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Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
Osteoarthritis: novel molecular mechanisms increase our understanding of the disease pathology
(2021)
Although osteoarthritis (OA) is the most common musculoskeletal condition that causes significant health and social problems worldwide, its exact etiology is still unclear. With an aging and increasingly obese population, OA is becoming even more prevalent than in previous decades. Up to 35% of the world’s population over 60 years of age suffers from symptomatic (painful, disabling) OA. The disease poses a tremendous economic burden on the health-care system and society for diagnosis, treatment, sick leave, rehabilitation, and early retirement. Most patients also experience sleep disturbances, reduced capability for exercising, lifting, and walking and are less capable of working, and maintaining an independent lifestyle. For patients, the major problem is disability, resulting from joint tissue destruction and pain. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Here, we elucidate novel concepts and hypotheses regarding disease progression and pathology, which are relevant for understanding underlying the molecular mechanisms as a prerequisite for future therapeutic approaches. Emphasis is placed on topographical modeling of the disease, the role of proteases and cytokines in OA, and the impact of the peripheral nervous system and its neuropeptides.
Background and Purpose: Sexual dysfunction (SD) is a frequent side effect associated with radical prostatectomy (RP) for prostate cancer (PCa). Some studies have showed the benefit associated with preoperative sexual rehabilitation (prehabilitation) and Enhanced Recovery After Surgery (ERAS) for RP, but no clear clinical recommendations are available yet. Our aim was to conduct a systematic review on sexual prehabilitation prior to RP for patients with a localized PCa and analyze the impact on postoperative sexual health compared with the standard post-operative care.
Methods: We performed a systematic review of the literature following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) recommendations.
Results: Four randomized control trials and one retrospective comparative study were included in the analyses. Three of the five studies showed an improved EF recovery post-RP in the prehabilitation group compared to the standard of care represented by: higher International Index of Erectile Function 5 score (IIEF5) or IIEF score (p < 0.0001) and a higher percentage of patients reporting return of EF based on the Sexual Encounter Profile (SEP) (56 vs. 24%, p = 0.007). Self-confidence, therapeutic alliance, and adherence to treatment were stronger for patients with preoperative consultations (p < 0.05) and EF recovery was better in cases of a higher number of follow-up visits (OR 4–5 visits vs. 1:12.19, p = 0.002).
Discussion: Despite heterogenous methods and high risks of bias in this systematic review, starting sexual rehabilitation prior to surgery seems to ensure better EF recovery. This prehabilitation should include information of both the patient and his or her partner, with a closer follow up and the use of a multimodal treatment approach that still remains to be defined and validated (oral medication, vacuum devices, pelvic floor muscle training, etc.).
Aims: The study aimed to evaluate the prevalence of mental distress in patients with newly diagnosed bladder cancer, the cancer-information search behavior, and the influence of information seeking on distress. Methods: One hundred and one bladder cancer patients answered 2 established questionnaires (“Hospital Anxiety and Depression Scale” [HADS] and the “Fragebogen zur Belastung von Krebskranken” [FBK-R23]) for evaluation of mental distress and a self-developed questionnaire with questions concerning information seeking and socioeconomic facts. Results: Regarding risk group stratification, 57.4% were classified as high-risk and 42.6% as low-risk tumor-bearing patients. Analysis of mental distress showed that 23.2% had a score above the HADS-A cutoff, 25.3% above the HADS-D cutoff, and 21.4% showed a pathologic FBK-R23 score. Overall, 75% felt well informed about their illness. Risk group stratification did not correlate with HADS-A, HADS-D, or FBK-R23 score. Furthermore, active search for information or the use of the Internet did not correlate with the HADS-A, HADS-D, or FBK-R23 score. However, the quality of the urologist’s information and the feeling of being informed correlated with the grade of mental distress. Conclusion: Besides the treatment of bladder cancer, informing the patient about the disease in a psychologically wholesome manner and working together with psycho-oncologically trained psychologists are essential tasks for the treating urologist.
Introduction: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. Materials and methods: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. Results: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. Conclusion: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.
Einfluss eines Erste-Hilfe-Kurses für Medizinstudierende auf notfallmedizinische Basiskompetenzen
(2021)
Medizinstudierende sind bereits in der Vorklinik häufig mit Situationen konfrontiert, in denen medizinische Notfälle passieren, die unter anderem wegen der Lage des Universitätscampus und den damit verbundenen Kontakt zu Patientinnen und Patienten oder in den Pflegepraktika. Tritt in diesen Situationen ein medizinischer Notfall ein, müssen sie Erste Hilfe leisten können. Das Ziel der vorliegenden Arbeit ist daher die Erfassung notfallmedizinischer Basiskompetenzen von Medizinstudierenden der Vorklinik und die Frage, ob diese ausreichend sind, um den Anforderungen ihres Umfeldes gerecht zu werden. Des Weiteren wurde ein Erste-Hilfe-Kurs speziell für Vorklinikstudierende basierend auf dem ABCDE-Schema konzipiert, implementiert und evaluiert, ob die erfassten Kompetenzdefizite behoben werden konnten.
In einem Pre-Post-Design wurde die theoretische Kompetenz anhand eines 10 Items Multiple-Choice-Tests und die praktischen Kompetenzen anhand von 3 OSCE-/OSPE-Stationen (je 5 min) erfasst. Sowohl der MC-Test als auch die OSCE-/OSPE-Stationen wurden in Probeläufen getestet und überarbeitet. Soziodemographische Daten wurden mittels Fragebogen erhoben. Der entwickelte Kurs umfasst 9 UE (davon 6 UE praktische Übungen) in denen die zu erlernenden Erste-Hilfe-Maßnahmen strukturiert und in logischer Reihenfolge anhand des etablierten ABCDE-Schemas vermittelt werden. Jeweils 8 Teilnehmende werden von zwei geschulten Peer-Dozierenden unterrichtet. Im Anschluss an das Training erfolgte eine erneute Erhebung der theoretischen und praktischen Kompetenzen. Die Eingabe der Rohdaten erfolgte in Microsoft Excel (Microsoft Inc., Redmond, WA, USA). Die weitere Auswertung erfolgte mittels SPSS (SPSS Inc., Chicago, IL, USA).
160 Studierende aus den ersten beiden Studienjahren konnten in die Studie eingeschlossen werden. Im Basis-Assessment demonstrierten nur 25% der Studierenden zwei Minuten lang eine suffiziente Kompression mit richtiger Frequenz und Drucktiefe, nur 29% überstreckten am Ende der Seitenlage den Kopf des Patienten und öffneten den Mund. Im Anschluss an das Training erzielten die Studierenden an allen OSCE/OSPE-Stationen signifikant bessere Ergebnisse: Bei der stabilen Seitenlage steigerten sie sich durchschnittlich um 5,3 Punkte (max. 14), bei der Reanimation um 6,8 Punkte (max. 18). Während sich vor dem Kurs 33% der Studierenden in der Lage fühlten, Wiederbelebungsmaßnahmen durchzuführen, waren dies nach dem Kurs 98%. Die Kursevaluation war durchweg positiv.
