alexandrite, and 1064-nm Nd:YAG lasers. The objective of this study was to investigate the optimal wavelength for PWS’s laser treatment. A two-scale mathematic model was constructed to simultaneously quantify macroscale laser energy attenuation in two-layered bulk skin and microscale local energy absorption on target blood vessels within Krogh unit. The effects of morphological parameters, including epidermal melanin content, epidermal thickness, dermal blood content, blood vessel depth, and diameter on laser energy deposition within target blood vessels, were investigated from the visible to near-infrared bands (500–1100 nm). The energy deposition ratio of target blood vessel to epidermal surface was proposed to determine the optimal laser wavelength for PWS with different skin morphological parameters. The bioheat transfer modeling and animal experiment are also conducted to prove our wavelength optimization. The optimal wavelengths for lightly pigmented skin with small and shallow target blood vessels are 580–610 nm in the visible band. This wavelength coincides with commercially used PDL. The optimal wavelength shifts to 940 nm as the epidermal pigmentation increases or the size and blood vessel depth increases. The optimal wavelength changes to 1005 nm as the epidermal pigmentation or the size and burying depth of target blood vessel further increases. Nine hundred forty nanometers can be selected as a general wavelength in PWS treatment to meet the need in most widely morphological structure. Lasers with wavelengths in the 580–610, 940, and 1005 nm regions are effective for treating PWS because of their high optical selectivity in blood over the epidermis.

Cloned animals are prone to abnormal phenotypes such as enlarged tongue, fetal oversize, and progeria. In the present study, whole-genome bisulfite sequencing and mRNA sequencing were performed on tongue and biceps femoris muscles of cloned piglets with and without macroglossia, in an attempt to elucidate the epigenetic causes of the macroglossia phenotype. We identified 14 958 and 18 752 differentially methylated regions in the tongue and biceps femoris muscles, respectively, of macroglossia piglets and these correspond to 4574 and 4772 differentially methylated genes compared with the control group (piglets without macroglossia). Larger methylation difference was found in tongue muscle than in biceps femoris muscle. In total, 114 genes in tongue and 72 genes in biceps femoris muscles were found to be differentially expressed between the two groups. Of these differentially expressed genes in tongue muscle, 31 were also differentially methylated genes, among which DIO3 and ZIC1 were imprinting or predicted imprinting genes. These two and another six overlapping genes (ALDH1A2, MKX, MAB21L2, CA3, RANBP3L, and MYL10) are crucial factors involved in embryonic development or tissue and organ development. GO enrichment analysis suggested possible alteration of these processes. Our study provides novel molecular insights into the formation of macroglossia in cloned pigs.

Methylation of N6-adenosine (m6A) is the most prevalent internal RNA modification and is especially common among the messenger RNAs. These m6A modifications regulate splicing, translocation, stability and translation of RNA through dynamic and reversible interactions with m6A-binding proteins, namely the writers, erasers and readers. RNA methyltransferases catalyze the m6A modifications, while demethylases reverse this methylation. Deregulation of the m6A modification process has been implicated in human carcinogenesis, including melanoma—which carries one of the highest mutant rates. In this review, we provide an up-to-date summary of m6A regulation and its biological impacts on normal and cancer cells, with emphasis on the deregulation of m6A modification and m6A regulators in melanoma. In addition, we highlight the prospective potential of exploiting m6A modification in the treatment of melanoma and non-cancer diseases.

The paroxysmal dyskinesias are a diverse group of genetic disorders that manifest as episodic movements, with specific triggers, attack frequency, and duration. With recent advances in genetic sequencing, the number of genetic variants associated with paroxysmal dyskinesia has dramatically increased, and it is now evident that there is significant genotype-phenotype overlap, reduced (or incomplete) penetrance, and phenotypic variability. In addition, a variety of genetic conditions can present with paroxysmal dyskinesia as the initial symptom. This review will cover the 34 genes implicated to date and propose a diagnostic workflow featuring judicious use of whole-exome or -genome sequencing. The goal of this review is to provide a common understanding of paroxysmal dyskinesias so basic scientists, geneticists, and clinicians can collaborate effectively to provide diagnoses and treatments for patients.

Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.

