Energy dispersive spectroscopy-scanning transmission electron microscope observations of free radical production in human polymorphonuclear leukocytes phagocytosing non-opsonized Tannerella forsythia

Abstract

We investigated the association between human polymorphonuclear leukocytes (PMNs) and non-opsonized Tannerella forsythia ATCC 43037 displaying a serum-resistant surface layer (S-layer). When PMNs were mixed with T. forsythia in suspension, the cells phagocytosed T. forsythia cells. Nitro blue tetrazolium (NBT) reduction, indicative of production, was observed by light microscopy; cerium (Ce) perhydroxide deposition, indicative of H₂O₂ production, was observed by electron microscopy. We examined the relationship between high-molecular-weight proteins of the S-layer and Ce reaction (for T. forsythia phagocytosis) using electron microscopic immunolabeling. Immunogold particles were localized within the PMNs and on cell surfaces, labelling at the same Ce-reacted sites where the S-layer was present. We then used energy dispersive spectroscopy (EDS)-scanning transmission electron microscope (STEM) to perform Ce and nitrogen (N) (for S-layer immunocytochemistry) elemental analysis on the phagocytosed cells. That is, the elemental mapping and analysis of N by EDS appeared to reflect the presence of the same moieties detected by the 3,3′-diaminobenzidine-tetrahydrochloride (DAB) reaction with horseradish peroxidase (HRP)-conjugated secondary antibodies, instead of immunogold labeling. We focused on the use of EDS-STEM to visualize the presence of N resulting from the DAB reaction. In a parallel set of experiments, we used EDS-STEM to perform Ce and gold (Au; from immunogold labeling of the S-layer) elemental analysis on the same phagocytosing cells.

We investigated the association between leukocytes and T. forsythia (T.f.) by EDS-STEM. We detected Ce, H₂O₂ production, and nitrogen (S-layer from T. f, DAB with HRP instead of immunogold labeling) elements on the same sites of leukocyte cytoplasm.

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IJERPH, Vol. 14, Pages 457: Designing Fit for Purpose Health and Social Services for Ageing Populations

Population ageing is occurring in all countries, regardless of the level of economic development. While the rising burden of chronic diseases and disabilities as a consequence of this demographic transition is well recognized, the increasing prevalence of geriatric syndromes as a public health issue is not as well recognized. Recently the World Health Organization’s World Health and Ageing Report emphasized functional ability as an important outcome for aging populations, highlighting the concept of raising intrinsic capacity throughout the life course. The complementary perspective is the prevention of frailty, which has physical, cognitive, social and psychological dimensions. Therefore, services for older people should encompass medical as well as social components. The need and evolution for a transition in health and social services in Hong Kong, a special administrative region of China which has a population with the world’s highest life expectancy, is presented as an example of how one developed economy attempts to meet the challenges of population ageing. There is a need to shift to integrated care in the community instead of specialty dominated hospital care, and to establish regular activities in the community to adopt and maintain a lifestyle that reduces frailty and disability (or promotes intrinsic capacity). A top down approach with financial incentives, together with public education to help drive policy changes, are key drivers of change. It is expected that there will be much heterogeneity between different countries in terms of barriers and facilitators, such that each country needs to document their needs and design appropriate services.

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IJERPH, Vol. 14, Pages 455: Exclusive Breastfeeding Practice and Its Association among Mothers of under 5 Children in Kwango District, DR Congo

The benefit of the breastfeeding has been well-established. In comparison to partial breast feeding, exclusive breastfeeding has even more benefits. The aim of this study was to identify the factors associated with breastfeeding exclusivity during the first 6 months of life in order to better target public health interventions in this community towards healthier infant nutrition and address child mortality in this population. A cross-sectional survey among 1145 random households was conducted in the Kwango district of the Democratic Republic of the Congo (DRC) during 2 November 2015 to 13 November 2015. Women of reproductive age from 15–49 years and having less than 5 years old child were selected for the study. Chi-squared test and bivariate and multivariate analyses were performed using SPSS. A major finding of this study is 49.2% of the mothers are exclusively breastfeeding their children, and marital status, literacy, place of delivery, knowledge of exclusive breastfeeding and access to radio are the key indicators for exclusive breastfeeding. Exclusive breastfeeding rate is almost equivalent to the national prevalence rate for the DRC. Providing adequate knowledge to raise awareness of exclusive breast feeding and increase involvement of health care providers in enhancing knowledge through antenatal care and during delivery and postnatal care will be the best approaches to increase exclusive breastfeeding practice.

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IJERPH, Vol. 14, Pages 454: The Effects of Taekwondo Training on Peripheral Neuroplasticity-Related Growth Factors, Cerebral Blood Flow Velocity, and Cognitive Functions in Healthy Children: A Randomized Controlled Trial

Although regular Taekwondo (TKD) training has been reported to be effective for improving cognitive function in children, the mechanism underlying this improvement remains unclear. The purpose of the present study was to observe changes in neuroplasticity-related growth factors in the blood, assess cerebral blood flow velocity, and verify the resulting changes in children’s cognitive function after TKD training. Thirty healthy elementary school students were randomly assigned to control (n = 15) and TKD (n = 15) groups. The TKD training was conducted for 60 min at a rating of perceived exertion (RPE) of 11–15, 5 times per week, for 16 weeks. Brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) levels were measured by blood sampling before and after the training, and the cerebral blood flow velocities (peak systolic [MCAs], end diastolic [MCAd], mean cerebral blood flow velocities [MCAm], and pulsatility index [PI]) of the middle cerebral artery (MCA) were measured using Doppler ultrasonography. For cognitive function assessment, Stroop Color and Word Tests (Word, Color, and Color-Word) were administered along with other measurements. The serum BDNF, VEGF, and IGF-1 levels and the Color-Word test scores among the sub-factors of the Stroop Color and Word Test scores were significantly higher in the TKD group after the intervention (p < 0.05). On the other hand, no statistically significant differences were found in any factors related to cerebral blood flow velocities, or in the Word test and Color test scores (p > 0.05). Thus, 16-week TKD training did not significantly affect cerebral blood flow velocities, but the training may have been effective in increasing children’s cognitive function by inducing an increase in the levels of neuroplasticity-related growth factors.

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Keratoacanthoma, palmoplantar keratoderma developing in an advanced melanoma patient treated with vemurafenib regressed by blockade of mitogen-activated protein kinase kinase signaling

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Novel nonsense mutation in SERPINB7 and the treatment of foot odor in a patient with Nagashima-type palmoplantar keratosis

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Angioleiomyoma mimicking pes anserinus bursitis: A case report

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Biologic treatments for elderly patients with psoriasis

Abstract

The number of elderly patients with psoriasis is increasing in Japan. However, biologic treatment is generally considered to be challenging in elderly patients, due to their increased risk of complications compared with younger patients. Our retrospective study aimed to evaluate the safety profile and efficacy of biologics in senior elderly patients (≥75 years old) with psoriasis. The study involved a cohort of 27 patients aged 75–88 years who were being treated with biologics over a period of more than 1 year. Initial biologics administrated to were adalimumab (five cases) and ustekinumab (22 cases). Eight patients discontinued treatment: two developed cancer; one was transferred to hospital; and five others experienced either bone fracture, interstitial pneumonia, cerebral hemorrhage resulting in death, decrepitude or developed hepatopathy following prophylactic tuberculosis treatment. Efficacy, evaluated by the percentage of patients achieving 75% reduction of Psoriasis Area and Severity Index score, was 76.9% at week 16 (n = 26), 88.0% at week 24 (n = 25) and 90.5% at week 52 (n = 21). Biologic treatments thus show clear efficacy in elderly patients with psoriasis, however, the increased frequency of adverse events requires rigorous patient observation.

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Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy

Background

Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered.

Objective

To identify common genetic variants associated with tonsillectomy.

Methods

We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls.