Die Erfassung notfallmedizinischer Basiskompetenzen von Medizinstudierenden der Vorklinik zeigte, dass diese nicht ausreichend geschult sind, um Notfallsituationen adäquat zu bewältigen. Vor diesem Hintergrund muss eine dem Anforderungsprofil entsprechende Ausbildung in Erster Hilfe bereits in der Vorklinik an der Universität gewährleistet werden. Die vorliegenden Ergebnisse zeigen, dass mithilfe eines speziell auf Medizinstudierende ausgerichteten Erste-Hilfe-Kurs eine deutliche Steigerung notfallmedizinischer Basiskompetenzen erfolgen kann.
Trehalose, a sugar from fungi, mimics starvation due to a block of glucose transport and induces Transcription Factor EB- mediated autophagy, likely supported by the upregulation of progranulin. The pro-autophagy effects help to remove pathological proteins and thereby prevent neurodegenerative diseases such as Alzheimer’s disease. Enhancing autophagy also contributes to the resolution of neuropathic pain in mice. Therefore, we here assessed the effects of continuous trehalose administration via drinking water using the mouse Spared Nerve Injury model of neuropathic pain. Trehalose had no effect on drinking, feeding, voluntary wheel running, motor coordination, locomotion, and open field, elevated plus maze, and Barnes Maze behavior, showing that it was well tolerated. However, trehalose reduced nerve injury-evoked nociceptive mechanical and thermal hypersensitivity as compared to vehicle. Trehalose had no effect on calcium currents in primary somatosensory neurons, pointing to central mechanisms of the antinociceptive effects. In IntelliCages, trehalose-treated mice showed reduced activity, in particular, a low frequency of nosepokes, which was associated with a reduced proportion of correct trials and flat learning curves in place preference learning tasks. Mice failed to switch corner preferences and stuck to spontaneously preferred corners. The behavior in IntelliCages is suggestive of sedative effects as a 'side effect' of a continuous protracted trehalose treatment, leading to impairment of learning flexibility. Hence, trehalose diet supplements might reduce chronic pain but likely at the expense of alertness.
Synovial adipose stem cells (sASC) can be differentiated into catecholamine-expressing sympathetic neuron-like cells to treat experimental arthritis. However, the pro-inflammatory tumor necrosis factor (TNF) is known to be toxic to catecholaminergic cells (see Parkinson disease), and this may prevent anti-inflammatory effects in inflamed tissue. We hypothesized that TNF exhibits inhibitory effects on human differentiated sympathetic tyrosine hydroxylase-positive (TH+) neuron-like cells. For the first time, iTH+ neuron-like sympathetic cells were generated from sACSs of rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Compared to untreated controls in both OA and RA, TNF-treated iTH+ cells demonstrated a weaker staining of catecholaminergic markers in cell cultures of RA/OA patients, and the amount of produced noradrenaline was markedly lower. These effects were reversed by etanercept. Exposure of iTH+ cells to synovial fluid of RA patients showed similar inhibitory effects. In mixed synovial cells, significant effects of TNF on catecholamine release were observed only in OA. This study shows that TNF inhibits iTH+ synovial cells leading to the decrease of secreted noradrenaline. This might be a reason why discovered newly appearing TH+ cells in the synovium are not able to develop their possible full anti-inflammatory role in arthritis.
Einleitung: OTSC Proctology ist ein Verfahren in der Analfistelchirurgie dessen Erfolgsaussichten auch 9 Jahre nach der ersten klinischen Anwendung nicht abschließend beurteilt werden können. Die wenigen bisher publizierten Studien zeigen sehr divergente Ergebnisse mit Heilungsraten von 10 bis 90%.
Material und Methoden: Wir führten eine retrospektive Auswertung der Behandlungsergebnisse aller konsekutiven Patienten, die in dem Zeitraum vom 01.03.2014 bis 31.03.2017 in der koloproktologischen Abteilung der DKD Helios Klinik Wiesbaden mittels OTSC-Verfahren wegen Analfisteln operiert wurden, durch. Erfasst wurden Alter, Geschlecht, OP- und Aufenthaltsdauer, Operateur, Fistelart und –lokalisation, Vorhandensein von Stoma und CED, plastischer Fistelverschluss (PFV) in der Anamnese, Clipverbleib nach der OP, Dauer des Follow-ups, Komplikationen sowie postoperative Schmerzsituation. Die Datenauswertung erfolgte mittels deskriptiver Statistik bei Subgruppenanalyse unter Verwendung der Statistiksoftware SPSS 20.
Ergebnisse: Es wurden insgesamt 68 Fälle eingeschlossen, davon 37% weiblich und 63% männlich. Das durchschnittliche Alter betrug 52 Jahre (25 – 81). 19 (28%) Patienten litten an CED, 11 (16%) Patienten hatten ein Stoma. 34 (50%) der Patienten hatten plastischen Fistelverschluss in der Anamnese. Die Verteilung nach Fisteltyp war wie folgt: 58 (85%) transsphinktär, 4 (6%) suprasphinktär, 3 (4%) intersphinktär, 1 (1,5%) rektovaginal, 1 (1,5%) rektourethral und 1 (1,5%) Pouchfistel. Die häufigsten Fistelokalisationen waren bei 6 h (N = 26, 38%), 12 h (N = 14, 21%), 7 h (N = 7, 10%) und 3h (N = 5, 7%) SSL. Die durchschnittlichen OP-Dauer und stationärer Aufenthalt betrugen 25 min (6 – 90) und 7 Tage (1 – 14 Tage) entsprechend. Die durchschnittliche Dauer des Follow-ups betrug 29 Monate (10 – 36).
Die Fistelheilung im Gesamtkollektiv lag bei 48,5%, 1 (1,5%) Patient war lost-tofollow-up. In der weiblichen (N = 25) und männlichen (N = 43) Kohorte fand die Heilung in 40% und 53% der Fälle entsprechend statt. Die Heilungsraten bei intersphinktären (N = 3), transsphinktären (N = 58) und suprasphinktären (N = 4) Fisteln lagen bei 100%, 46,5% und 50% entsprechend, eine rektovaginale und eine rektourethrale Fistel sind nicht geheilt. Eine Pouchfistel ist geheilt.
Die Heilungsraten bei 6h und 12h SSL lagen bei 58% und 14% entsprechend mit deutlichem Vorteil bei posteriorer Fistellage. Dieser Vorteil blieb nach der Aufteilung der Fisteln in anteriore (N = 30) und posteriore (N = 38), mit
Heilungsraten von 33% und 60,5% entsprechend, bestehen. In den Subgruppen ohne CED (N = 49) und mit CED (N = 19) lagen die Heilungsraten bei 53% und 35% entsprechend. In den Subgruppen ohne PFV (N = 34) und mit PFV (N = 34) lagen die Heilungsraten bei 59% und 38% entsprechend. In der Subgruppe ohne Stoma (N = 57) wurde eine Heilung in 47% der Fälle, in der Subgruppe mit Stoma (N = 11) in 55% beobachtet. In der Subgruppe mit den kryploglandulären Fisteln (N = 47) war die Heilung in 55,3% zu sehen und in der Subgruppe mit
kryptoglandulären Fisteln ohne PFV (N = 27) bei 63%.