PURPOSE The High-Dose-Rate (HDR) vaginal cylinder treatment is typically designed using the initial CT, while the subsequent implants are verified using rudimentary methods (i.e., visual inspection, ruler measurements, etc.) and/or X-ray imaging. We are proposing the use of a 3D-printed individualized template that could provide simple and reproducible vaginal cylinder insertion. MATERIAL AND METHODS Six patients were included in the study with prescriptions of 6 Gy/fraction for 2 to 5 fractions (total 27 treatments). The first 1 to 2 treatments were delivered without the template and the rest with the CT-based 3D-printed templates. Cone beam CTs (CBCTs) were acquired to verify the cylinder placement for all treatments. D2cc of the bladder and rectum are recorded on both planning CT and the following on-treatment CBCTs. RESULTS By using the templates, the tip position variation on average (±1 SD) reduced from 0.8±0.5 cm to 0.6±0.4 cm, and angular difference decreased from 5.3±3.5° to 4.7±2.4°. The pitch and yaw deviation are reduced from 0.9 ± 5.8° and 0.4±2.9° to 0.0±3.9° and -0.2±3.0°, respectively. The deviation of D2cc to bladder from the plan reduced from 6±4% to 5±3%, and rectum from 5±2% to 4±4%. CONCLUSION The 3D-printed patient-specific cylinder templates could potentially improve the geometrical reproducibility of cylinder treatments at no cost of additional imaging. The D2cc for the bladder and rectum are determined by the treatment length rather than their respective volumes.

Aims To assess circulating fetuin-B concentrations in subjects with different degrees of glucose tolerance and to analyze the association of fetuin-B concentrations with insulin resistance and the first phase of glucose-stimulated insulin secretion. Methods Plasma fetuin-B concentrations were analyzed in 149 subjects with normal glucose tolerance (NGT, n =54), impaired glucose regulation (preDM, n =42) and newly diagnosed type-2 diabetes mellitus (nT2DM, n =53). Intravenous glucose tolerance tests (IVGTTs) and biochemical parameters were also assessed in all participants. Results Plasma fetuin-B concentrations were significantly higher in nT2DM patients compared with NGT and preDM subjects (both P 1c , hsCRP, FINS and TG ( P P P Conclusion Patients with nT2DM have significantly higher concentrations of plasma fetuin-B compared with NGT subjects and plasma fetuin-B is strongly associated with glucose and lipid metabolism, chronic inflammation and first-phase glucose-stimulated insulin secretion and insulin resistance.

The purpose of this study is to explore the association of CYP3A5, ABCB1, and CYP2C8 polymorphisms with the risk of developing early kidney impairment in Chinese liver transplant recipients receiving tacrolimus.CYP3A5, ABCB1, and CYP2C8 polymorphisms were genotyped in the Chinese liver transplant recipients in the study receiving tacrolimus for at least 2 years by polymerase chain reaction and high-resolution melting method. Serum cystatin C and urine microprotein (α1-microglobulin, microalbumin, transferrin, and immunoglobulin) of liver transplant recipients were used to determine both the status of early renal injury and the lesion part.We documented 3 genotypes of CYP3A5 and ABCB1 and only 2 genotypes of CYP2C8 in our cohort. The levels of cystatin C and all 4 indicators of the urine microprotein in the recipient group were significantly higher than those in the control group (P .05). The concentrations of transferrin differed significantly in each CYP3A5 genotype group (P .05). Based on diverse CYP2C8 genotypes, we divided all the recipients into 2 groups: CYP2C8*1*1 group and CYP2C8*3*1 group. The concentrations of α1-microglobulin and cystatin C differed significantly between the 2 groups (P .05). For CYP2C8*3, the positive predictive value is 68.5% and negative predictive value is 70.2%. For CYP3A5*3, the positive predictive value is 55.3% and negative predictive value is 60.4%.CYP2C8*3 and CYP3A5*3 appear to be predictive of risk of tacrolimus-induced early renal impairment. CYP3A5*3 was associated with the risk of early renal glomerular lesion, while CYP2C8*3 was associated with the risk of the tubulointerstitial injury. ABCB1 polymorphisms (both C3435T and C1236T) were not associated with the early renal injury in liver transplant recipients.

Purpose The purpose of this study was to investigate the contemporary distribution of medical physics (MP) employment opportunities across the United States. Methods and Materials An annual record (2018-2019) of advertised full-time MP jobs was created using publicly available information from the American Association of Physicists in Medicine and Indeed websites. Listed jobs were categorized based on position name, work experience, job function, and geographic region. To account for regional population differences, a preponderance of employment opportunities per 10 million people was computed. Using Commission on Accreditation of Medical Physics Education Programs residency accreditation data, the nationwide locations of the MP training centers and the number of residency positions per annum were identified. A chi-square goodness-of-fit test was used for statistical analysis. Results A total of 441 unique MP jobs were identified nationwide per annum (2018-2019). The highest percentage of MP jobs was reported from the South region (33.6%), and the lowest (17.2%) was from the West. Analysis revealed that 148 jobs (33.6%) were academic and 293 (66.4%) were nonacademic. The South had the most academic jobs overall (31.8%), whereas the West had the fewest (13.5%). Regionally, the highest percentage of academic jobs (46.9%) was reported from the Northeast, whereas the West had the lowest percentage (26.3%). The analysis of academic versus nonacademic job comparison by regions showed statistically significant differences (P = .0133). The Midwest and the West regions, respectively, showed the highest (18.2) and lowest (10.24) number of jobs per unit population, measured in 10 million. Conclusions To our knowledge, this is one of the first national quantitative job data analyses of MP job distributions. This study revealed the level of demand for qualified candidates in 2018 to 2019, showing an imbalance between academic and nonacademic positions across the regions of the United States. Moreover, the geographic distribution of job listings deviated significantly from expectation given the relative population of each region.

