Synthesis of carbohydrate capped silicon nanoparticles and their reduced cytotoxicity, in vivo toxicity, and cellular uptake

The development of smart targeted nanoparticles (NPs) that can identify and deliver drugs at a sustained rate directly to cancer cells may provide better efficacy and lower toxicity for treating primary and advanced metastatic tumors. Obtaining knowledge of the diseases at the molecular level can facilitate the identification of biological targets. In particular, carbohydrate‐mediated molecular recognitions using nano‐vehicles are likely to increasingly affect cancer treatment methods, opening a new area in biomedical applications. Here, silicon NPs (SiNPs) capped with carbohydrates including galactose, glucose, mannose, and lactose are successfully synthesized from amine terminated SiNPs. The MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] analysis shows an extensive reduction in toxicity of SiNPs by functionalizing with carbohydrate moiety both in vitro and in vivo. Cellular uptake is investigated with flow cytometry and confocal fluorescence microscope. The results show the carbohydrate capped SiNPs can be internalized in the cells within 24 h of incubation, and can be taken up more readily by cancer cells than noncancerous cells. Moreover, these results reinforce the use of carbohydrates for the internalization of a variety of similar compounds into cancer cells

Messverfahren für die pulverbettbasierte additive Fertigung zur Sicherstellung der Konformität mit geometrischen Produktspezifikationen

Due to insufficient standards for in-process manufacturing and quality control, decisive prerequisites are still missing in additive manufacturing that are necessary for industrial series production. In addition to numerous efforts of various standardisation committees to standardise the additive manufacturing process gradually, the present work also deals with basic scientific methods for referenced in-process monitoring as well as derived approaches for the analysis of geometric manufacturing and measurement deviations. The aim is to contribute to a consistent procedure for process monitoring to ensure the conformity of geometric product specifications in additive manufacturing. In order to correct the detected geometric deviations during the process with appropriate control strategies, an exact allocation is necessary to be able to assign the measurement data precisely at any time of the manufacturing process in addition to a sufficient controllability. For a better assessment of the required comprehensive observability of the measured variables, a novel referencing concept for the position determination of the melt pool contours is provided, based on a powder bed based selective laser beam melting process. The acquisition of four referencing pipes, integrated in the powder bed, cause a shortening of the measuring circuit and increase the accuracy of the measurement data acquisition. This allows a better allocation of the causes of manufacturing and measurement deviations. Based on the referenced contour analysis of the melt pool and the detection of the shining heat radiation of the component contours after powder application, a metrological verification of lateral contour displacements is provided.In der additiven Fertigung fehlen aufgrund unzureichender Standards zur prozessbegleitenden Fertigungs- und Qualitätskontrolle derzeit entscheidende Voraussetzungen, die für eine industrielle Serienproduktion erforderlich sind. Neben zahlreichen Bemühungen verschiedener Normungsgremien den additiven Fertigungsprozess schrittweise zu standardisieren, beschäftigt sich auch die vorliegende Arbeit mit grundlagenwissenschaftlichen Methoden zur referenzierten in-Prozess Überwachung sowie daraus abgeleiteten Ansätzen zur Analyse geometrischer Fertigungs- und Messabweichungen. Dadurch soll ein Beitrag für ein einheitliches Vorgehen bei der Prozessüberwachung zur Sicherstellung der Konformität geometrischer Produktspezifikationen in der additiven Fertigung geleistet werden. Um die erfassten geometrischen Abweichungen prozessbegleitend mit entsprechenden Regelstrategien zu korrigieren, bedarf es neben einer ausreichenden Steuerbarkeit der Fertigungsanlage einer exakten Zuordenbarkeit der Messdaten zu jedem Zeitpunkt des Fertigungsprozesses. Um diese geforderte Beobachtbarkeit der Messgrößen besser beurteilen zu können, wird ein neuartiges Referenzierungskonzept zur exakten Lagebestimmung der Schmelzbadkonturen am Beispiel eines pulverbettbasierten selektiven Laserstrahlschmelzprozesses bereitgestellt. Durch die Erfassung von vier im Pulverbett integrierten Referenzierungsrohren kann mit einer Verkürzung des Messkreises die Genauigkeit der Messdatenerfassung erhöht werden. Dadurch ist eine bessere Zuordenbarkeit der Entstehungsursachen von Fertigungs- und Messabweichungen möglich. Basierend auf der referenzierten Konturanalyse des Schmelzbades und der Erfassung der durchschimmernden Wärmestrahlung der Bauteilkonturen nach dem Pulverauftrag, werden messtechnische Nachweise lateraler Konturverlagerungen erbracht