In 48 (70,6%) Fällen wurde der Clip aktiv entfernt, in 11 (16,2%) Fällen kam es zum Spontanverlust und in 8 (11,8%) Fällen blieb der Clip in situ. Die durchschnittliche Zeit bis zur Klammerentfernung betrug 4 Monate. Die Heilungsraten bei Clipentfernung, Clipverbleib und Clipspontanabgang lagen bei 42%, 100% und 45% entsprechend.
Der maximale Schmerz nach NRS 0 – 2 bei 61% der Patienten, NRS 3 – 4 bei 28% und NRS 5 – 7 nur bei 11%. Bei 50% der Fälle war kein Opiat erforderlich und bei 39% der Fälle erfolgte die Opiateinnahme nicht länger als 2 Tage.
Die Komplikationen waren sehr selten: eine Nachblutung mit Clipdislokation (1,5%), ein Analabszess (1,5%), 2 Fälle (3%) der neuaufgetretenen Stuhlschmieren und 1 (1,5%) Wundheilungsstörung intraanal, die spontan abheilte. In 4 (6%) Fällen kam es zur Klammerdislokation vom inneren
Fistelostium mit konsekutiver Fistelpersistenz.
Fazit: OTSC ist ein komplikationsarmes und schmerzarmes Verfahren mit kurzer OP-Zeit und könnte einen festen Platz in der Analfistelchirurgie einnehmen. Die bestmöglichen Ergebnisse lassen sich bei dorsal gelegenen Analfisteln in
nichtvoroperierten Patienten ohne CED erzielen.
In humans, alterations of circadian rhythms and autophagy are linked to metabolic, cardiovascular and neurological dysfunction. Autophagy constitutes a specific form of cell recycling in many eukaryotic cells. Aging is the principal risk factor for the development of neurodegenerative diseases. Thus, we assume that both the circadian clock and autophagy are indispensable to counteract aging. We have previously shown that the hippocampus of Per1−/−-mice exhibits a reduced autophagy and higher neuronal susceptibility to ischemic insults compared to wild type (WT). Therefore, we chose to study the link between aging and loss of clock gene Per1−/−-mice. Young and aged C3H- and Per1−/−-mice were used as models to analyze the hippocampal distribution of Aβ42, lipofuscin, presenilin, microglia, synaptophysin and doublecortin. We detected several changes in the hippocampus of aged Per1−/−-mice compared to their wild type littermates. Our results show significant alterations of microglia morphology, an increase in Aβ42 deposition, overexpression of presenilin, decrease in synaptophysin levels and massive accumulation of lipofuscin in the hippocampus of 24-month-old Per1−/−-mice, without alteration of adult neurogenesis. We suggest that the marked lipofuscin accumulation, Aβ42 deposition, and overexpression of presenilin-2 observed in our experiments may be some of the consequences of the slowed autophagy in the hippocampus of aged Per1−/−-mice. This may lead during aging to excessive accumulation of misfolded proteins which may, consequently, result in higher neuronal vulnerability.
The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.
The purpose of the study was to investigate the bacterial viability of the initial biofilm on the surface of experimental modified dental resin composites. Twenty-five healthy individuals with good oral hygiene were included in this study. In a split-mouth design, they received acrylic splints with five experimental composite resin specimens. Four of them were modified with either a novel polymeric hollow-bead delivery system or methacrylated polymerizable Irgasan (Antibacterial B), while one specimen served as an unmodified control (ST). A delivery system based on Poly-Pore® was loaded with one of the active agents: Tego® Protect 5000 (Antiadhesive A), Dimethicone (Antiadhesive B), or Irgasan (Antibacterial A). All study subjects refrained from toothbrushing during the study period. Specimens were detached from the splints after 8 h and given a live/dead staining before fluorescence microscopy. A Friedman test and a post hoc Nemenyi test were applied with a significance level at p < 0.05. In summary, all materials but Antibacterial B showed a significant antibacterial effect compared to ST. The results suggested the role of the materials’ chemistry in the dominance of cell adhesion. In conclusion, dental resin composites with Poly-Pore-loaded active agents showed antibacterial effectiveness in situ.
Für Patienten mit lebensbedrohlichen Herzkrankheiten ist die Extracorporeal-Life-Support-Behandlung (ECLS) eine sinnvolle Therapiemöglichkeit. Sie bietet für Patienten im kardiogenen Schock ein Zeitfenster, um eine myokardiale Erholung zu erreichen. Hierbei kann in Abhängigkeit vom Krankheitsbild die zusätzliche Anwendung von IABP die Heilungschancen begünstigen. In der durchgeführten retrospektiven Studie wurden 118 Patienten betrachtet, die in der Klinik für Thorax-, Herz- und thorakale Gefäßchirurgie der Universität Frankfurt am Main im Zeitraum von Dezember 2001 bis Ende 2013 eine ECLS-Therapie erhalten haben. Bei 59 Patienten wurde die ECLS-Unterstützung in Kombination mit IABP durchgeführt. Die beiden Patientenkollektive - mit und
ohne IABP- sind hinsichtlich ihrer Risikofaktoren vergleichbar. Ausgehend von der Zielsetzung dieser Arbeit wurde analysiert, ob der gleichzeitige Einsatz der IABP bei ECLS – Therapie von Vor- oder sogar von Nachteil ist. Hierfür wurden für die beiden Therapiegruppen Überlebenszeitanalysen nach Kaplan-Meier durchgeführt. Der statistische Vergleich der Überlebensraten und des Weaningerfolgs erfolgte mit Hilfe des Log-Rank-Tests.
Die Auswertung der erhobenen Daten hat ergeben, dass kein signifikanter Unterschied bei der 30-Tages-Überlebensrate und dem Weaningerfolg für die beiden Patientenkollektive mit und ohne zusätzliche IABP-Anwendung vorhanden ist. Risikofaktoren wie ein hohes Lebensalter oder eine bereits vor Einlieferung stattgefundene Intubation verringern außerdem die Überlebenschancen nach ECLS - Therapie. Ein fortgeschrittenes NYHA-Stadium konnte nicht als negativer prädiktiver Faktor identifiziert werden.
In der Literatur kommt man bezüglich der Mortalität unter alleiniger ECLS-Therapie oder dem zusätzlichen Einsatz einer IABP zu unterschiedlichen Ergebnissen. Diese besagen teilweise, dass ECLS und IABP einander ergänzende Methoden sind, die sich durchaus synergistisch auf den Behandlungserfolg auswirken können und dass die Mortalität beim zusätzlichen Einsatz einer IABP signifikant niedriger ist. Die Durchführung weiterer prospektiver Studien mit vergleichbaren Patientenkollektiven zur Untersuchung des Outcomes bei den unterschiedlichen Behandlungsmethoden ist jedoch erforderlich, um ein aussagekräftiges Fazit ziehen zu können.