In this paper, we report on the fabrication of Ga-doped zinc oxide (GZO) channel ultraviolet (UV) phototransistors. Under dark measurement conditions, it is found that the values of μFE, VT, SS, and ION/IOFF of the fabricated device are 25.8 cm2/Vs, 0.35 V, 0.2 V/decade, and 1 × 105, respectively. Unpassivated devices have a negative VTH shift with positive bias stress, which results from the interactions of the moisture present in air with the GZO channel during the fabrication procedure and/or storage. Furthermore, it is found that the deep-UV to visible-rejection ratio can reach 1.1 × 102 for the fabricated phototransistor. These electro-optical properties indicate that the fabricated devices not only present good performance as thin-film transistors (TFTs), but are also useful for deep-UV light sensing applications.

Progressive tendon adhesion is a major challenge in flexor tendon repair. The authors developed a bifunctional anti-adhesion scaffold and hypothesized that its application would reduce adhesion formation and deliver mesenchymal stem cells (MSCs) to enhance tendon healing. The scaffold was fabricated by an electrospinning machine before surface modification. The flexor tendons of 29 New Zealand rabbits underwent surgical repair and randomized to control, scaffold and scaffold loaded with MSC group. At 3 and 8 weeks post-surgery, range of motion (ROM), biomechanical properties, and histology were examined. There was no significant increase in ROM and biomechanical properties between the three groups. The histology showed successful delivery of MSCs but no significant difference in nuclear morphometry. This barrier delivers and retains MSCs within the tendon repair site. However, its sheet form and wrapping around the repair site may not be optimal for tendon healing. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2605-2614, 2018.

Purpose/Objective(s) Radiation therapy requires immobilization hardware that may produce significant anxiety for a patient under treatment, particularly when covering the face. In cases where such anxiety is treatment limiting, 3D printing can provide for a better tolerated custom immobilization. The technical hurdles, fidelity of positioning, and clinical outcomes are reviewed for the treatment of oropharyngeal cancer in a patient who was unable to tolerate traditional mask-based immobilization. Materials/Methods A 3D printer was used to create a custom immobilization cradle for the treatment of squamous cell carcinoma of the oropharynx. This was used in the treatment of a patient who was unable to be simulated despite nine separate attempts, using a variety of open-faced immobilization techniques, anxiolytics, and coaching. Operative management was not feasible due to the patient's habitus and comorbidities. Despite acknowledging the severity of the situation, the patient could not complete simulation. Thus, after he was confirmed to still have locoregionally limited disease, we proposed creation of a 3D-printed cradle for the back of his head and neck, based on CT imaging without immobilization. Three separate attempts were made to complete the printing of the cradle. Major issues stemmed from the need to find a set of support structures that would allow for the proper printing of the area supporting the ears, as well as the back of the head. Ultimately, a dense array of column supports was successful, but still required buttressing of the columns with tape at several points during the print. In total, 664g of polylactic acid filament was used, as well as 525g of polyvinyl alcohol, a water soluble support material. Total print time was just under 78 hours for the final successful print. Results The patient was able to tolerate simulation and the full course of fractionated chemoradiotherapy. The cradle provided for a setup requiring mean absolute shift of 0.35 mm in the anterior-posterior direction, 0.17 cm in the cranio-caudal direction, and 0.36 cm in the lateral direction, and a couch kick of 1.28 degrees to bring the patient into alignment on final imaging. The patient is currently in stable condition and following up with both medical oncology and radiation oncology at regular intervals. Imaging and laryngoscopy, conducted at multiple time points following completion, shows him to have no evidence of disease, now at 10 months. Conclusion The full uses of 3D printing are still developing, as evidenced by the difficulty of creating a workable print, both in terms of prototyping and the time needed to create a print. The impact of 3D printing within the context of radiation oncology, as well as in other specialties, will undoubtedly continue to increase the variety of viable treatment options available to patients as the technology improves.