Auswirkungen des Anti-Interleukin-17A-Antikörpers Secukinumab auf das klinische Bild und die Lebensqualität von Patienten mit Psoriasis und Psoriasis-Arthritis

Objective: Psoriasis (Pso) and psoriasic arthritis (PsA) belong to the most prevalent chronic inflammatory diseases with high personal and economic impact. Based on latest research about the pathogenesis of PsA and Pso and the central role of Interleukin 17A, the IL-17 inhibitor Secukinumab has been developed. The objective is to evaluate the influence of Secukinumab on the clinical signs and quality of life of patients with Pso and PsA. Methods: This thesis is based on data of the prospective open-label study PSARTROS, where patients with Pso (n = 20) and patients with psoriatic arthritis (n = 20) were treated with 300 mg Secukinumab for 24 weeks. On the one hand clinical assessments such as psoriatic lesions and swollen and tender joint counts were recorded to validate therapy outcome. On the other hand patient reported outcome measures were taken to evaluate the patients quality of life. Results: A total of 50,0 % of patients with Pso and 35,3 % of patients with PsA achieved a 90 percent reduction in Psoriasis Area and Severity Index (PASI 90) after 24 weeks. Patients with PsA experience a significant reduction (p ≤ 0,05) of tender and swollen joints. Treatment with Secukinumab leads to a significant improvement of quality of life in both groups of patients, in the sense of, for example, a reduction of discomfort or shame or an increase in physical resilience. To make quality of life less abstract, the two subgroups psyche and physical function were regarded seperately. In the study, Pso patients report significant improvement in their psychological distress, which is foregrounded by visible skin lesions. The mean DLQI score drops from 10.7 points to an average of 4.5 points after twelve weeks. PsA patients primarily see themselves limited by decreased physical functionality and lack of resilience due to joint pain, which also improves significantly over the course of the study. Regarding the EULAR response criteria, 69% of PsA patients showed a good response to the study medication. 52.9% of PsA patients achieved a 50% and 35.3% of PsA patients even a 70% reduction in ACR criteria after 24 weeks. No serious adverse events were reported during treatment with secukinumab in the course of the study, but mild to moderate adverse events occurred in 36% of patients. Implications: The evaluation of the success of the therapy takes into account not only the clinical symptoms, but also the subjective perception of the disease and the patient's quality of life. For PsA patients, joint pain and the physical limitations in everyday life play a role in particular; for Pso patients, skin lesions and the associated psychological stress are most likely to play a role. The patient groups of both syndromes benefit in terms of their clinical symptoms and quality of life by treatment with secukinumab. For example, significant reductions in DLQI or PASI can be shown in Pso patients, as well as significant changes in TJC/SJC or the performance aspect of PsAID in PsA patients. With at the same time low side effect profile, the use of the IL-17 inhibitor should be discussed in the future, based on the current study results, as a fixed component of the therapy of Pso and PsA when indicated.Zielsetzung: Psoriasis (Pso) und