Cancer is the major cause of death besides cardiovascular disease. Leukaemia represents the most prevalent malignancy in children with a frequency of 30 % and is one of the ten leading types of cancer in adults. Philadelphia Chromosome-positive B-ALL (Ph+ B-ALL) is driven by the cytogenetic aberration of the reciprocal chromosomal translocation t(9;22)(q34;q11) leading to the formation of the Philadelphia chromosome with a BCR-ABL1 fusion gene. This fusion gene encodes a BCR-ABL1 oncoprotein which is characterized by a constitutively enhanced tyrosine kinase activity promoting amplified proliferation, differentiation arrest and resistance to cell death. Ph+ B-ALL is considered the most aggressive ALL subtype with a long-term survival rate in the range of only 30 % despite intensive standard of care including chemotherapy in combination with a tyrosine kinase inhibitor (TKI) followed by allogeneic stem cell transplantation after remission for clinically fit patients.
The efficacy of chemotherapy has long been mainly attributed to tumour cell toxicity while immune modulating effects have been overlooked, especially in light of known immunosuppressive properties. Accumulative evidence, however, emphasizes the ability of chemotherapeutic agents, including TKIs, to normalise or re-educate a dysfunctional tumour microenvironment (TME) resulting in enhanced anti-tumour immunity. One of the underlying mechanisms of immune modulation is the induction of immunogenic cell death (ICD). ICD is an anti-tumour agent-induced cell death modality determined by the capacity to convert cancer cells into anti-cancer vaccines. The induction of ICD relies on the release of damage-associated molecular patterns (DAMPs) from dying tumour cells succumbing to ICD. Translocation of CALR to the cell surface, extracellular secretion of ATP and release of HMGB1 from the nucleus are key hallmarks of ICD that mediate anti-tumour immunity upon binding to antigen presenting cells resulting in a tumour antigen-specific immune response. Besides these molecular determinants, ICD is functionally defined by the inhibition of tumour growth in a vaccination assay in which mice are injected with tumour cells exposed to the potential ICD inducer in-vitro and then re-challenged with live tumour cells of the same cancer type. Both molecular and functional criteria determine the gold standard approach to assess ICD. By increasing the immunogenicity of cancer cells, ICD contributes to the restoration of immunosurveillance as an essential feature of tumour rejection, which is clinically reflected by improved therapeutic efficacy and disease outcome in patients. Therefore, identifying novel ICD inducers is an objective of interest in the context of cancer therapy.
In respect of these considerations, the aim addressed in the present work is the examination of the second-generation TKI Nilotinib for the ability to induce ICD. The thesis is set in the context of the group's research on the role of Gas6/TAM signalling within the TME regarding the pathogenesis of acute leukaemia. In in-vivo experiments of our research group it has been consistently observed that the use of Nilotinib enhances the anti-leukaemic immunity mediated by a deletion of Gas6. Against the background of increasing importance of chemotherapeutic agents as potent modulators of a dysregulated TME, it was hypothesized that Nilotinib may synergize with a Gas6-deficient environment by inducing ICD in Ph+ B-ALL cells.
In growth inhibition and Annexin V/Propidium iodide cell death assays Nilotinib was shown to induce cell death in concentration-dependent manner that occurs bimodally in terms of cell death modality ranging between apoptosis and necrosis. By ICD marker analysis, comprising flow-cytometric detection of CALR exposure, chemoluminescence-based ATP measurement and immunoblotting for HMGB1, it was found that Nilotinib-induced cell death is not accompanied by CALR exposure and ATP secretion, but is associated with the release of HMGB1. In macrophages co-culture experiments with Nilotinib-treated leukaemic cells, no relevant shift in terms of macrophages activation and polarisation was observed in either a juxtacrine or paracrine setup. In consistency with the results obtained in the in-vitro experiments, Nilotinib was not potent to elicit a protective immune response in mice within a vaccination assay.
Conclusively, Nilotinib was identified to not qualify as bona fide ICD inducer. The role of Nilotinib-induced cell death and HMGB1 release are proposed as objective for further investigation concerning the synergistic interplay between Nilotinib and a Gas6-deficient environment. Efforts addressing exploration and optimisation of the immunological potential of chemotherapeutic agents are a promising approach aimed at providing cancer patients with the best possible treatment in future.
Purpose This study aims to define the extent of additional surgical procedures after abdominal wall closure (AWC) in patients with gastroschisis (GS) and omphalocele (OC) with special focus on gastrointestinal related operations. Methods A retrospective chart review was performed including all operations in GS and OC patients in the first year after AWC (2010–2019). The risk for surgery was calculated using the one-year cumulative incidence (CI). Results 33 GS patients (18 simple GS, 15 complex) and 24 OC patients (12 without (= OCL), 12 OC patients with liver pro-trusion (= OCL +)) were eligible for analysis. 43 secondary operations (23 in GS, 20 in OC patients) occurred after a median time of 84 days (16–824) in GS and 114.5 days (12–4368) in OC. Patients with complex versus simple GS had a significantly higher risk of undergoing a secondary operation (one-year CI 64.3% vs. 24.4%; p = 0.05). 86.5% of surgical procedures in complex GS and 36.3% in OCL + were related to gastrointestinal complications. Complex GS had a significantly higher risk for GI-related surgery than simple GS. Bowel obstruction was a risk factor for surgery in complex GS (one-year CI 35.7%). Conclusion Complex GS and OCL + patients had the highest risk of undergoing secondary operations, especially those with gastrointestinal complications
Im Rahmen der Serie „Biomarker“, die im Zentralblatt für Arbeitsmedizin und Ergonomie publiziert wird, ist das Angiotensin-Converting Enzyme (ACE) zugehörig als häufiger Marker in der Diagnostik von pulmonalen und extrapulmonalen Erkrankungen. Die Bestimmung von ACE stellt einen wesentlichen Bestandteil der Diagnostik von pulmonalen und extrapulmonalen Erkrankungen dar. Der Einfluss von Tabakkonsum, Medikamenten, Zink-Chelatoren auf die ACE-Konzentration wird eruiert. ACE erwies sich als Marker mit einer hohen Sensitivität und Spezifität bei Lungenerkrankungen.
Hintergrund und Ziel der Studie: Steigende Erwartungen der Kataraktpatienten führen zu stetigen Weiterentwicklungen in der Linsenchirurgie. Der Wunsch nach einem perfekten Sehvermögen und nach Brillenfreiheit ist ein häufiges Anliegen insbesondere jüngerer Patienten. Die Einführung von Multifokallinsen hat die Therapie der Katarakt revolutioniert. Mit ihnen kann der Patient sowohl in der Nähe und Ferne als auch im Intermediärbereich scharf sehen. Für die präoperative Berechnung der Linsenstärke sind verschiedene Formeln verfügbar. Bis jetzt wurde keine Studie publiziert, die die Präzision dieser Formeln für die Kalkulation der Stärke von Tri- oder Quadrifokallinsen untersucht hat. Das Ziel dieser Studie war die Evaluation neun moderner Formeln für die Berechnung der Linsenstärke der quadrifokalen AcrySof IQ PanOptix TFNT00.
Methoden:
Die vorliegende Studie ist eine retrospektive konsekutive Fallserie, die an der Augenklinik der Johann Wolfgang Goethe-Universität Frankfurt am Main durchgeführt wurde. Es wurden alle Patienten eingeschlossen, die sich einer Femtosekundenlaser-assistierten Operation mit Implantation der quadrifokalen Intraokularlinse unterzogen. Mit dem IOLMaster 500 wurden die präoperativen Biometrie- und Keratometriemessungen durchgeführt. Das Scheimpflug-System Pentacam wurde zur Bestimmung der zentralen Hornhautdicke genutzt. Drei Monate nach der Operation fand eine subjektive Refraktionsbestimmung statt.