Results

The variant rs2412971, intronic in HORMAD2 at chromosome 22q12.2, was robustly associated with tonsillectomy (OR=1.22; p=1.48x10^–9) and is highly correlated with SNPs previously found to be associated with IgA nephropathy, Crohn's disease (CD) and early onset inflammatory bowel disease (IBD). The risk allele for tonsillectomy corresponded to increased risk of IgA nephropathy and decreased risk of CD and IBD. We further performed lookup analyses of the top SNP for outcomes related to tonsillectomy in the combined discovery and replication sample and found that rs2412971 was associated with acute tonsillitis (OR=1.19; p=7.82x10^–4), chronic disease of the tonsils (OR=1.19; p=2.32x10^–6) and appendectomy (OR=1.18; p=1.13x10^–3).

Conclusions

We identified and replicated a genetic association at 22q12.2 with tonsillectomy. Further functional investigation is required to illuminate whether the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system.

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Gastric cancer: somatic genetics as a guide to therapy

Gastric cancer is the leading cause of cancer-related mortality across the world, with poor prognosis and a median overall survival of ≤12 months for advanced stage gastric cancer. Environmental, genetic and other predisposing factors contribute to the development of gastric cancer and a predominant factor was found to be infection of Helicobacter pylori. Advances in understanding the deranged signalling pathways that are critical for normal cellular homeostasis helped in the development of novel drugs that target specific proteins and pathways to curtail the growth of gastric cancer. Genetic studies revealed several single nucleotide polymorphisms, chromosomal aberrations and epigenetic alterations that likely play a major role in elevating the susceptibility to develop gastric cancer. Methylation pattern of specific genes may likely prove to be a valid biomarker for early detection of gastric cancer, but much progress is needed to establish specific markers. Important developments have been made in targeting human epidermal growth factor receptor-2 and vascular endothelial growth factor receptor 2 for treating advanced gastro-oesophageal junction cancer, using specific monoclonal antibodies. Lack of efficacy with regard to targeting other signalling pathways including mesenchymal-epithelial transition/hepatocyte growth factor and mammalian target of rapamycin is probably due to suboptimal patient selection for these clinical trials, which is probably due to the lack of appropriate biomarkers, to decide on responsive patient population. Besides the development of antagonists for the cell growth-related signalling pathways, advances are also being made to tackle gastric cancer by immunotherapies, targeting immune check-points, which may hold promise for better treatment options in future.

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Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B

Background

Haemophilia B is caused by genetic aberrations in the F9 gene. The majority of these are non-synonymous mutations that alter the primary structure of blood coagulation factor IX (FIX). However, a synonymous mutation c.459G>A (Val107Val) was clinically reported to result in mild haemophilia B (FIX coagulant activity 15%–20% of normal). The F9 mRNA of these patients showed no skipping or retention of introns and/or change in mRNA levels, suggesting that mRNA integrity does not contribute to the origin of the disease in affected individuals. The aim of this study is to elucidate the molecular mechanisms that can explain disease manifestations in patients with this synonymous mutation.

Methods

We analyse the molecular mechanisms underlying the FIX deficiency through in silico analysis and reproducing the c.459G>A (Val107Val) mutation in stable cell lines. Conformation and non-conformation sensitive antibodies, limited trypsin digestion, activity assays for FIX, interaction with other proteins and post-translation modifications were used to evaluate the biophysical and biochemical consequences of the synonymous mutation.

Results

The Val107Val synonymous mutation in F9 was found to significantly diminish FIX expression. Our results suggest that this mutation slows FIX translation and affects its conformation resulting in decreased extracellular protein level. The altered conformation did not change the specific activity of the mutated protein.

Conclusions

The pathogenic basis for one synonymous mutation (Val107Val) in the F9 gene associated with haemophilia B was determined. A mechanistic understanding of this synonymous variant yields potential for guiding and developing future therapeutic treatments.

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A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

Background

Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

Methods and results

We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, p_interaction=3.9e^–9) and rs9830388 in UBE2E2 (β=25.2, p_interaction=1.7e^–8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, p_interaction=2.55e^–8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (p_interaction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

Conclusions

Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

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Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance

Background

Individuals with hereditary non-polyposis colorectal cancer (HNPCC) have a high risk of colorectal cancer (CRC). The benefits of colonic surveillance in Lynch syndrome and Amsterdam-positive (familial CRC type X familial colorectal cancer type X (FCCTX)) families are clear; only the interval between colonoscopies is debated. The potential benefits for families not fulfilling the Amsterdam criteria are uncertain. The aim of this study was to compare the outcome of colonic surveillance in different hereditary subgroups and to evaluate the surveillance programmes.

Methods

A prospective, observational study on the outcome of colonic surveillance in different hereditary subgroups based on 24 years of surveillance data from the national Danish HNPCC register.

Results

We analysed 13 444 surveillance sessions, including 8768 incidence sessions and 20 450 years of follow-up. CRC was more incident in the Lynch subgroup (2.0%) than in any other subgroup (0.0–0.4%, p<0.0001), but the incidence of advanced adenoma did not differ between the Lynch (3.6%) and non-Lynch (2.3–3.9%, p=0.28) subgroups. Non-Lynch Amsterdam-positive and Amsterdam-negative families were similar in their CRC (0.1–0.4%, p=0.072), advanced adenoma (2.3–3.3%, p=0.32) and simple adenoma (8.4–9.9%, p=0.43) incidence. In moderate-risk families, no CRC and only one advanced adenoma was found.

Conclusions

The risk of CRC in Lynch families is considerable, despite biannual surveillance. We suggest less frequent and more individualised surveillance in non-Lynch families. Individuals from families with a strong history of CRC could be offered 5-year surveillance colonoscopies (unless findings at the preceding surveillance session indicate shorter interval) and individuals from moderate-risk families could be handled with the population-based screening programme for CRC after an initial surveillance colonoscopy.

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No correlation between mtDNA amount and methylation levels at the CpG island of POLG exon 2 in wild-type and mutant human differentiated cells

Background

While mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation and according to cell type, very little is known regarding the mechanism which accurately controls mtDNA copy number in human. Exon 2 of the human POLG gene, encoding the catalytic subunit of the mitochondrial-specific DNA polymerase gamma, contains a CpG island, highly conserved in mice and human. Changes of DNA methylation at the POLG locus have been shown to modulate mtDNA copy number during cell differentiation in both mouse and human.

Methods

We have investigated the epigenetic modification of the POLG gene, by assessing the methylation level of its exon 2 using deep-Next Generation Sequencing analysis of bisulfite-treated DNA. Analysis were performed on various tissues at either postnatal or prenatal stages, on samples from carriers of mtDNA mutations, patients carrying two loss-of-function POLG mutations and controls.

Results

Very high methylation levels at POLG exon 2 were found (94±3%) and no variation was observed according to either developmental stage or tissue of origin, except for sperm samples for which lower methylation levels were found (80%). This high level of methylation was neither correlated with the presence of mtDNA mutations (94±1% of methylated alleles), nor with biallelic POLG mutations (93%±2%), even in tissues where a mtDNA depletion had been observed.

Conclusions

This study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified.

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Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy

Background

Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin.

Methods

We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica.

Results

We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.

Conclusions

Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.

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ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism

Background

Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role.

Methods

We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing.

Results

We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation. No effect on pexophagy was found.

Conclusions

Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent β-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease.

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Decreased telomere length in children with cartilage-hair hypoplasia

Background

Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features.

Methods

The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0–70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR.

Results

Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=–0.482, p<0.001) and non-carriers (r=–0.498, p<0.001), but not in patients (r=–0.236, p=0.107). In particular children (<18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics.

Conclusions

Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.

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One in three with cancer diagnosed as emergency had not seen GP, study finds

Nearly a third of patients with cancer diagnosed as an emergency presentation had not previously consulted their GP about relevant symptoms, a UK study has found.1Many patients with cancer have it...