The sparing of the parotid glands in the treatment of head and neck cancers is of clinical relevance as high doses to the salivary glands may result in xerostomia. Xerostomia is a major cause of decreased quality of life for head and neck patients. This paper explores the relationship between the overlap of the target volumes and their expansions with the parotid glands for helical delivery plans and their ability to be spared. Various overlapping volumes were examined, and an overlap with a high statistical relevance was found. A model that predicts exceeding tolerance parotid mean dose based on its fractional overlapping volume with PTVs was developed. A fractional overlapping volume of 0.083 between the parotid gland and the high dose PTV plus 5 mm expansion – was determined to be the threshold value to predict parotid Dmean > 26 Gy for parotids that overlap with the high dose PTV plus 5 mm expansion. If the parotid gland only overlaps with the intermediate dose target (and/or low dose target) and the overlapping volume of the parotid gland and the intermediate dose target is less than 25%, the parotid mean dose is likely less than 26 Gy. If the parotid overlaps with the low dose target only then the mean dose to the parotid is likely to be less than 26 Gy. This finding will prove as a very useful guide for the physicians and planners involved in the planning process to know prior whether the parotid glands will be able to be spared with the current set of target volumes or if revisions are necessary. This work will serve as a helpful guide in the planning process of head and neck target cases.

Background This study aimed to describe the burden of community-acquired acute kidney injury (AKI) in China based on a nationwide survey about AKI. Study Design Cross-sectional and retrospective study. Setting & Participants A national sample of 2,223,230 hospitalized adult patients from 44 academic/local hospitals in Mainland China was used. AKI was defined according to the 2012 KDIGO AKI creatinine criteria or an increase or decrease in serum creatinine level of 50% during the hospital stay. Community-acquired AKI was identified when a patient had AKI that could be defined at hospital admission. Predictors The rate, cause, recognition, and treatment of community-acquired AKI were stratified according to hospital type, latitude, and economic development of the regions in which the patients were admitted. Outcomes All-cause in-hospital mortality and recovery of kidney function at hospital discharge. Results 4,136 patients with community-acquired AKI were identified during the 2 single-month snapshots (January 2013 and July 2013). Of these, 2,020 (48.8%) had cases related to decreased kidney perfusion; 1,111 (26.9%), to intrinsic kidney disease; and 499 (12.1%), to urinary tract obstruction. In the north versus the south, more patients were exposed to nephrotoxins or had urinary tract obstructions. 536 (13.0%) patients with community-acquired AKI had indications for renal replacement therapy (RRT), but only 347 (64.7%) of them received RRT. Rates of timely diagnosis and appropriate use of RRT were higher in regions with higher per capita gross domestic product. All-cause in-hospital mortality was 7.3% (295 of 4,068). Delayed AKI recognition and being located in northern China were independent risk factors for in-hospital mortality, and referral to nephrology providers was an independent protective factor. Limitations Possible misclassification of AKI and community-acquired AKI due to nonstandard definitions and missing data for serum creatinine. Conclusions The features of community-acquired AKI varied substantially in different regions of China and were closely linked to the environment, economy, and medical resources.

// Yong Wu 1 , Min Su 1 , ShuX Zhang 1 , Yu Cheng 1 , Xiao Y. Liao 1 , Bao Y. Lin 1 , Yuan Z. Chen 1 1 Fujian Institute of Hematology, Department of Hematology, Union Hospital, Fujian Medical University, Fuzhou, China Correspondence to: Yuanzhong Chen, email: chenyz@mail.fjmu.edu.cn Keywords: TGF-β, type II receptor, isoform, myeloid, leukemia Received: April 14, 2016 Accepted: November 30, 2016 Published: December 28, 2016 ABSTRACT Altered transforming growth factor-beta (TGF-β) signaling has been implicated in the pathogenesis of leukemia. Although TGF-β type II receptor (TβRII) isoforms have been isolated from human leukemia cells, their expression patterns and functions of these variants are unclear. In this study, we determined that two TβRII isoforms (TβRII and TβRII-B) are abnormally expressed in leukemic cells, as compared to normal hematopoietic cells. TβRII-B, but not TβRII, was found to promote cell cycle arrest, apoptosis, and differentiation of leukemic cells. TβRII-B also enhanced TGF-β1 binding and downstream signaling and reduced tumorigenicity in vivo . By contrast, TβRII blocked all-trans retinoic acid-induced differentiation through inhibition of TβRII-B. Overall survival was significantly lower in acute myeloid leukemia (AML) patients with high compared to low TβRII expression. Thus, whereas TβRII-B is a potent inducer of cell cycle arrest, apoptosis, and differentiation, higher TβRII expression correlates with poor clinical prognosis in AML.