Psoriasis Arthritis (PsA) gehören zu den häufigsten chronisch entzündlichen Erkrankungen mit großen persönlichen und ökonomischen Auswirkungen. Basierend auf den neusten Forschungsergebnissen bezüglich der Pathogenese von Pso und PsA und der zentralen Rolle von Interleukin (IL-) 17-A ist der IL-17-Inhibitor Secukinumab entwickelt worden. Ziel dieser Arbeit ist es, den Einfluss von Secukinumab auf das klinische Bild und die Lebensqualität von Patienten mit Pso und PsA zu evaluieren. Methoden: Diese Dissertation basiert auf den Daten der einarmigen prospektiven PSARTROS-Studie, in der Patienten mit Pso (n = 20) und PsA (n = 20) über 24 Wochen mit 300 mg Secukinumab behandelt worden sind. Zur Evaluation des Therapieerfolgs werden klinische Parameter wie psoriatische Hautläsionen und die Anzahl geschwollener und schmerzhafter Gelenke herangezogen. Anhand von Patienten-orientierten Fragebögen (DLQI, PSAID, PSAQOL, HAQ und SF-36) werden weiterhin die Krankheitsaktivität und Lebensqualität der Patienten im Behandlungsverlauf beurteilt. Ergebnisse: Insgesamt 50 % der Pso- sowie 35,3 % der PsA-Patienten erreichen nach 24 Wochen eine 90 %ige Reduktion des Psoriasis Area and Severity Index (PASI 90). PsA-Patienten erfahren im Studienverlauf eine signifikante Reduktion (p ≤ 0,05) der Anzahl symptomatischer Gelenke. Beide Patientengruppen profitieren hinsichtlich ihrer Lebensqualität im Sinne von beispielsweise einer Reduktion von Unbehagen und Scham oder einer Steigerung der körperlichen Belastbarkeit. Im Rahmen der Studie geben Pso-Patienten eine signifikante Besserung ihrer durch sichtbare Hautläsionen im Vordergrund stehenden psychischen Belastung an. Der Mittelwert des DLQI sinkt von 10,7 Punkten auf durchschnittlich 4,5 Punkte nach zwölf Wochen. PsA-Patienten sehen sich primär durch verminderte körperliche Funktionalität und mangelnde Belastbarkeit aufgrund von Gelenkschmerzen eingeschränkt, die sich ebenfalls im Studienverlauf signifikant verbessern. Hinsichtlich der EULAR Response Kriterien zeigen 69 % der PsA-Patienten ein gutes Ansprechen auf die Studienmedikation. 52,9 % der PsA-Patienten weisen eine 50 % ige und 35,3 % der PsA-Patienten sogar eine 70 % ige Reduktion der ACR-Kriterien nach 24 Wochen auf. Während der Behandlung mit Secukinumab sind im Studienverlauf keine schwerwiegenden, jedoch bei 36 % der Patienten leichte bis moderate Nebenwirkungen aufgetreten. Schlussfolgerungen: In die Evaluation des Therapieerfolgs fließen nicht nur die klinische Symptomatik, sondern auch das subjektive Krankheitsempfinden und die Lebensqualität der Patienten ein. Für PsA-Patienten spielen insbesondere Gelenkschmerzen und die körperlichen Einschränkungen im Alltag eine Rolle, für Pso-Patienten am ehesten Hautläsionen und die damit einhergehende psychische Belastung. Die Patientengruppen beider Krankheitsbilder profitieren hinsichtlich ihrer klinischen Symptome und der Lebensqualität durch die Behandlung mit Secukinumab. Hierbei können beispielsweise signifikante Reduktionen im DLQI oder im PASI bei Pso-Patienten gezeigt werden, ebenso wie signifikante Veränderungen des TJC/SJC oder dem Teilaspekt Leistungsfähigkeit im PsAID bei PsA-Patienten. Bei gleichzeitig niedrigem Nebenwirkungsprofil ist der Einsatz des IL-17-Inhibitorszukünftig, basierend auf den aktuellen Studienergebnissen, bei entsprechender Indikation als fester Bestandteil der Therapie von Pso und PsA zu diskutieren