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Therapeutic effects of Argyrin F in pancreatic adenocarcinoma

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Xi Chen, Khac Cuong Bui, Samarpita Barat, Mai Ly Thi Nguyen, Przemyslaw Bozko, Bence Sipos, Markus Kalesse, Nisar P. Malek, Ruben R. Plentz
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options. The proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. We hypothesize that his analogue Argyrin F (AF) may also prevent PDAC progression. We have used PDAC cells and engineered mice (Pdx1-Cre; LSL-KrasG12D; p53 ^lox/+) to assess AF anticancer activity. We analyzed the effect of AF on proliferation and epithelial plasticity using MTT-, wound healing-, invasion-, colony formation-, apoptosis-, cell cycle- and senescence assays. In vivo treatment with AF, Gemcitabine (G) and combinational treatment (AF + G) was performed for survival analysis. AF inhibited cell proliferation, migration, invasion and colony formation in vitro. AF impaired epithelial-mesenchymal transition (EMT), caused considerable apoptosis and senescence in a dose- and time-dependent manner and affected cell cycle G1/S phase transition. G treatment achieved longest mice survival, followed by AF + G and AF compared to vehicle group. However, AF + G treatment induced the largest reduction in tumor spread and ascites. In conclusion, we have demonstrated that AF prevents PDAC progression and that combined therapy was superior to AF monotherapy. Therefore, AF treatment might be useful as an additional therapy for PDAC.



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IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Asona J. Lui, Eric S. Geanes, Joshua Ogony, Fariba Behbod, Jordan Marquess, Kelli Valdez, William Jewell, Ossama Tawfik, Joan Lewis-Wambi
Interferon induced transmembrane protein 1 (IFITM1) belongs to a family of interferon stimulated genes (ISGs) that is associated with tumor progression and DNA damage resistance; however, its role in endocrine resistance is not known. Here, we correlate IFITM1 expression with clinical stage and poor response to endocrine therapy in a tissue microarray consisting of 94 estrogen receptor (ER)-positive breast tumors. IFITM1 overexpression is confirmed in the AI-resistant MCF-7:5C cell line and not found in AI-sensitive MCF-7 cells. In this study, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer are used to assess tumor growth and invasion in vivo. Lentivirus-mediated shRNA knockdown of IFITM1 in AI-resistant MCF-7:5C cells diminished tumor growth and invasion and induced cell death, whereas overexpression of IFITM1 in wild-type MCF-7 cells promoted estrogen-independent growth and enhanced their aggressive phenotype. Mechanistic studies indicated that loss of IFITM1 in MCF-7:5C cells markedly increased p21 transcription, expression and nuclear localization which was mediated by JAK/STAT activation. These findings suggest IFITM1 overexpression contributes to breast cancer progression and that targeting IFITM1 may be therapeutically beneficial to patients with endocrine-resistant disease.

Graphical abstract

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Mumps

Mumps: An acute (sudden, shortlived) viral illness that usually presents with inflammation of the salivary glands, particularly the parotid glands. A child with mumps often looks like a chipmunk with a full mouth due to the swelling of the parotids (the salivary glands near the ears).

Mumps can also cause inflammation of other tissues, most frequently the covering and substance of the central nervous system (meningoencephalitis), the pancreas (pancreatitis) and, after adolescence, the ovary (oophoritis) and the testis (orchitis). The testis is particularly susceptible to damage from mumps; the damage can lead to infertility.

Together with the likes of measles and chickenpox, mumps was once considered one of the inevitable infectious diseases of childhood. Since a mumps vaccine became available in 1967, the incidence of mumps has declined in the U.S., but there are still many underimmunized populations (for example, more blacks than whites have not yet been immunized).

Treatment is with rest and non-aspirin pain relievers to ease pain in swollen areas. Rarely, mumps can cause a form of meningitis, in which case hospitalization may be needed. Prevention is by immunization with the vaccine.

The origin of the word mumps is not clear. It may have to do with the English usage, now obsolete, of "mump" to mean a grimace. More probably, mumps comes from a colder climate, Iceland, where mumpa meant to fill the mouth too full.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Plenary Session 3

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Psoriasis Symposium

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Genital Dermatology

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Contact Dermatitis

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Global Dermatology Symposium

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Non-Melanoma Skin Cancer Symposium

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Plenary Session 4

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Surgery Update for General Dermatologists Session 2

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Art of Dermatology and Other Surprises

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Posters

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Registrars’ Forum

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Medical Dermatology Update

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Registrars and Fellows Update Session 3

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Acne

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Registrars and Fellows Update Session 2

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Surgery Update for General Dermatologists Session 1

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Dermatology Hospitalists

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A pseudotumour of the thigh: tensor fasciae latae muscle hypertrophy due to an underlying abductor tendon tear

We present a patient with an asymptomatic unilateral swelling of the anterolateral thigh. MRI showed hypertrophy of the tensor fasciae latae muscle due to an underlying gluteus minimus tendon tear.

Abductor tendon tears can present with swelling of the thigh due to secondary tensor fasciae latae muscle hypertrophy.

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Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks

Publication date: Available online 24 April 2017
Source:Cellular Signalling
Author(s): Suleiman W. Bahouth, Mohammed M. Nooh
Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted “barcodes” that recruit β-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or “barcodes” within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes. Given the vast number of diverse sequences in GPCR, several trafficking mechanisms for endosomal GPCR have been described. The majority of recycling GPCR, are sorted out of endosomes in a “sequence-dependent pathway” anchored around a type-1 PDZ-binding module found in their C-tails. For a subset of these GPCR, a second “barcode” imprinted onto specific GPCR serine/threonine residues by compartmentalized kinase networks was required for their efficient recycling through the “sequence-dependent pathway”. Mutating the serine/threonine residues involved, produced dramatic effects on GPCR trafficking, indicating that they played a major role in setting the trafficking itinerary of these GPCR. While endosomal SNX27, retromer/WASH complexes and actin were required for efficient sorting and budding of all these GPCR, additional proteins were required for GPCR sorting via the second “barcode”. Here we will review recent developments in GPCR trafficking in general and the human β1-adrenergic receptor in particular across the various trafficking roadmaps. In addition, we will discuss the role of GPCR trafficking in regulating endosomal GPCR signaling, which promote biochemical and physiological effects that are distinct from those generated by the GPCR signal transduction pathway in membranes.



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Sunitinib specifically augments glucose-induced insulin secretion

Publication date: Available online 24 April 2017
Source:Cellular Signalling
Author(s): Stefan Z. Lutz, Axel Ullrich, Hans-Ulrich Häring, Susanne Ullrich, Felicia Gerst
The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting β-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2μM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on β-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans.



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RNAi induced silencing of pathogenicity genes of Fusarium spp. for vascular wilt management in tomato

Abstract

The necessity to develop new strategies for the control of Fusarium wilt of tomato signifies the identification of pathogencity genes and ascertaining their role to use them as molecular tools for fungicide development or to develop transgenics. Semi-quantitative gene expression studies have identified two pathogenicity genes, FOW2 and chsV, reported as ZnII)2Cys6-type transcription regulator and class V chitin synthase, respectively, as potential ones for being secreted all the time. The roles of these genes in the pathogenicity of Fusarium oxysporum and F. solani have been established by RNA interference (RNAi)-induced silencing (knockdown). The silencing vector encoding hairpin RNA of each of the gene fragment was constructed in a two-step PCR-based cloning, and introduced into the fungal genomic DNA. Silencing of either of the genes resulted in less virulent fungal phenotypes with altered physiological characteristics like sporulation and growth on solid media and a reduction in mRNA expression. The results therefore demonstrate the applicability of these pathogenicity genes as useful molecular targets for exploitation in Fusarium wilt control in tomato.

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Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes [Research]

Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein–expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90-positive fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. In vivo, Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from SCC patients’ sera were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.—Overmiller, A. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., Luginbuhl, A., Curry, J., Harshyne, L. A., Wahl, J. K. III, South, A. P., Mahoney, M. G. Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes.