Background The English National Institute for Health Research Clinical Research Network first established Hyperacute Stroke Research Centres (HSRCs) in 2010 to support multicentre hyperacute (

Rotavirus and poliovirus continue to present significant risks and burden of disease to children in developing countries. Developing a combined vaccine may effectively prevent both illnesses and may be advantageous in terms of maximizing compliance and vaccine coverage at the same visit. Recently, we sought to generate a vaccine vector by incorporating multiple epitopes into the rotavirus group antigenic protein, VP6. In the present study, a foreign epitope presenting a system using VP6 as a vector was created with six sites on the outer surface of the vector that could be used for insertion of foreign epitopes, and three VP6-based PV1 epitope chimeric proteins were constructed. The chimeric proteins were confirmed by immunoblot, immunofluorescence assay, and injected into guinea pigs to analyze the epitope-specific humoral response. Results showed that these chimeric proteins reacted with anti-VP6F and -PV1 antibodies, and elicited antibodies against both proteins in guinea pigs. Antibodies against the chimeric proteins carrying PV1 epitopes neutralized rotavirus Wa and PV1 infection in vitro. Our study contributes to a better understanding of the use of VP6-based vectors as multiple-epitope delivery vehicles and the epitopes displayed in this form could be considered for development of epitope-based vaccines against rotavirus and poliovirus.

The c-MYB transcription factor is a key regulator of hematopoietic cell proliferation and differentiation, and dysregulation of c-MYB activity often associates with various hematological disorders. Yet, its pathogenic role remains largely unknown due to lack of suitable animal models. Here, we report a detail characterization of a c-myb-gfp transgenic zebrafish harboring c-Myb hyperactivity (named c-mybhyper). This line exhibits abnormal granulocyte expansion that resembles human myelodysplastic syndrome (MDS) from embryonic stage to adulthood. Strikingly, a small portion of c-mybhyper adult fish develops acute myeloid leukemia-like or acute lymphoid leukemia-like disorders with age. The myeloid and lymphoid malignancies in c-mybhyper adult fish are likely caused by the hyperactivity of c-myb, resulting in the dysregulation of a number of cell-cycle-related genes and hyperproliferation of hematopoietic precursor cells. Finally, treatment with c-myb target drug flavopiridol can relieve the MDS-like symptoms in both c-mybhyper embryos and adult fish. Our study establishes a zebrafish model for studying the cellular and molecular mechanisms underlying c-Myb-associated leukemogenesis as well as for anti-leukemic drug screening.

Aim The aim is to determine the incidence and timing of urethrocutaneous fistula diagnosis after hypospadias surgery. Methods A retrospective review of all patients who had both initial hypospadias surgery and subsequent fistula repair from 1995 to 2012. A comparison was made between patients who had an initial onlay island flap procedure and those who had a tubularised incised plate repair. Results Patient age at initial surgery ranged from 6 months to 16 years of age. The median time to fistula presentation was 8.5 months with a range of less than 1 month to 13.9 years post-hypospadias surgery. The median time to fistula repair was 17 months. The overall fistula rate was 8%. There was no significant difference between the rates of fistulae for onlay island flap (9%) versus tubularised incised plate procedure (7%). Conclusions Urethrocutaneous fistulae can present many years after the original hypospadias repair. The majority are diagnosed within the first year after surgery. Rates of fistulae are probably underreported due to short follow-up, but more importantly, due to patients transferring to other surgeons for fistula repair.

Micro-injection molding or micro-hot embossing is a highly effective process for fabricating micro-devices with microfeatures in polymer. Based on the strong demand on the precision components in the precision machinery industrial, two major concerns are the time and expense required for producing a precision mold for microfabrication. To enhance the competitiveness in the market of micorcomponents, this study presents six approaches for manufacturing precision epoxy resin molds with microfeatures. Evolutions manufacturing processes are described experimentally. Characteristics and applications of micro-featured epoxy resin mold are introduced in detail.

AIM To evaluate the preoperative differentiation between the minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) in patients with sub-solid pulmonary nodules using a radiomics nomogram. MATERIALS AND METHODS A total of 100 patients with sub-solid pulmonary nodules who had pathologically confirmed MIA (43 patients, 13 male and 30 female) or IAC (57 patients, 26 male and 31 female) were recruited retrospectively. Radiomics features were extracted from computed tomography (CT) images. A radiomics signature was constructed by the least absolute shrinkage and selection operator (LASSO) algorithm. Solid presence, lesion size, shape regularity, and margins of pulmonary nodules were assessed to construct a subjective finding model. An integrated model of radiomics signatures and CT-based subjective findings, which was presented as a radiomics nomogram, was developed based on a multivariate logistic regression. The nomogram performance was assessed by its calibration, discrimination, and clinical usefulness. RESULTS The radiomics signature, which consisted of 11 radiomics features, showed good discrimination accuracy. The radiomics nomogram showed good calibration and discrimination in the training set (AUC [area under the curve] 0.943; 95% confidence interval [CI]: 0.895–0.991) and validation set (AUC 0.912; 95% CI: 0.780–1.000). The radiomics nomogram was determined to be clinically useful in the decision curve analysis (DCA). CONCLUSION The proposed radiomics nomogram has the potential to preoperatively differentiate MIA and IAC in patients with sub-solid pulmonary nodules.