Die folgenden Formeln wurden untersucht: Holladay 1, Sanders-Retzlaff-Kraff/ theoretical (SRK/T), Hoffer Q, T2, Holladay 2, Haigis, Barrett Universal II, Olsen und Hill-radiale Basisfunktion (RBF). Aus den präoperativ gemessenen Parametern und der implantierten Linsenstärke wurde für jedes Auge die postoperative Refraktion berechnet. Der Vorhersagefehler (PE) ist definiert als die Differenz zwischen dem tatsächlich erreichten postoperativen sphärischen Äquivalent und dem vorhergesagten postoperativen sphärischen Äquivalent. Zur Reduktion systematischer Fehler und somit des mittleren PE wurden die Linsenkonstanten optimiert. Primäre Endpunkte waren die Unterschiede der mittleren absoluten Vorhersagefehler (MAE) zwischen den Formeln. Die Standardabweichung sowie mediane und maximale absolute PE wurden ebenso untersucht wie die Prozent-zahlen der Augen, deren PE innerhalb von ± 0,25 Dioptrien (dpt), ± 0,5 dpt, ± 1,0 dpt und ± 2,0 dpt lagen.
Ergebnisse: 75 Augen von 38 Patienten wurden in die vorliegende Studie eingeschlossen. Es gab signifikante Unterschiede zwischen den Formeln bezüglich des MAE (p Wert < 0,001). Die Rangfolge der Formeln entsprechend ihrer MAE lautet wie folgt: Barrett Universal II (0,294 dpt), Hill-RBF (0,332 dpt), Olsen (0,339 dpt), T2 (0,351 dpt), Holladay 1 (0,381 dpt), Haigis (0,382 dpt), SRK/T (0,393 dpt), Holladay 2 (0,399 dpt) und Hoffer Q (0,410 dpt). Den niedrigsten maximalen absoluten PE erreichte die Barrett Universal II. Bei der Verwendung der Haigis, Barrett Universal II, Olsen und Hill-RBF hatten 80% der Augen einen PE innerhalb von ± 0,5 dpt. In der Subgruppe der kurzen Augen wurde der niedrigste PE mit der Hill-RBF erreicht, in der Subgruppe der langen Augen mit der Barrett Universal II und mit der Olsen. Die Unterschiede zwischen den Formeln in den Subgruppenanalysen waren jedoch nicht signifikant.
Schlussfolgerung:Die exaktesten Vorhersagen der postoperativen Refraktion konnten mit der Barrett Universal II erzielt werden. Diese Formel sollte daher künftig für die Berechnung der Linsenstärke der quadrifokalen PanOptix genutzt werden. Die T2, Olsen und Hill-RBF führten ebenfalls zu niedrigen PE. Weitere Studien sollten durchgeführt werden, um insbesondere die neuen Formeln im Zusammenhang mit verschiedenen Multifokallinsen zu untersuchen. Um die Vorhersagegenauigkeit der Formeln in Augen mit extremen Achsenlängen zu bewerten, sind Studien mit größeren Fallzahlen nötig.
Purpose: Bilateral vocal cord dysfunction (bVCD) is a rare but feared complication of thyroid surgery. This long term retrospective study determined the effect of intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) during thyroid surgeries with regard to the rate of bVCD and evaluated the frequency as well as the outcome of staged operations. Methods: Retrospective analysis of prospectively documented data (2000–2019) of a tertiary referral centers’ database. IONM started in 2000 and, since 2010, discontinuation of surgery was encouraged in planned bilateral surgeries to prevent bVCD, if non-transient loss of signal (ntLOS) occurred on the first side. Datasets of the most recent 40-month-period were assessed in detail to determine the clinical outcome of unilateral ntLOS in planned bilateral thyroid procedures. Results: Of 22,573 patients, 65 had bVCD (0.288%). The rate of bVCD decreased from 0.44 prior to 2010 to 0.09% after 2010 (p < 0.001, Chi2). Case reviews of the most recent 40 months period identified ntLOS in 113/3115 patients (3.6%, 2.2% NAR), of which 40 ntLOS were recorded during a planned bilateral procedure (n = 952, 2.1% NAR). Of 21 ntLOS occurring on the first side of the bilateral procedure, 15 procedures were stopped, subtotal contralateral resections were performed, and thyroidectomy was continued in 3 patients respectively, with the use of continuous vagal IONM. Eighteen cases of VCD were documented postop, and all but one patient had a full recovery. Seven patients had staged resections after 1 to 18 months (median 4) after the first procedure. Conclusion: IONM facilitates reduced postoperative bVCD rates. IONM is, therefore, recommendable in planned bilateral procedures. The rate of non-complete bilateral surgery after intraoperative non-transient LOS was 2%.
Posterior fossa tumor surgery is challenging due to the proximity and exposure of cerebellar structures. A favorable operative approach is unknown. Following lesions to the dentato–rubro–olivary-pathway, a neurodegenerative disease called hypertrophic olivary degeneration (HOD) can occur. This study for the first time demonstrates that paravermal trans-cerebellar approaches are associated with a significantly higher likelihood of HOD on MRI when compared to other approaches. This finding can well be attributed to dentate nucleus (DN) injury. Furthermore, cerebellar mutism syndrome (CMS) was discussed in the literature to be correlated with HOD due to a functional overlap of pathways involved. We found no such correlation in this study, but HOD was shown to be a reliable indicator for surgical disruption of efferent cerebellar pathways involving the DN. Henceforth, neurosurgeons should consider more midline or lateral approaches in posterior fossa surgery to spare the DN whenever feasible, and focus on cerebellar functional anatomy in their preoperative planning.
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with a lack of a curative treatment. In this study, we evaluated the effect of short-chain, cell-permeable C6 Ceramide (C6Cer) on CTCL cell lines and keratinocytes. C6Cer significantly reduced cell viability of CTCL cell lines and induced cell death via apoptosis and necrosis. In contrast, primary human keratinocytes and HaCaT keratinocytes were less affected by C6Cer. Both keratinocyte cell lines showed higher expressions of ceramide catabolizing enzymes and HaCaT keratinocytes were able to metabolize C6Cer faster and more efficiently than CTCL cell lines, which might explain the observed protective effects. Along with other existing skin-directed therapies, C6Cer could be a novel well-tolerated drug for the topical treatment of CTCL.
Background: Excessive alcohol intake is associated with adverse immune response-related effects, however, acute and chronic abuse differently modulate monocyte activation. In this study, we have evaluated the phenotypic and functional changes of monocytes in acutely intoxicated healthy volunteers (HV).
Methods: Twenty-two HV consumed individually adjusted amounts of alcoholic beverages until reaching a blood alcohol level of 1‰ after 4h (T4). Peripheral blood was withdrawn before and 2h (T2), 4h (T4), 6h (T6), 24h (T24), and 48h (T48) after starting the experiment and stained for CD14, CD16 and TLR4. CD14brightCD16-, CD14brightCD16+ and CD14dimCD16+ monocyte subsets and their TLR4 expression were analyzed by flow cytometry. Inflammasome activation via caspase-1 in CD14+ monocytes was measured upon an ex vivo in vitro LPS stimulation. Systemic IL-1β and adhesion capacity of isolated CD14+ monocytes upon LPS stimulation were evaluated.