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Coupling fire behaviour modelling and stand characteristics to assess and mitigate fire hazard in a maritime pine landscape in Portugal

Abstract

Silvicultural models are often developed and applied without due consideration of fire modelling. Yet, this information is important for designing treatment options to lower fire hazard. We used the FlamMap software to assess potential fire behaviour under extreme fire weather conditions within a 10,881-ha maritime pine landscape in central Portugal, the Leiria National Forest. Models describing fire hazard and providing information to assess potential benefits of stand-level fuel treatments were developed based on fire behaviour simulation. These models use as predictors stand variables and may assist forest managers in identifying hazardous areas in pine forests. Models were built from a database comprising 94,207 unique combinations of variables to detect significant fire-landscape interactions between stand-level features and fire behaviour. A set of compatible models that express crown fire likelihood and tree mortality were fitted using logistic regression. Additionally, classification tree analysis was used to model the type of fire, fire suppression difficulty, and tree mortality. The results highlight the potential of this methodology to explain the influences of fuel- and stand-related variables on fire hazard. This approach allowed the identification of straightforward discrimination rules to implement fuel treatments that prevent crown fires, enhancing the effectiveness of fire suppression and thereby reducing fire damage in fire-prone forest stands. Results further allow developing specific hazard-reduction prescriptions based on common forest metrics without resorting to advanced simulation modelling.

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Programmed Death Ligand 1 Expression in Paired Non–Small Cell Lung Cancer Tumor Samples

Microabstract (≤60 words, accessible to a nonexpert audience. Should describe the area and reason for the study, the approach taken (including sample size aspects), the overall result, and the general significance of the findings); currently 58 We measured PD-L1 expression in paired tumor tissue samples collected at different dates and lesions from 91 patients with NSCLC. There was a statistically significant correlation in PD-L1 scores, with a 67% concordance rate when samples were categorized as PD-L1 positive and PD-L1 negative. These findings should be considered when selecting patients for clinical trials or treatment based on PD-L1 expression.

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Hypofractionated short-course radiotherapy in elderly patients with glioblastoma multiforme: an analysis of the National Cancer Database

Abstract

For elderly patients with glioblastoma multiforme (GBM), randomized trials have shown similar survival with hypofractionated short-course radiotherapy (SCRT) compared to conventionally fractionated long-course radiotherapy (LCRT). We evaluated the adoption of SCRT along with associated factors and survival in a national patient registry. Using the National Cancer Data Base (NCDB), we identified patients aged ≥70 years with GBM, diagnosed between 1998 and 2011, who received SCRT (34–42 Gy in 2.5–3.4 Gy fractions), or LCRT (58–63 Gy in 1.8–2.0 Gy fractions). Crude and adjusted hazard ratios (HR) were calculated using Cox regression modeling. 4598 patients were identified, 304 (6.6%) in the SCRT group and 4294 (93.4%) in the LCRT group. Median follow-up was 8.4 months. Median age was 78 versus 75 years, respectively (P < 0.0001). Patients who received SCRT had higher Charlson–Deyo comorbidity scores versus LCRT (score of ≥2: 16.9% vs. 10.8%, respectively; P = 0.006), and were more likely to be female (53.0% vs. 44.6%, P = 0.005). Patients who received SCRT were less likely to undergo chemotherapy (42.8% vs. 79.3%, P < 0.0001), more likely to undergo biopsy only (34.5% vs. 19.5%, P < 0.0001), and more likely to receive treatment at academic/research programs (49.2% vs. 37.2%, P = 0.0001). Median survival was 4.9 months versus 8.9 months, respectively (P < 0.0001). The survival detriment with SCRT persisted on multivariable analysis [HR 1.51 (95% CI: 1.33–1.73, P < 0.0001)], adjusting for age, gender, race, comorbidities, diagnosis year, facility type, surgery, and chemotherapy. In conclusion, hypofractionated SCRT was associated with worse survival compared to conventionally fractionated LCRT for elderly patients with GBM. Patients who received SCRT were older with worse comorbidities, and were less likely to undergo chemotherapy or resection.

In this analysis of elderly patients with glioblastoma multiforme registered in the National Cancer Data Base, hypofractionated short-course radiotherapy was associated with worse survival compared to conventionally fractionated long-course radiotherapy. Patients who received short-course radiotherapy were older, had more comorbidities, and were less likely to undergo chemotherapy or tumor resection.

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Elevated glypican-1 expression is associated with an unfavorable prognosis in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer in humans, with a 5-year survival rate of <5%. Recently, glypican-1 (GPC1)-expressing circulating exosomes were found to be a promising diagnostic tool for PDAC. However, the aberrant expression of GPC1 has not been systematically evaluated in large-scale clinical samples of PDAC. Here, we performed a comprehensive analysis of GPC1 mRNA and protein expression features. Included in this study were 178 PDAC patients from the cancer genome atlas (TCGA) and 186 subjects whose tissues were used in immunohistochemical staining assays. We demonstrated that GPC1 mRNA was silenced in normal pancreata; however, it was re-expressed in PDAC tissues probably because of the promoter hypomethylation. The GPC1 protein was barely expressed in the normal and adjacent noncancerous pancreata. In tumor tissues, 59.7% (111/186) of the detected samples showed positive expression. Notably, GPC1 was elevated in 63.6% (34/55) of early stage cases. High levels of GPC1 were associated with poorer differentiation and larger tumor diameters. Kaplan–Meier analysis showed a significant difference in overall survival between the groups categorized by GPC1 expression (P = 0.0028). Multivariate analyses indicated that GPC1 was a significant risk factor for poor overall survival with a 1.82-fold increase in the hazard ratio (P = 0.0022). In conclusion, during pancreatic tumorigenesis, GPC1 was ectopically expressed and served as an independent poor prognostic factor. Our findings highlighted the alluring prospect of GPC1 as an early diagnostic and prognostic marker as well as a therapeutic target for PDAC.

GPC1 protein expression was associated with poor prognosis in PDAC.

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MiR-145 inhibits human colorectal cancer cell migration and invasion via PAK4-dependent pathway

Abstract

MicroRNA-145 (miR-145), as a tumor-suppressive miRNA, has been demonstrated down-regulated in colorectal cancer (CRC) cells, and could inhibit CRC cells growth. However, the molecular pathway in which miR-145 modulates CRC malignant transformation has not been fully revealed. Here, we reported an intense correlation between the expressions of PAK4 and miR-145 in human CRC cell lines. Transwell assay verified overexpression of miR-145, as well as knockdown of PAK4, significantly suppressed cell migration and invasion ability. The impaired migration and invasion ability of SW1116 cells was affected through the down-regulation of phosphorylation level of LIMK1 and cofilin in a PAK4-dependent manner. Collectively, we have demonstrated that miR-145 suppressed CRC migration and invasion through PAK4 pathway, which provides an attractive microRNA-based therapeutic target for CRC.

The molecular mechanism by which miR-145, a tumor-suppressive miRNA, modulates colorectal cancer cells malignant transformation has been revealed in this manuscript.

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Overcoming Linsitinib intrinsic resistance through inhibition of nuclear factor-κB signaling in esophageal squamous cell carcinoma

Abstract

The aim of this study is to evaluate the efficacy of insulin-like growth factor 1 receptor (IGF-1R) inhibitor Linsitinib, in esophageal squamous cell carcinoma (ESCC), and to characterize special biomarker to screen Linsitinib-sensitive patients as well as explore the molecular-resistant mechanism to Linsitinib in ESCC. Our study evaluated the sensitivity of insulin-like growth factor 1 receptor (IGF-1R) inhibitor, Linsitinib in ESCC cells with MTT assay. After Linsitinib treatment, the expressions of downstream signaling molecules and apoptosis pathways were measured by western blot. And the antitumor effect of Linsitinib and JSH-23, an inhibitor of nuclear factor-κB transcriptional activity, was analyzed both as single agent and in combination in ESCC. Apoptosis, cell viability, and clonogenic survival analysis were also investigated. The sensitivity of Linsitinib was relatively variable in patient-derived primary ESCC cells as well as in human commercial cell lines. And the downstream AKT/mTOR and ERK signaling pathways were inhibited by Linsitinib, while phosphorylation level of NF-κB p65 was obviously activated to reduce apoptosis effect in Linsitinib-resistant cell lines. Most importantly, blockage of NF-κB activity by JSH-23 could sensitize resistant cells to Linsitinib treatment. Results from this study demonstrated that the intrinsic resistance to Linsitinib was predominantly mediated by NF-κB activation in ESCC. Moreover, combination of Linsitinib and JSH-23 as therapy provides a novel strategy to overcome resistance to Linsitinib in ESCC.