Many membrane proteins sense and induce membrane curvature for function, but structural information about how proteins modulate their structures to cause membrane curvature is sparse. We review our recent solid-state NMR studies of two virus membrane proteins whose conformational equilibrium is tightly coupled to membrane curvature. The influenza M2 proton channel has a drug-binding site in the transmembrane (TM) pore. Previous chemical shift data indicated that this pore-binding site is lost in an M2 construct that contains the TM domain and a curvature-inducing amphipathic helix. We have now obtained chemical shift perturbation, protein-drug proximity, and drug orientation data that indicate that the pore-binding site is restored when the full cytoplasmic domain is present. This finding indicates that the curvature-inducing amphipathic helix distorts the TM structure to interfere with drug binding, while the cytoplasmic tail attenuates this effect. In the second example, we review our studies of a parainfluenza virus fusion protein that merges the cell membrane and the virus envelope during virus entry. Chemical shifts of two hydrophobic domains of the protein indicate that both domains have membrane-dependent backbone conformations, with the β-strand structure dominating in negative-curvature phosphatidylethanolamine (PE) membranes. 31 P NMR spectra and 1 H- 31 P correlation spectra indicate that the β-strand-rich conformation induces saddle-splay curvature to PE membranes and dehydrates them, thus stabilizing the hemifusion state. These results highlight the indispensable role of solid-state NMR to simultaneously determine membrane protein structures and characterize the membrane curvature in which these protein structures exist. ©2019, NIH (grant no.GM088204), NIH (grant no. GM066976)

Objective:Chronic kidney disease (CKD) has emerged as a global health problem of epidemic proportions. The purpose of this study was to explore the predictors of urinary albumin-to-creatinine ratio (uACR), estimated glomerular filtration ratio (eGFR) and their progressions in Chinese cohort over a 1

Introduction Glycosylation controls diverse protein functions and regulates various cellular phenotypes. Trophoblast invasion is essential for normal placental development. However, the role of glycosylation in human placenta throughout pregnancy is still unclear. The β-1,4-galactosyltransferase III (B4GALT3) has been found to regulate cancer cell invasion. We therefore investigated the expression of B4GALT3 in placenta and its roles in trophoblast. Methods B4GALT3 protein expression was examined by quantitative Western blotting analysis in human placentas. For identification of B4GALT3-positive cells in normal human placenta, immunohistochemistry and immunofluorescence methods were used. To investigate effects of B4GALT3 on extravillous trophoblast (EVT)-like cell and primary EVT cells, we analyzed cell growth, adhesion, migration, and invasion in mock and B4GALT3-transfected cell. Results B4GALT3 expression significantly increased in third trimester human placenta. Immunostaining revealed that B4GALT3 expressed in placental villous cytotrophoblast, syncytiotrophoblast, and a subpopulation of EVT cells throughout pregnancy. Interestingly, we found increases in the expression level and percentage of B4GALT3-positive cells in third trimester EVT, but not in syncytiotrophoblasts and cytotrophoblasts of placental villi. Overexpression of B4GALT3 in HTR8/SVneo cells and primary trophoblast cells significantly suppressed cell migration. In addition, B4GALT3 suppressed cell invasion, and enhanced cell adhesion to laminin in HTR8/SVneo cells. Notably, we found that B4GALT3 modified glycans on β1-integrin, suppressed focal adhesion kinase (FAK) signaling, and enhanced β1-integrin degradation. Discussion We propose that B4GALT3-mediated glycosylation change not only enhances β1-integrin binding to laminin, but also attenuates β1-integrin stability. Our findings suggest that B4GALT3 is a critical regulator for suppressing EVT invasion in the late stages of pregnancy.

Purpose The Xoft Axxent Electronic Brachytherapy System (Xoft, Inc., San Jose, CA) is a viable option for intraoperative radiation therapy (IORT) treatment of early-stage breast cancer. The low-energy (50-kVp) X-ray source simplifies shielding and increases relative biological effectiveness but increases dose distribution sensitivity to medium composition. Treatment planning systems typically assume homogenous water for brachytherapy dose calculations, including precalculated atlas plans for Xoft IORT. However, Xoft recommends saline for balloon applicator filling. This study investigates dosimetric differences due to increased effective atomic number (Z eff ) for saline (Z eff = 7.56) versus water (Z eff = 7.42). Methods Balloon applicator diameters range from 3 to 6 cm. Monte Carlo N-Particle software is used to calculate dose at the surface ( D s ) of and 1 cm away ( D 1cm ) from the water-/saline-filled balloon applicator using a single dwell at the applicator center as a simple estimation of the dosimetry and multiple dwells simulating the clinical dose distributions for the atlas plans. Results Single-dwell plans show a 4.4–6.1% decrease in D s for the 3- to 6-cm diameter applicators due to the saline. Multidwell plans show similar results: 4.9% and 6.4% D s decrease, for 4-cm and 6-cm diameter applicators, respectively. For the single-dwell plans, D 1cm decreases 3.6–5.2% for the 3- to 6-cm diameter applicators. For the multidwell plans, D 1cm decreases 3.3% and 5.3% for the 4-cm and 6-cm applicators, respectively. Conclusions The dosimetric effect introduced by saline versus water filling for Xoft balloon applicator–based IORT treatments is ∼5%. Users should be aware of this in the context of both treatment planning and patient outcome studies.