Results: The percentage of CD14+ monocyte did not change following alcohol intoxication, whereas CD14brightCD16- monocyte subset significantly increased at T2 and T24, CD14brightCD16+ at T2, T4 and T6 and CD14dimCD16+ at T4 and T6. The relative fraction of TLR4 expressing CD14+ monocytes as well as the density of TLR4 surface presentation increased at T2 and decreased at T48 significantly. TLR4+CD14+ monocytes were significantly enhanced in all subsets at T2. TLR4 expression significantly decreased in CD14brightCD16- at T48, in CD14brightCD16+ at T24 and T48, increased in CD14dimCD16+ at T2. IL-1β release upon LPS stimulation decreased at T48, correlating with TLR4 receptor expression. Alcohol downregulated inflammasome activation following ex vivo in vitro stimulation with LPS between T2 and T48 vs. T0. The adhesion capacity of CD14+ monocytes decreased from T2 with significance at T4, T6 and T48. Following LPS administration, a significant reduction of adhesion was observed at T4 and T6.
Conclusions: Alcohol intoxication immediately redistributes monocyte subsets toward the pro-inflammatory phenotype with their subsequent differentiation into the anti-inflammatory phenotype. This is paralleled by a significant functional depression, suggesting an alcohol-induced time-dependent hyporesponsiveness of monocytes to pathogenic triggers.
Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5–10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that exogenous expression of the kinase fusions in HEK 293T cells leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1, and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
Traditional ergonomic risk assessment tools such as the Rapid Upper Limb Assessment (RULA) are often not sensitive enough to evaluate well-optimized work routines. An implementation of kinematic data captured by inertial sensors is applied to compare two work routines in dentistry. The surgical dental treatment was performed in two different conditions, which were recorded by means of inertial sensors (Xsens MVN Link). For this purpose, 15 (12 males/3 females) oral and maxillofacial surgeons took part in the study. Data were post processed with costume written MATLAB® routines, including a full implementation of RULA (slightly adjusted to dentistry). For an in-depth comparison, five newly introduced levels of complexity of the RULA analysis were applied, i.e., from lowest complexity to highest: (1) RULA score, (2) relative RULA score distribution, (3) RULA steps score, (4) relative RULA steps score occurrence, and (5) relative angle distribution. With increasing complexity, the number of variables times (the number of resolvable units per variable) increased. In our example, only significant differences between the treatment concepts were observed at levels that are more complex: the relative RULA step score occurrence and the relative angle distribution (level 4 + 5). With the presented approach, an objective and detailed ergonomic analysis is possible. The data-driven approach adds significant additional context to the RULA score evaluation. The presented method captures data, evaluates the full task cycle, and allows different levels of analysis. These points are a clear benefit to a standard, manual assessment of one main body position during a working task.
The kidneys play a vital role in the basic physiological functions of the body. Kidney dysfunction impairs these physiological functions and can lead to a wide range of diseases. Damage to the kidney cells can be caused by a variety of ischemic, toxic or immunological complaints that lead to inflammation and cell death, which can lead to organ damage and, ultimately, complete failure. Although the mechanisms underlying acute kidney injury (AKI) and chronic kidney disease (CKD) are quite distinct, clinical evidence suggests that the two conditions are inextricably interconnected [1]. AKI and CKD, regardless of the underlying cause, have inflammation and activation of the immune system as the common underlying mechanisms. Inflammation, a process aimed, in principle, at detecting and fighting harmful pathogens, is, therefore, a major pathogenic mechanism for both AKI and CKD [1]. While the kidney has the remarkable ability to regenerate after an acute injury and can recover completely, depending on the type of kidney lesion, the options for clinical interventions are currently limited to fluid management and extracorporeal kidney support. However, persistent chronic inflammation can trigger renal fibrosis and chronic kidney disease. The investigation of the molecular mechanisms involved in each individual injury is currently insufficiently understood.
Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment.
Dopamine in fear extinction
(2021)
The ability to extinguish fear memories when threats are no longer present is critical for adaptive behavior. Fear extinction represents a new learning process that eventually leads to the formation of extinction memories. Understanding the neural basis of fear extinction has considerable clinical significance as deficits in extinction learning are the hallmark of human anxiety disorders. In recent years, the dopamine (DA) system has emerged as one of the key regulators of fear extinction. In this review article, we highlight recent advances that have demonstrated the crucial role DA plays in mediating different phases of fear extinction. Emerging concepts and outstanding questions for future research are also discussed.
Local anesthetics are commonly administered by nuchal infiltration to provide a temporary interscalene brachial plexus block (ISB) in a surgical setting. Although less commonly reported, local anesthetics can induce central nervous system toxicity. In this case study, we present three patients with acute central nervous system toxicity induced by local anesthetics applied during ISB with emphasis on neurological symptoms, key neuroradiological findings and functional outcome. Medical history, clinical and imaging findings, and outcome of three patients with local anesthetic-induced toxic left hemisphere syndrome during left ISB were analyzed. All patients were admitted to our neurological intensive care unit between November 2016 and September 2019. All three patients presented in poor clinical condition with impaired consciousness and left hemisphere syndrome. Electroencephalography revealed slow wave activity in the affected hemisphere of all patients. Seizure activity with progression to status epilepticus was observed in one patient. In two out of three patients, cortical FLAIR hyperintensities and restricted diffusion in the territory of the left internal carotid artery were observed in magnetic resonance imaging. Assessment of neurological severity scores revealed spontaneous partial reversibility of neurological symptoms. Local anesthetic-induced CNS toxicity during ISB can lead to severe neurological impairment and anatomically variable cerebral lesions.
The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex vivo generated NK cell-enriched products utilized for adoptive immunotherapy. Over the past decades, various immunotherapies have been developed, including cytokine-induced killer (CIK) cells, as a peripheral blood mononuclear cells (PBMCs)-based therapeutic product, the adoptive transfer of specific T and NK cell products, and the NK cell line NK-92. In addition to allogeneic NK cells, NK-92 cell products represent a possible “off-the-shelf” therapeutic concept. Recent approaches have successfully enhanced the specificity and cytotoxicity of T, NK, CIK or NK-92 cells towards tumor-specific or associated target antigens generated by genetic engineering of the immune cells, e.g., to express a chimeric antigen receptor (CAR). Here, we will look into the history and recent developments of T and NK cell-based immunotherapy.