The intrinsic resistance of esophageal squamous cell carcinoma (ESCC) to Linsitinib may be mediated by NF-κB activation. A combined therapy that targets both IGF-1R and NF-κB provides a novel strategy to overcome resistance to Linsitinib in ESCC.

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MiR-372-3p promotes cell growth and metastasis by targeting FGF9 in lung squamous cell carcinoma

Abstract

The aim of this study was to study the role of miR-372-3p in lung squamous cell carcinoma (LSCC) cell proliferation and invasion by suppressing FGF9. RT-PCR was used to determine miR-372-3p and FGF9 mRNA expression in tissues and cells. Western blot was used to determine FGF9 expression in tissues and NCI-H520 cell line. Dual luciferase reporter gene assay was conducted to confirm that FGF9 can be directly targeted by miR-372-3p. MTT, colony formation assays were conducted to investigate the effects of ectopic miR-372-3p and FGF9 expression on NCI-H520 cell growth. Flow cytometry was used to analyze the influence of miR-372-3p and FGF9 expression on cell cycle distribution and apoptosis. Transwell assay was also conducted to see the effects of miR-372-3p and FGF9 expression on NCI-H520 cell invasiveness. MiR-372-3p was found significantly overexpressed in both LSCC tissues and cell lines, whereas FGF9 mRNA was found underexpressed in LSCC tissues. MiR-372-3p directly bound to wild-type FGF9 mRNA 3′UTR, therefore led to the reduction in FGF9 expression. The upregulation of FGF9 or the downregulation of miR-372-3p substantially retarded LSCC cell growth, mitosis, and invasion. MiR-372-3p enhanced LSCC cell proliferation and invasion through inhibiting FGF9.

MiR-372-3p enhanced LSCC cell proliferation and invasion through inhibiting FGF9.

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miR-148b inhibits glycolysis in gastric cancer through targeting SLC2A1

Abstract

Although the molecular biology of GC has been well characterized, early diagnostic biomarkers and effective therapeutic options in gastric cancer are still under investigation. Here, we found that miR-148b expression decreased in human gastric cancer tissues compared with matched adjacent nontumor tissues by q-PCR analysis and in situ hybridization. Further investigation revealed that overexpression of miR-148b limited glycolysis including glucose consumption, lactate production in gastric cancer cell lines BGC-823 and MKN45. Bioinformatics prediction uncovered that a dedicated transporters solute carrier family 2 member 1 (SLC2A1), also called GLUT1, was the direct target of miR-148b. The target effects were further confirmed by luciferase assay and western blot analysis. Besides, a reverse correlation was observed between relative SLC2A1 and miR-148b expression in human GC tissues compared with matched adjacent nontumor tissues. Subsequently, SLC2A1 suppression by SLC2A1 siRNA or specific inhibitor restricted the reduced effects of glycolysis mediated by miR-148b while SLC2A1 overexpression abrogated the effect of miR-148b on glycolysis. Our findings provided new evidence of miR-148b in GC development through restraining glycolysis, highlighting the role of miR-148b as a new target for GC treatment.

miR-148b inhibits GC development through restraining glycolysis, highlighting the role of miR-148b as a new target for GC treatment.

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The effective introduction of Lifebox pulse oximetry to Malawi

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Lifebox pulse oximeter implementation in Malawi: evaluation of educational outcomes and impact on oxygen desaturation episodes during anaesthesia

Summary

Pulse oximetry is an essential monitor for safe anaesthesia but is often not available in low-income countries. The aim of this study was to determine whether the introduction of pulse oximetry with training was feasible and could reduce the incidence of oxygen desaturation during anaesthesia in a low-income country. Pulse oximeters were donated, with training, to 83 non-physician anaesthetists in Malawi. Knowledge was tested immediately before and after training and at follow-up. Providers were asked to record the lowest peripheral oxygen saturation (SpO₂) for the first 100 cases anaesthetised after training. The primary clinical outcome was the proportion of cases with an oxygen desaturation event (SpO₂ < 90%). Seventy-seven of 83 (93%) participants completed all pre- and post-training tests. Pulse oximetry knowledge improved after training from a median (IQR [range]) score of 39 (37–42 [28–48]) to 44 (42–46 [35–50]) and this knowledge was maintained for 8 months (p < 0.001). Oxygen saturation data and provider responses were recorded for 4772 cases. The proportion of oxygen desaturation episodes decreased from 17.2% to 6.5%, representing a 36% reduction in the odds of an oxygen desaturation event in the second 50 cases compared with the first 50 (OR 0.64, 95%CI 0.50–0.82, p < 0.001). We conclude that donation of pulse oximeters, with training, in Malawi was feasible, improved knowledge and reduced the incidence of oxygen desaturation events.

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Scrotal lymphangiectasia following scrofuloderma

Debabrata Bandyopadhyay

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):397-398



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Seborrheic melanosis: An entity worthy of mention in dermatological literature

Shyam B Verma, Resham J Vasani, Laxmisha Chandrashekar, Mary Thomas

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):285-289



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Leaving a mark: Multiple geometric areas of alopecia

Hima Gopinath, Maria Kuruvila, Ramadas Naik, Suja Sreedharan

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):373-375



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Autophagy: A brief overview in perspective of dermatology

Rahul Nagar

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):290-297

Autophagy, literally meaning “self-eating,” is an intracellular catabolic process of delivering cytosol and/or its specific content to the lysosomes for degradation.The resulting macromolecular constituents are recycled and utilized again by the cells. Basal level autophagy plays an important role in cellular homeostasis through the elimination of the old or damaged organelles, as well as aggregated intracellular proteins. Autophagy refers to sequestration of intact organelles along with a portion of cytosol, into a double-or multi-membrane structure known as phagophore, which elongates, and after closure, forms a vesicular structure known as the autophagosome. Subsequently, the mature autophagosome fuses with a lysosome, thereby forming a single membrane structure, an autolysosome. Autophagy plays a critical role in inflammation, autoimmunity and cellular differentiation. Skin serves as the first line of defense against a variety of environmental insults and autophagy is thought to be a form of an endogenous defense mechanism against such environmental derangements. Autophagy has been linked with keratinocyte differentiation and melanocyte survival, as well as with the pathogenesis of diverse skin disorders including systemic lupus erythematosus, systemic sclerosis, psoriasis, vitiligo, infectious skin diseases and cancer. Autophagy has been one of the most studied phenomena in cell biology and pathophysiology, and given its broad clinical implications, has become a major target for drug discovery. The last decade has seen a substantial upsurge in autophagy-related research and publications; still, the dermatology literature appears to be less initiated. Autophagy will probably change our understanding of dermatological disorders/medicines. Hence, a basic knowledge of autophagy is a prerequisite to understand the developments in the field of autophagy-related research.