Enantioselective Total Synthesis of (‐)‐Finerenone using Asymmetric Transfer Hydrogenation

(−)‐Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6‐step synthesis of (−)‐finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (−)‐finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.<br/

Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation—data from the prospective IVEPSA study

Background A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015

Alcohol and cardio-respiratory deaths in Chinese: a population-based case-control study of 32,462 older Hong Kong adults

Background: In observational studies moderate alcohol use reduces cardio-respiratory mortality. However observational studies may be biased by many factors including residual confounding by unmeasured differences between moderate alcohol users and other groups or by changes in alcohol use with ill-health and aging. We used two different analytic strategies in an under-studied population, i.e. southern Chinese, to provide an assessment of the specific impact of moderate alcohol use on mortality from ischemic heart disease (IHD) and chronic obstructive pulmonary diseases (COPD). Methods: In a population-based case-control study of all adult deaths in Hong Kong Chinese in 1998, we used adjusted logistic regression to compare alcohol use in decedents aged ≥ 60 years from IHD (2270) and COPD (1441) with 10,320 living and 9043 dead controls (all non-alcohol related deaths). We also examined whether the association of alcohol use with death from IHD or COPD varied with sex or smoking status. Results: Using living controls and adjusted for age, socio-economic status and lifestyle, occasional and moderate alcohol use were generally associated with lower mortality from IHD and COPD. However, using dead controls the protection of occasional and moderate alcohol use appeared to be limited to ever-smokers for IHD (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.46 to 0.73 for moderate compared to never-use in ever-smokers, but OR 1.07, 95% CI 0.76 to 1.50 in never-smokers), and possibly to men for COPD. High alcohol use was associated with lower IHD mortality and possibly with lower COPD mortality. Conclusion: High levels of alcohol use in an older Chinese population were associated with lower IHD mortality. Moderate alcohol use was less consistently protective against IHD mortality. Alcohol use was associated with lower COPD mortality particularly in men, either due to some yet to be clarified properties of alcohol or as the artefactual result of genetic selection into alcohol use in a Chinese population. Given the increasing use of alcohol in China with economic development, other designs and analytic strategies are needed to assess the impact of alcohol in this population, so that an evidence-based public health policy can be formulated.link_to_subscribed_fulltex

Neutrophil Elastase Promotes Linker Cleavage and Paclitaxel Release from an Integrin-Targeted Conjugate

This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte-secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP-RGD) was found to accumulate on the surface of αv β3 integrin-expressing human renal cell carcinoma 786-O cells. The ligand was conjugated to the anticancer drug paclitaxel through a Asn-Pro-Val (NPV) tripeptide linker, which is a substrate of neutrophil-secreted elastase. In vitro linker cleavage assays and cell antiproliferative experiments demonstrate the efficacy of this tumor-targeting conjugate, opening the way to potential therapeutic applications

Does economic development contribute to sex differences in ischaemic heart disease mortality? Hong Kong as a natural experiment using a case-control study

<p>Abstract</p> <p>Background</p> <p>The male excess risk of premature ischemic heart disease (IHD) mortality may be partially due to an unknown macro-environmental influence associated with economic development. We examined whether excess male risk of IHD mortality was higher with birth in an economically developed environment.</p> <p>Methods</p> <p>We used multivariable logistic regression in a population-based case-control study of all adult deaths in Hong Kong Chinese in 1998 to compare sex differences in IHD mortality (1,189 deaths in men, 1,035 deaths in women and 20,842 controls) between Hong Kong residents born in economically developed Hong Kong or in contemporaneously undeveloped Guangdong province in China.</p> <p>Results</p> <p>Younger (35–64 years) native-born Hong Kong men had a higher risk of IHD death than such women (odds ratio 2.91, 95% confidence interval 1.66 to 5.13), adjusted for age, socio-economic status and lifestyle. There was no such sex difference in Hong Kong residents who had migrated from Guangdong. There were no sex differences in pneumonia deaths by birth place.</p> <p>Conclusion</p> <p>Most of these people migrated as young adults; we speculate that environmentally mediated differences in pubertal maturation (when the male disadvantage in lipids and fat patterning emerges) may contribute to excess male premature IHD mortality in developed environments.</p

Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors

<p>Abstract</p> <p>Background</p> <p>We conducted a case-control study in the greater Toronto area to evaluate potential lung cancer risk factors including environmental tobacco smoke (ETS) exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases with special consideration given to never smokers.</p> <p>Methods</p> <p>445 cases (35% of which were never smokers oversampled by design) between the ages of 20-84 were identified through four major tertiary care hospitals in metropolitan Toronto between 1997 and 2002 and were frequency matched on sex and ethnicity with 425 population controls and 523 hospital controls. Unconditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk.</p> <p>Results</p> <p>Any previous exposure to occupational exposures (OR total population 1.6, 95% CI 1.4-2.1, OR never smokers 2.1, 95% CI 1.3-3.3), a previous diagnosis of emphysema in the total population (OR 4.8, 95% CI 2.0-11.1) or a first degree family member with a previous cancer diagnosis before age 50 among never smokers (OR 1.8, 95% CI 1.0-3.2) were associated with increased lung cancer risk.</p> <p>Conclusions</p> <p>Occupational exposures and family history of cancer with young onset were important risk factors among never smokers.</p