The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
Recent reports have shown a dramatic loss in insect species and biomass. Since forensic entomology relies on the presence of insects, the question is whether this decline effects the discipline. The present review confirms that numerous studies document insect population declines or even extinction, despite the fact that the rates of decline and the methods used to demonstrate it are still much debated. However, with regard to a decline in necrophagous insects, there is little or only anecdotal data available. A hypothetical decrease in species diversity and population density in necrophagous insects could lead to a delayed colonization of dead bodies and a modified succession pattern due to the disappearance or new occurrence of species or their altered seasonality. Climate change as one of the drivers of insect decline will probably also have an impact on necrophagous insects and forensic entomology, leading to reduced flight and oviposition activity, modified growth rates and, therefore, an over- or underestimation of a minimum postmortem interval. Global warming with increased temperature and extreme weather requires a better understanding about necrophagous insect responses to environmental variations. Here, transgeneration effects in particular should be analysed in greater depth as this will help to understand rapid adaptation and plasticity in insects of forensic importance.
Climate change and variability affect virtually everyone and every region of the world but the effects are nowhere more prominent than in mountain regions and people living therein. The Hindu Kush Himalayan (HKH) region is a vast expanse encompassing 18% of the world’s mountainous area. Sprawling over 4.3 million km2, the HKH region occupies areas of eight countries namely Nepal, Bhutan, Afghanistan, Bangladesh, China, India, Myanmar, and Pakistan. The HKH region is warming at a rate higher than the global average and precipitation has also increased significantly over the last 6 decades along with increased frequency and intensity of some extreme events. Changes in temperature and precipitation have affected and will like to affect the climate-dependent sectors such as hydrology, agriculture, biodiversity, and human health. This paper aims to document how climate change has impacted and will impact, health and well-being of the people in the HKH region and offers adaptation and mitigation measures to reduce the impacts of climate change on health and well-being of the people. In the HKH region, climate change boosts infectious diseases, non-communicable diseases (NCDs), malnutrition, and injuries. Hence, climate change adaptation and mitigation measures are needed urgently to safeguard vulnerable populations residing in the HKH region.
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of the present study was to clarify the association of intratumoural SPTAN1 expression levels with treatment and survival outcomes in patients with CRC. The analysis was based on histologic assessment of SPTAN1 protein levels in our own CRC cohort, and transcriptome data of 573 CRC cases from The Cancer Genome Atlas (TCGA). We first establish that high intratumoural levels of SPTAN1 protein and mRNA associate with favourable survival outcomes in patients with CRC. Next, a response prediction signature applied to the TCGA data reveals a possible link between high SPTAN1 transcript levels and improved patient responses to FOLFOX chemotherapy. Complementary in vitro experiments confirm that SPTAN1 knockdown strains of the colon cancer cell lines HT-29, HCT116 mlh1-2 and Caco-2 are less responsive to FOLFOX chemotherapy compared with SPTAN1-proficient control strains. Taken together, we identify SPTAN1 as a novel prognostic biomarker in CRC and show that SPTAN1 expression levels may predict patient responses to chemotherapy. These investigations illustrate how an affordable, histology-based diagnostic test could directly impact therapeutic decision-making at the bedside.
A new and readily available pentafluorothiophenyl-substituted N-methyl-piperidone curcuminoid 1a was prepared and investigated for its anti-proliferative, pro-apoptotic and cancer stem cell-differentiating activities against a panel of human tumor cell lines derived from various tumor entities. The compound 1a was highly anti-proliferative and reached IC50 values in the nanomolar concentration range. 1a was superior to the known anti-tumorally active curcuminoid EF24 (2) and its known N-ethyl-piperidone analog 1b in all tested tumor cell lines. Furthermore, 1a induced a noticeable increase of intracellular reactive oxygen species in HT-29 colon adenocarcinoma cells, which possibly leads to a distinct increase in sub-G1 cells, as assessed by cell cycle analysis. A considerable activation of the executioner-caspases 3 and 7 as well as nuclei fragmentation, cell rounding, and membrane protrusions suggest the triggering of an apoptotic mechanism. Yet another effect was the re-organization of the actin cytoskeleton shown by the formation of stress fibers and actin aggregation. 1a also caused cell death in the adherently cultured glioblastoma cell lines U251 and Mz54. We furthermore observed that 1a strongly suppressed the stem cell properties of glioma stem-like cell lines including one primary line, highlighting the potential therapeutic relevance of this new compound.
Doppler examination of the umbilical artery and the fetal middle cerebral artery is evaluated predominantly in pregnancies with fetuses in cephalic presentation and never has been elucidated in breech presentation. Evidence on the accuracy of fetal weight estimation in dependence of the fetal presentation is controversial. Nevertheless, clinical decisions including recommendations for a cesarean section or labor induction based on these examinations are applied to pregnancies with fetuses in breech presentation. The objective of this study was to investigate the influence of the fetal presentation on fetal weight estimation accuracy, umbilical artery and middle cerebral artery resistance indices (RI) in a prospective case control study. Ultrasound examinations in 305 uncomplicated term pregnancies (153 vertex presentations, 152 breech) were investigated. Non-parametric variables were compared using Pearson’s chi2 test and Wilcoxon chi2 test, depending on variable scaling. Fetal weight estimation accuracy was not significantly different between vertex presentation group (VP) (6.97%) and breech presentation group (BP) (7.96%, p = 0.099). Fetal head circumference measurements were significantly larger in BP (350 mm vs. 341 mm in VB, p > 0.0001) while abdominal circumferences were significantly smaller (VP: 338 mm, BP: 331 mm, p = 0.0039) and weight estimation was not significantly different. Umbilical artery RIs were not significantly different between VP (54.5) and BP (55.3, p = 0.354). Fetal middle cerebral artery RIs also showed no significant differences (VP: 71.2, BP: 70.7, p = 0.335). Our study shows that fetal Doppler (RI) and weight estimation ultrasound originally calibrated in cephalic pregnancies are applicable to pregnancies with fetuses in breech presentation.
The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it promotes the proliferation of metastases. Furthermore, as a centrosome kinase, SIK2 has been shown to regulate the G2/M transition, and its depletion sensitizes ovarian cancer to paclitaxel-based chemotherapy. Here, we report the consequences of SIK2 inhibition on mitosis and synergies with paclitaxel in ovarian cancer using a novel and selective inhibitor, MRIA9. We show that MRIA9-induced inhibition of SIK2 blocks the centrosome disjunction, impairs the centrosome alignment, and causes spindle mispositioning during mitosis. Furthermore, the inhibition of SIK2 using MRIA9 increases chromosomal instability, revealing the role of SIK2 in maintaining genomic stability. Finally, MRIA9 treatment enhances the sensitivity to paclitaxel in 3D-spheroids derived from ovarian cancer cell lines and ovarian cancer patients. Our study suggests selective targeting of SIK2 in ovarian cancer as a therapeutic strategy for overcoming paclitaxel resistance.
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies.