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Erratum: Digital volumetric measurement of cutaneous leishmaniasis lesions: Blur estimation method

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):414-414



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Update on etiopathogenesis and treatment of Acne

Yasmeen Jabeen Bhat, Insha Latief, Iffat Hassan

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):298-306

Acne, the most common skin disease, is a disorder of pilosebaceous units that affects adolescents mainly and adults occasionally. The pathogenesis is multifactorial. Besides genetic predisposition, other major factors include the action of androgens, pro-inflammatory lipids acting as ligands of peroxisome proliferator-activated receptors in the sebocytes, toll-like receptor-2 acting on keratinocytes, recognition of pathogen-associated molecular patterns, cytokines, chemokines, inflammasomes, neuroendocrine regulatory mechanisms, diet and other pro-inflammatory targets implicated in the activation of immune detection and response. Most of these factors converge on mammalian target of rapamycin complex1 (mTORC1) activation which is further enhanced by the nutrient signaling of Western diet. This multitude of pathogenic factors has led to a new armamentarium of drugs for the treatment of acne. Topical anti-androgens, insulin-like growth factor-1 inhibitors, peroxisome proliferator-activated receptor-modulators, acetylcholine inhibitors, topical retinoic acid metabolism-blocking agents, vitamin D analogues, antimicrobial peptides, interleukin-1α and interleukin-1β blockers and immunotherapy are some of the novel treatment options.

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Dermatoscopic evaluation of three cases of nevus lipomatosus cutaneous superficialis

Keshavamurthy Vinay, Gitesh U Sawatkar, Uma Nahar Saikia, Muthu Sendhil Kumaran

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):383-386



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Digital volumetric measurement of cutaneous leishmaniasis lesions: Blur estimation method

Ahmad Reza Taheri, Saeid Alikhani, Ameneh Sazgarnia, Maryam Salehi, Sadegh Vahabi Amlashi

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):307-311

Background: Cutaneous leishmaniasis is a common parasitic infestation in Iran. With recent advantages in digital imaging, we have devised a novel non-contact objective method of measuring lesions. Aim: The aim of the study was to design a software system that analyzes images of cutaneous leishmaniasis lesions, objectively assess and monitor volume. Methods: A photographic technique along with an image processing algorithm was applied to extract a three-dimensional map of the lesion from a simple two-dimensional picture. This method recovers depth on the basis of blur estimation. A macro lens with a low depth of field was used to blur the objects out of focus. To assess and compare the results, a polymer mold of the corresponding lesion was made and filled with liquid. The volume of liquid corresponded to the volume of the lesion. A total of thirty-seven patients were enrolled, and 48 lesions were analyzed. Results: The mean volume measured by image processing was 159 μl (range: 8–685 μl), in comparison to an average of 170 μl (range: 6–800 μl) obtained from the molds. This was not significantly different. Statistical analysis by the Pearson correlation test showed a 'very good fit' correlation between these measured volumes (P < 0.001, r = 0.938). Limitation: The location and height of lesions were two important limitations in implementing this technique. If the lesion location is in the curvature region of body or the lesion height is less than 1 mm or more than 1 cm, this method will lose precision and accuracy. Conclusion: Image processing with blur estimation technique is an accurate and precise method to measure the volume of lesions in cutaneous leishmaniasis.

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Giant, mutilating facial lupus vulgaris due to long-term misdiagnosis

Li Xue, Wei Li, Xiaoyan Lv, Li Li

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):412-412



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Effectiveness, safety and tolerability of cyclosporine versus supportive treatment in Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis: A record-based study

Swosti Mohanty, Anupam Das, Anupama Ghosh, Amrita Sil, Ramesh Chandra Gharami, Debabrata Bandyopadhyay, Nilay Kanti Das

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):312-316

Background: Toxic epidermal necrolysis and Stevens–Johnson syndrome comprise life-threatening, drug-induced mucocutaneous disease spectrum. Interest in cyclosporine, a calcineurin inhibitor that can block the function of T-cells, has increased with the discovery of the importance of granulysin in apoptosis in toxic epidermal necrolysis. In our hospital, cyclosporine is given to Stevens–Johnson syndrome/toxic epidermal necrolysis patients as an adjunctive therapy. Aims: This study is an observational, record-based study comparing the effectiveness and safety of patients receiving cyclosporine versus only supportive therapy. Methodology: Medical records as bed-head tickets and laboratory investigation reports of Stevens–Johnson syndrome/toxic epidermal necrolysis patients admitted in the hospital over a period of 1 year were collected. Data regarding clinico-demographic profile, suspected drug causing Stevens–Johnson's syndrome/toxic epidermal necrolysis, SCORTEN, body surface area involved, treatment received and outcome were obtained. Results: Twenty-eight patients were analyzed. Nineteen belonged to the cyclosporine group (supportive treatment + cyclosporine), nine to supportive treatment only group. Among the suspected drugs, antiepileptics formed the major group (28.6%). Five patients in the supportive only group and one in the cyclosporine group died. Time for stabilization and reepithelialization and duration of recovery were significantly lower in the cyclosporine group (P < 0.001, P= 0.007, P= 0.01, respectively). The standardized mortality ratio was 0.32 in cyclosporine group which is nearly 3.3 times lower than the only supportive treatment. Limitations: As it was a record-based study, certain confounding factors (serum blood urea nitrogen) could not be adjusted. Conclusion: Cyclosporine (5 mg/kg/day) for 10 days from onset of Stevens–Johnson syndrome/toxic epidermal necrolysis may decrease the risk of dying, may provide faster healing of lesions and might lead to early discharge from hospital.

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Unilateral monomorphic hypopigmented macules: A variant of Darier disease

Jagdish Sakhiya, Neha C Virmani, Yugal K Sharma, Uday Khopkar, Shamsudheen Karuthedath Vellarikkal

Indian Journal of Dermatology, Venereology, and Leprology 2017 83(3):369-371



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An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure [Protein Structure and Folding]

Protein aggregation resulting from disruptions in proteostasis in the brains of patients with chronic mental illness is an emerging theme particularly in the study of schizophrenia. For example, proteins such as Disrupted in Schizophrenia 1 (DISC1) and dysbindin-1B are present in insoluble aggregates, detectable within brain homogenates from such patients. Using an epitope discovery and proteomics approach to compare post-mortem brain samples from schizophrenia patients and controls, we recently identified TRIO-Binding Protein 1 (TRIOBP-1, also known as Tara) as another aggregation-associated protein. We hypothesized that TRIOBP-1 aggregation likely arises from a specific subcellular process, and therefore that it should be possible to identify regions of the TRIOBP-1 protein that are essential for its aggregation. Here, we probed the domain organization of TRIOBP-1, via solubility and stability testing of recombinant protein fragments, and found that it possesses two distinct coiled-coil domains: the central and C-terminal domains. The central domain inhibited the de-polymerization of F-actin and was also responsible for TRIOBP-1 oligomerization and, along with an N-terminal Pleckstrin homology domain, affected neurite outgrowth. In neuroblastoma cells, the aggregation propensity of TRIOBP-1 arose from its central domain, and a short linker region, narrowed to within amino acids 324-348, between its first two coiled-coils was identified as being essential for TRIOBP-1 aggregate formation. We conclude that TRIOBP-1 appears to aggregate via one or more cellular mechanisms, which have the potential to be of physiological relevance for the biological processes underlying the development of chronic mental illness.

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Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab [Protein Structure and Folding]

Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically-approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE.

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A Wnt/Notch/Pax7 signaling network supports tissue integrity in tongue development [Developmental Biology]

The tongue is one of the major structures involved in human food intake and speech. Tongue malformations such as aglossia, microglossia, and ankyloglossia are congenital birth defects, greatly affecting individuals' quality of life. However, the molecular basis of the tissue-tissue interactions that ensure tissue morphogenesis to form a functional tongue remains largely unknown. Here we show that ShhCre-mediated epithelial deletion of Wntless (Wls), the key regulator for intracellular Wnt trafficking, leads to lingual hypoplasia in mice. Disruption of epithelial Wnt production by Wls deletion in epithelial cells led to a failure in lingual epidermal stratification and, loss of the lamina propria and the underlying superior longitudinal muscle in developing mouse tongues. These defective phenotypes resulted from a reduction in epithelial basal cells positive for the basal epidermal marker protein P63, and from impaired proliferation and differentiation in connective tissue and paired box 3 (Pax3)- and Pax7-positive muscle progenitor cells. We also found that epithelial Wnt production is required for activation of the Notch signaling pathway, which promotes proliferation of myogenic progenitor cells. Notch signaling in turn negatively regulated Wnt signaling during tongue morphogenesis. We further show that Pax7 is a direct Notch target gene in the embryonic tongue. In summary, our findings demonstrate a key role for the lingual epithelial signals in supporting the integrity of the lamina propria and muscular tissue during tongue development and that a Wnt/Notch/Pax7 genetic hierarchy is involved in this development.