8 p., Background Most data on mortality and prognostic factors in patients with heart failure come from North America and Europe, with little information from other regions. Here, in the International Congestive Heart Failure (INTERCHF) study, we aimed to measure mortality at 1 year in patients with heart failure in Africa, China, India, the Middle East, southeast Asia and South America; we also explored demographic, clinical, and socioeconomic variables associated with mortality. Methods We enrolled consecutive patients with heart failure (3695 [66%] clinic outpatients, 2105 [34%] hospital in patients) from 108 centres in six geographical regions. We recorded baseline demographic and clinical characteristics and followed up patients at 6 months and 1 year from enrolment to record symptoms, medications, and outcomes. Time to death was studied with Cox proportional hazards models adjusted for demographic and clinical variables, medications, socioeconomic variables, and region. We used the explained risk statistic to calculate the relative contribution of each level of adjustment to the risk of death. Findings We enrolled 5823 patients within 1 year (with 98% follow-up). Overall mortality was 16·5%: highest in Africa (34%) and India (23%), intermediate in southeast Asia (15%), and lowest in China (7%), South America (9%), and the Middle East (9%). Regional differences persisted after multivariable adjustment. Independent predictors of mortality included cardiac variables (New York Heart Association Functional Class III or IV, previous admission for heart failure, and valve disease) and non-cardiac variables (body-mass index, chronic kidney disease, and chronic obstructive pulmonary disease). 46% of mortality risk was explained by multivariable modelling with these variables; however, the remainder was unexplained. Interpretation Marked regional differences in mortality in patients with heart failure persisted after multivariable adjustment for cardiac and non-cardiac factors. Therefore, variations in mortality between regions could be the result of health-care infrastructure, quality and access, or environmental and genetic factors. Further studies in large, global cohorts are needed. Funding The study was supported by Novartis.

Background: Based primarily on studies concerning early-stage tumours (treated surgically), and locally advanced disease (treated with chemoradiation), the prognosis for women with adenocarcinoma (AC) or adenosquamous (AS) carcinoma has been reported to be poorer than those with squamous cell carcinoma (SCCA) of the cervix. It is unclear whether differences in prognosis also persist in the setting of recurrent or metastatic disease treated using chemotherapy doublets with or without bevacizumab. Methods: Cases were pooled from three Gynaecologic Oncology Group randomised phase III trials of chemotherapy doublets. Pearson’s test was used to evaluate response rate (RR) of AC/AS vs SCCA, Kaplan–Meier method to estimate progression-free survival (PFS) and overall survival (OS), and Cox proportional hazards model to estimate the impact of histology on PFS and OS. Results: Of 781 evaluable patients, 77% (N=599) had SCCA and 23% (N=182) AC/AS. There were no significant differences in RRs between histologic subgroups. The adjusted hazard ratio (HR) for death for SCCA vs AC/AS was 1.13 (95% CI 0.93, 1.38 P=0.23). When comparing SC/AS (N=661, 85%) to AC alone (N=120, 15%), the adjusted HR for death was 1.23 (95% CI 0.97, 1.57, P=0.09). Conclusions: AC/AS and SCCA have similar survival in recurrent or metastatic cervical carcinoma when treated with chemotherapy doublets.