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IL-1{beta} transcriptionally activates hepcidin by inducing C/EBP{delta} expression in hepatocytes [Molecular Bases of Disease]

Hepcidin is a liver-derived hormone that negatively regulates serum iron levels and is mainly regulated at the transcriptional level. Previous studies have clarified that in addition to hepatic iron levels, inflammation also efficiently increases hepatic hepcidin expression. The principle regions responsible for efficient hepcidin transcription are bone morphogenetic protein-responsive elements (BMP-REs) 1 and 2 as well as the signal transducer and activator of transcription 3-binding site (STAT-BS). Here, we show that the proinflammatory cytokine interleukin-1β (IL-1β) efficiently increases hepcidin expression in human HepG2 liver-derived cells and primary mouse hepatocytes. The region responsible for IL-1β-mediated hepcidin transcription was the putative CCAAT-enhancer-binding protein (C/EBP)-binding site (C/EBP-BS) at the hepcidin promoter spanning nt -329 to nt -320. IL-1β induces the expression of C/EBPδ but neither C/EBPα nor C/EBPβ in hepatocytes, and C/EBPδ bound to the C/EBP-BS in an IL-1β-dependent manner. Lipopolysaccharide (LPS) induced the expression of IL-1β in Kupffer cells and hepatocytes in the mouse liver; furthermore, the culture supernatants from the macrophage-like cell line RAW264.7 treated with LPS potentiated the stimulation of hepcidin expression in hepatocytes. The present study reveals that 1) inflammation induces IL-1β production in Kupffer cells and hepatocytes, 2) IL-1β increases C/EBPδ expression in hepatocytes, and 3) induction of C/EBPδ activates hepcidin transcription via the C/EBP-BS that has been uncharacterized yet. In cooperation with the other pathways activated by inflammation, IL-1β pathway stimulation leads to excess production of hepcidin, which could be causative to anemia of inflammation.

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RANKL Cytokine Enhances TNF-induced Osteoclastogenesis Independently of TNF Receptor Associated Factor (TRAF) 6 by Degrading TRAF3 in Osteoclast Precursors [Cell Biology]

Cytokines, including receptor activator of nuclear factor kappa B ligand (RANKL) and TNF, induce increased osteoclast (OC) formation and bone loss in postmenopausal osteoporosis and inflammatory arthritides. RANKL and TNF can independently induce OC formation in vitro from WT OC precursors via TNF receptor-associated factor (TRAF) adaptor proteins, which bind to their receptors. Of these, only TRAF6 is required for RANKL-induced osteoclastogenesis in vitro. However, the molecular mechanisms involved remain incompletely understood. Here, we report that RANKL induced formation of bone-resorbing OCs from TRAF6-/- OC precursors when cultured on bone slices, but not on plastic. The mechanisms involved increased TNF production by TRAF6-/- OC precursors resulting from their interaction with bone matrix and release of active TGF beta from the resorbed bone, coupled with RANKL-induced autophagolysosomal degradation of TRAF3, a known inhibitor of OC formation. Consistent with these findings, RANKL enhanced TNF-induced OC formation from TRAF6-/- OC precursors. Moreover, TNF induced significantly more OCs from mice with TRAF3 conditionally deleted in myeloid lineage cells, and it did not inhibit RANKL-induced OC formation from these cells. TRAF6-/- OC precursors that over-expressed TRAF3 or were treated with the autophagolysosome inhibitor, chloroquine, formed significantly fewer OCs in response to TNF alone or in combination with RANKL. We conclude that RANKL can enhance TNF-induced OC formation independently of TRAF6 by degrading TRAF3. These findings suggest that preventing TRAF3 degradation with drugs like chloroquine could reduce excessive OC formation in diseases in which bone resorption is increased in response to elevated production of these cytokines.

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G protein Gi1 exhibits basal coupling but not preassembly with G protein-coupled receptors [Cell Biology]

The Gi/o protein family transduces signals from a diverse group of G protein-coupled receptors (GPCRs). The observed specificity of Gi/o-GPCR coupling and high rate of Gi/o signal transduction have been hypothesized to be enabled by existence of stable associates between Gi/o proteins and their cognate GPCRs in the inactive state (Gi/o-GPCR preassembly). To test this hypothesis, we applied the recently developed technique of two-photon polarization microscopy (2PPM) to Gαi1 subunits labeled with fluorescent proteins and four GPCRs (the α2A-adrenergic receptor (α2A-AR), γ-aminobutyric acid receptor B (GABAB), cannabinoid receptor type 1 (CB1R) and dopamine receptor type 2 (D2R)). Our experiments with non-dissociating mutants of fluorescently labeled Gαi1 subunits (exhibiting impaired dissociation from activated GPCRs) showed that 2PPM is capable of detecting GPCR-G protein interactions. 2PPM experiments with non-mutated fluorescently labeled Gαi1 subunits and α2A-AR, GABAB or D2R receptors did not reveal any interaction between the Gi1 protein and the non-stimulated GPCRs. In contrast, non-stimulated CB1R shows interaction with the Gi1 protein. Further experiments revealed that this interaction is caused solely by CB1R basal activity; no preassembly between CB1R and the Gi1 protein could be observed. Our results demonstrate that four diverse GPCRs do not preassemble with non-active Gi1. However, we also show that basal GPCR activity allows interactions between non-stimulated GPCRs and Gi1 (basal coupling). These findings suggest that Gi1 interacts only with active GPCRs, and that the well-known high speed of GPCR signal transduction does not require preassembly between G proteins and GPCRs.

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The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalianTarget of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type.

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A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer

Triple-negative breast cancer (TNBC) treatment offers only limited benefits, and it is very relevant given the significant number of deaths that it causes. DNA repair pathways can enable tumor cells to survive DNA damage that is induced by chemotherapeutic or radiation treatments. Histone deacetylase inhibitors (HDACi) inhibited DNA repair proteins. However, the detailed mechanisms for this inhibition remain unclear. In the present study, we investigated whether a newly developed HDACi, TMU-35435, could enhance etoposide cytotoxicity by inhibiting DNA repair proteins in triple-negative breast cancer.

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A Perillyl Alcohol-Conjugated Analog of 3-Bromopyruvate Without Cellular Uptake Dependency on Monocarboxylate Transporter 1 and With Activity in 3-BP-Resistant Tumor Cells

The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218. NEO218 was synthesized by covalently conjugating 3-BP to perillyl alcohol (POH), a natural monoterpene.

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microRNA-7 impairs autophagy-derived pools of glucose to suppress pancreatic cancer progression

Pancreatic cancer commonly addicts to aerobic glycolysis, and abnormally activates autophagy to adapt the stringent metabolic microenvironment. microRNA-7 (miR-7) was supposed to modulate various gastrointestinal cancer progression. We wonder whether miR-7 could destroy the reprogrammed metabolic homeostasis in pancreatic cancer via modulating the level of autophagy, and further affect tumor proliferation and survival. Herein, we first reported that pancreatic cancer could take advantage of autophagy as a survival strategy to provide essential glucose required for glycolysis metabolism.

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The ErbB family and androgen receptor signaling are targets of Celecoxib in prostate cancer

Inflammation plays a central role in prostate cancer (PCa) development through significant crosstalk between the COX2- ErbB family receptor network and androgen receptor (AR)-EGFR signaling pathways. The purpose of this work was to determine the ability of the COX-2 inhibitor Celecoxib to modulate the EGFR-AR signaling pathway in androgen-dependent PCa cells and to provide a rationale for its beneficial use in chemopreventive strategies. Functional studies of Celecoxib activity were performed on LNCaP prostate cancer cells.

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Spatial and Temporal Patterns of Nasopharyngeal Carcinoma Mortality in China, 1973–2005

We fitted generalized linear models using data from three national retrospective surveys on cause of death in China to explore the spatial and temporal patterns of nasopharyngeal carcinoma (NPC) mortality over the period 1973 to 2005. The results suggest that there was a significant decrease in NPC mortality in China over time (p<0.0001), the mortality rate ratio (RR) for the two later time periods were 0.59 (95% CI: 0.55–0.64) for 1990–1992 and 0.42 (95% CI: 0.39–0.45) for 2004–2005 compared to that of 1973–1975.

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Safety of endoscopic sinus surgery in children with cystic fibrosis

Data on the safety of endoscopic sinus surgery (ESS) are limited in children with cystic fibrosis (CF). We used a multi-institutional surgical registry to examine ESS outcomes in children with CF.

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Otorhinolaryngologic Manifestations of Hartsfield Syndrome: Case Series and Review of Literature

Diagnosis of Hartsfield syndrome includes recognition of three distinct clinical anomalies: holoprosencephaly, ectrodactyly, and bilateral cleft-lip and palate syndrome. A family including three male siblings all affected by Hartsfield syndrome presented to our institution for care. An autosomal dominant variant in Fibroblast Growth Factor Receptor 1 (FGFR1) was identified. This report focuses on otorhinolaryngologic manifestationsof Hartsfield syndrome, previously undescribed, including midline defects of holoprosencephaly, bilateral cleft-lip and palate, retrognathia, gastroesophageal reflux disease, external ear anomalies, eustachian tube dysfunction, and midface abnormalities, in addition to multidisciplinary, long-term management strategies.

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The effect of perioperative dexamethasone dosing on post-tonsillectomy hemorrhage risk

Dexamethasone is currently recommended for routine prophylaxis against postoperative nausea and vomiting after tonsillectomy procedures. However, some studies have raised concern that dexamethasone use may lead to higher rates of post-tonsillectomy hemorrhage. Our objective was to determine whether higher doses of dexamethasone administered perioperatively during tonsillectomy procedures are associated with an increased risk of secondary post-tonsillectomy hemorrhage.

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The effect of blocking Notch signaling by γ-secretase inhibitor on allergic rhinitis

This study aimed to investigate the effect of blocking Notch signaling by γ-secretase inhibitor (GSI) on allergic rhinitis.

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The comparative study of resonance disorders for Vietnamese and Korean cleft palate speakers using nasometer

Abstract

Background

Nasalance is used to evaluate the velopharyngeal incompetence in clinical diagnoses using a nasometer. The aim of this study is to find the nasalance differences between Vietnamese cleft palate children and Korean cleft palate children by measuring the nasalance of five oral vowels.

Methods

Ten Vietnamese cleft palate children after surgery, three Vietnamese children for the control group, and ten Korean cleft palate children after surgery with the same age participated in this experimentation. Instead of Korean control, the standard value of Korean version of the simplified nasometric assessment procedures (kSNAP) was used.

Result

The results are as follows: (1) the highest nasalance score among the Vietnamese normal vowels is the low vowel /a/; however, that of Korean normal vowels is the high vowel /i/. (2) The average nasalance score of Korean cleft palate vowels is 18% higher than that of Vietnamese cleft palate vowels. There was a nasalance score of over 45% among the vowels /e/ and /i/ in Vietnamese cleft palate patients and /i/, /o/, and /u/ in Korean cleft palate patients.

Conclusion

These different nasalance scores of the same vowels seem to cause an ethnic difference between Vietnamese and Korean cleft palate children.

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Assessment and spontaneous healing outcomes of traumatic eardrum perforation with bleeding

This study investigated the influence of the degree of bleeding from the remnant eardrum on the spontaneous healing of human traumatic tympanic membrane perforations (TMPs).

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UK does more to protect marine areas overseas than at home

The government is failing to designate marine protected areas off its coast as promised, says a parliamentary report

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Inhibition of TGF-β Signaling Promotes Expansion of Human Epidermal Keratinocytes in Feeder Cell Co-culture

ABSTRACT

Cultured epidermal autografts have been used worldwide since 1981 for patients with extensive third-degree burn wounds and limited skin donor sites. Despite significant progress in techniques toward improving clinical outcome of skin grafts, the long in vitro preparation time of cultured autografts has remained a major factor limiting its widespread use. Here, we show that pharmacological inhibition of TGF-β signaling promotes the expansion of human epidermal keratinocytes (HEKs) with high proliferative potential in co-cultures with both murine 3T3-J2 cells and human feeder cells, including dermal fibroblasts and preadipocytes. In contrast, TGF-β signaling inhibition does not enhance the growth of HEKs in a serum- and feeder-free condition, an alternative approach to propagate HEKs for subsequent autograft production. Our results have important implications for the use of TGF-β signaling inhibition as a viable therapeutic strategy for improving Green's methodology and for more efficient production of customized skin autografts with human feeder cells. This article is protected by copyright. All rights reserved.

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Anti-inflammatory, Antipyretic, and Antinociceptive Effects of a Cressa cretica Aqueous Extract

Planta Med
DOI: 10.1055/s-0043-108650

Cressa cretica is a widely grown halophytic plant traditionally used for the treatment of different ailments. Previous investigations reported its biological activity on a wide spectrum of diseases. In this study, in vivo antinociceptive, anti-inflammatory, and antipyretic activities of C. cretica aqueous extract whole plant were evaluated. In addition, the total polyphenol content, the total flavonoid content, and the chemical characterization of the extract were performed. C. cretica showed writhing inhibition in acetic acid-induced peripheral nociception of 43 and 48 % at doses of 50 and 100 mg/kg, respectively. The same doses increased latency time in a hot plate model of central analgesia by 66 and 78 % compared to the control group, respectively. The acute anti-inflammatory effect of the extract was explored in the carrageenan-induced rat hind paw test. The inhibition of paw volume was better than that of the standard drug indomethacin. C. cretica significantly decreased rectal temperature in the rats injected with Brewerʼs yeast. C. cretica aqueous extract showed both central and peripheral antinociceptive activities and was effective as an anti-inflammatory and antipyretic. Phenolic compounds, including chlorogenic acids and flavonol glycosides, were identified by HPLC-PDA-ESI-MS techniques. These findings indicate the medicinal importance of this traditionally used plant as a therapeutic remedy for different ailments.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Potential of Bryophyllum pinnatum as a Detrusor Relaxant: An in Vitro Exploratory Study

Planta Med
DOI: 10.1055/s-0043-109097

An earlier prospective, randomised, placebo-controlled clinical trial had suggested that Bryophyllum pinnatum might have potential in the treatment of overactive bladder. Here we investigated the effects of B. pinnatum leaf press juice, fractions enriched in flavonoids and bufadienolides, and a flavonoid aglycon mixture and individual aglycons on detrusor contractility as a major target in overactive bladder treatment. The strength of the detrusor contractions was investigated using porcine muscle strips stimulated with KCl. B. pinnatum leaf press juice increased the contraction force of muscle strips. Treatment with the flavonoid-enriched fraction had almost no effect on contractility, while the bufadienolide-enriched fraction and flavonoid aglycons led to a concentration-dependent lowering of the contraction force. The data indicate that several components of B. pinnatum leaf press juice may contribute to the inhibitory effect on detrusor contractility, which in turn provides support to overactive bladder treatment with B. pinnatum.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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UK does more to protect marine areas overseas than at home

The government is failing to designate marine protected areas off its coast as promised, says a parliamentary report

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A Diagnostic Microdosing Approach to Investigate Platinum Sensitivity in Non-Small Cell Lung Cancer

Abstract

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts—the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [¹⁴C]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC₅₀ values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R²=0.95, p<0.0001) and correlated with IC₅₀ across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p=0.02 and p=0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK), and [¹⁴C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [¹⁴C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [¹⁴C]carboplatin formulation for the microdose was 10⁷ dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response. This article is protected by copyright. All rights reserved.

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