Purpose: High dose rate (HDR) volumetric brachytherapy is an effective method of treating advanced cervix carcinoma. Local failure is associated with multiple factors including higher maximal standardized uptake value (SUV) values in fluorodeoxyglucose positron emission tomography (FDG‐ PET) scans. The purpose of this study is to evaluate the ability to simultaneously boost regions of high SUV values using an in‐house adaptive simulated annealing (ASA) algorithm and the Oncentra® (Nucletron V.B., Veenendaal, The Netherlands) treatment planning system, thereby potentially improving local control. Methods: Five cervix cancers were evaluated for brachytherapy treatment (tandem/ring and/or interstitial needles). MRI and PETimages were obtained post‐implant and fused with treatment planning CTs to define a high‐risk (HR) CTV (cervix and tumor on MRI) and GTV (volume with >50% of the maximum SUV on PET). The prescribed dose was 5–6 Gy to the HR CTV and 7–9 Gy to the GTV. Treatment plans were first generated in Oncentra® with IPSA followed by manual graphic optimization by the physician. Plans were also independently optimized using the ASA program. The two plans were compared side by side and one was chosen for treatment. Dose‐volume parameters including D90, V100 of targets, D2cc to the critical organs, and generalized equivalent uniform dose (gEUD) of all structures were compared between the ASA and the Oncentra plans. Results: Both ASA and Oncentra plans were considered acceptable by the physician in four of five cases. Two ASA plans were chosen due to better critical organ sparing and tumor coverage. Two Oncentra plans were preferred because of lower doses to critical organs. One ASA plan was not accepted because of a higher bowel dose.Conclusions: Both ASA and Oncentra® planning methods produce acceptable treatment plans for optimized brachytherapy of cervix carcinoma. Continued studies are warranted to further determine the relative strength of each method. This study was supported in part by a research grant from Varian Medical System Inc.

To evaluate whether the effects of providing or receiving social support are more beneficial to reduce mortality risk among the elderly with different educational levels.In this long-term prospective cohort study, data were retrieved from the Taiwan Longitudinal Study on Aging. This study was initiated from 1996 until 2007. The complete data from 1492 males and 1177 females aged ≥67 years were retrieved. Participants received financial, instrumental, and emotional support, and they actively provided instrumental and emotional support to others and involved in social engagement. Education attainment was divided into two levels: high and low. The low education level included illiterate and elementary school. The high education level included junior high school to senior high school and above college. Cox regression analysis was used to examine the association between providing or receiving social support on mortality with different educational levels.The average age of the participants in 1996 was 73.0 (IQR=8.0) years, and the median survival following years (1996-2007) of participants was 10.3 (IQR=6.7) years. Most participants were low educational level including illiterate (39.3%) and elementary school (41.2%). Participants with high educational level tend to be younger and more male significantly. On the contrary, participants with low educational level tend to have significant more poor income, more depression, more cognition impairment, more with IADL and ADL disability than high educational level. Most participants received instrumental support from others (95.5%) and also provided emotional support to others (97.7%). Providing instrumental support can reduce 17% of mortality risk among the elderly with a low level of education after adjusting several covariates [Hazard ratio (HR) = 0.83; 95% confidence interval (CI) = 0.70-0.99; p = 0.036].Providing instrumental social support to others confer benefits to the giver and prolong life expectancy among the elderly with low educational levels.

Background: Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development of several human cancers. The present study was conducted to investigate the expression of GOLPH3 and its prognostic significance in renal cell carcinoma (RCC). Meanwhile, the function of GOLPH3 in human RCC was further investigated in cell culture models. Methods: Expression of GOLPH3 was examined in 43 fresh RCC tissues and paired adjacent normal renal tissues by real-time quantitative PCR and western blotting. Immunohistochemistry for GOLPH3 was performed on additional 218 RCC tissues. The clinical significance of GOLPH3 expression was analysed. Downregulation of GOLPH3 was performed using small-interfering RNA (siRNA) in Caki-1 and 786-O cells with high abundance of GOLPH3, and the effects of GOLPH3 silencing on cell proliferation, migration, invasion in vitro, and tumour growth in vivo were evaluated. Results: Expression of GOLPH3 was upregulated in the majority of the RCC clinical tissue specimens at both mRNA and protein levels. Clinicopathological analysis showed that GOLPH3 expression was significantly correlated with T stage (P

This paper aims to explore the dynamic characteristics and cutting stability of a surface grinder. In simulated grinding, the dynamically loaded worktable is described by the Euler–Bernoulli beam theory. In the model, the elastic worktable has both ends simply supported on a movable and massless rigid base. The analysis of the dynamics and stability of the worktable is complex due to the operating worktable being dynamically loaded in variable positions. With the Lagrange energy method combined with the assumed mode expansion method, the system dynamic equations are derived and a state space model for the dynamically loaded worktable subjected to simply supported conditions is developed. In this study, the maximum negative real part of the overall dynamic compliance and the limiting depth of cut are used as indicators to assess the structural static and dynamic performance of the worktable in various positions. The effects of worktable damping, contact stiffness, and damping between the tool and the workpiece on the system performance are studied. Based on the regenerative chatter and stability theory, the 3D stability lobes diagram is analyzed to optimize the maximum depth of cut at the highest available spindle speed. The cutting stability is verified by comparing the results obtained in the time domain analysis with the stability lobe diagram. The procedure illustrated in this study to improve the dynamics performance of a surface grinder can also be implemented in a similar fashion for many machine tool applications.

Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice. © The American Society of Gene & Cell Therapy.