Objective: We aimed to assess the correlation between serum prostate-specific antigen (PSA) and tumor burden in prostate cancer (PCa) patients undergoing radical prostatectomy (RP), because estimation of tumor burden is of high value, e.g., in men undergoing RP or with biochemical recurrence after RP. Patients and Methods: From January 2019 to June 2020, 179 consecutive PCa patients after RP with information on tumor and prostate weight were retrospectively identified from our prospective institutional RP database. Patients with preoperative systemic therapy (n=19), metastases (cM1, n=5), and locally progressed PCa (pT4 or pN1, n=50) were excluded from analyses. Histopathological features, including total weight of the prostate and specific tumor weight, were recorded by specialized uro-pathologists. Linear regression models were performed to evaluate the effect of PSA on tumor burden, measured by tumor weight after adjustment for patient and tumor characteristics. Results: Overall, median preoperative PSA was 7.0 ng/ml (interquartile range [IQR]: 5.41–10) and median age at surgery was 66 years (IQR: 61-71). Median prostate weight was 34 g (IQR: 26–46) and median tumor weight was 3.7 g (IQR: 1.8–7.1), respectively. In multivariable linear regression analysis after adjustment for patients and tumor characteristics, a significant, positive correlation could be detected between preoperative PSA and tumor weight (coefficient [coef.]: 0.37, CI: 0.15–0.6, p=0.001), indicating a robust increase in PSA of almost 0.4 ng/ml per 1g tumor weight. Conclusion: Preoperative PSA was significantly correlated with tumor weight in PCa patients undergoing RP, with an increase in PSA of almost 0.4 ng/ml per 1 g tumor weight. This might help to estimate both tumor burden before undergoing RP and in case of biochemical recurrence.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
Multinucleated giant cells (MNGCs) are frequently observed in the implantation areas of different biomaterials. The main aim of the present study was to analyze the long-term polarization pattern of the pro- and anti-inflammatory phenotypes of macrophages and MNGCs for 180 days to better understand their role in the success or failure of biomaterials. For this purpose, silk fibroin (SF) was implanted in a subcutaneous implantation model of Wistar rats as a model for biomaterial-induced MNGCs. A sham operation was used as a control for physiological wound healing. The expression of different inflammatory markers (proinflammatory M1: CCR-7, iNos; anti-inflammatory M2: CD-206, CD-163) and tartrate-resistant acid phosphatase (TRAP) and CD-68 were identified using immunohistochemical staining. The results showed significantly higher numbers of macrophages and MNGCs within the implantation bed of SF-expressed M1 markers, compared to M2 markers. Interestingly, the expression of proinflammatory markers was sustained over the long observation period of 180 days. By contrast, the control group showed a peak of M1 macrophages only on day 3. Thereafter, the inflammatory pattern shifted to M2 macrophages. No MNGCs were observed in the control group. To the best of our knowledge, this is study is the first to outline the persistence of pro-inflammatory MNGCs within the implantation bed of SF and to describe their long-term kinetics over 180 days. Clinically, these results are highly relevant to understand the role of biomaterial-induced MNGCs in the long term. These findings suggest that tailored physicochemical properties may be a key to avoiding extensive inflammatory reactions and achieving clinical success. Therefore, further research is needed to elucidate the correlation between proinflammatory MNGCs and the physicochemical characteristics of the implanted biomaterial.
Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
Adapting movements rapidly to unanticipated external stimuli is paramount for athletic performance and to prevent injuries. We investigated the effects of a 4-week open-skill choice-reaction training intervention on unanticipated jump-landings. Physically active adults (n = 37; mean age 27, standard deviation 2.7 years, 16 females, 21 males) were randomly allocated to one of two interventions or a control group (CG). Participants in the two intervention groups performed a 4-week visuomotor open skill choice reaction training, one for the upper and one for the lower extremities. Before and after the intervention, two different types of countermovement jumps with landings in split stance position were performed. In the (1) pre-planned condition, we informed the participants regarding the landing position (left or right foot in front position) before the jump. In the (2) unanticipated condition, this information was displayed after take-off (350–600 ms reaction time before landing). Outcomes were landing stability [peak vertical ground reaction force (pGRF) and time to stabilization (TTS)], and landing-related decision-making quality (measured by the number of landing errors). To measure extremity-specific effects, we documented the number of correct hits during the trained drills. A two-factorial (four repeated measures: two conditions, two time factors; three groups) ANCOVA was carried out; conditions = unanticipated versus pre-planned condition, time factors = pre versus post measurement, grouping variable = intervention allocation, co-variates = jumping time and self-report arousal. The training improved performance over the intervention period (upper extremity group: mean of correct choice reaction hits during 5 s drill: +3.0 hits, 95% confidence interval: 2.2–3.9 hits; lower extremity group: +1.6 hits, 0.6–2.6 hits). For pGRF (F = 8.4, p < 0.001) and landing errors (F = 17.1, p < 0.001) repeated measures effect occurred. Significantly more landing errors occurred within the unanticipated condition for all groups and measurement days. The effect in pGRF is mostly impacted by between-condition differences in the CG. No between-group or interaction effect was seen for these outcomes: pGRF (F = 0.4, p = 0.9; F = 2.3, p = 0.1) landing errors (F = 0.5, p = 0.6; F = 2.3, p = 0.1). TTS displayed a repeated measures (F = 4.9, p < 0.001, worse values under the unanticipated condition, improvement over time) and an interaction effect (F = 2.4, p = 0.03). Healthy adults can improve their choice reaction task performance by training. As almost no transfer to unanticipated landing successfulness or movement quality occurred, the effect seems to be task-specific. Lower-extremity reactions to unanticipated stimuli may be improved by more specific training regimens.
The purpose of this narrative review is to discuss and highlight recently published studies regarding the surgical management of patients suffering from prostate cancer treatment complications. Focus will be put on the recalcitrant and more complex cases which might lead to urinary diversion as a definite, last resort treatment. It is in the nature of every treatment, that complications will occur and be bothersome for both patients and physicians. A small percentage of patients following prostate cancer treatment (radical prostatectomy, radiation therapy, or other focal therapies) will suffer side effects and thus, will experience a loss of quality of life. These side effects can persist for months and even years. Often, conservative management strategies fail resulting in recalcitrant recurrences. Prostate cancer patients with “end-stage bladder,” “devastated outlet,” or a history of multiple failed interventions, are fortunately rare, but can be highly challenging for both patients and Urologists. In a state of multiple previous surgical procedures and an immense psychological strain for the patient, urinary diversion can offer a definite, last resort surgical solution for this small group of patients. Ideally, they should be transferred to centers with experience in this field and a careful patient selection is needed. As these cases are highly complex, a multidisciplinary approach is often necessary in order to guarantee an improvement of quality of life.
Mitofusin 2 (MFN2) is a mitochondrial outer membrane GTPase, which modulates mitochondrial fusion and affects the interaction between endoplasmic reticulum and mitochondria. Here, we explored how MFN2 influences mitochondrial functions and inflammatory responses towards zymosan in primary human macrophages. A knockdown of MFN2 by small interfering RNA decreased mitochondrial respiration without attenuating mitochondrial membrane potential and reduced interactions between endoplasmic reticulum and mitochondria. A MFN2 deficiency potentiated zymosan-elicited inflammatory responses of human primary macrophages, such as expression and secretion of pro-inflammatory cytokines interleukin-1β, -6, -8 and tumor necrosis factor α, as well as induction of cyclooxygenase 2 and prostaglandin E2 synthesis. MFN2 silencing also increased zymosan-induced nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinases inflammatory signal transduction, without affecting mitochondrial reactive oxygen species production. Mechanistic studies revealed that MFN2 deficiency enhanced the toll-like receptor 2-dependent branch of zymosan-triggered responses upstream of inhibitor of κB kinase. This was associated with elevated, cytosolic expression of interleukin-1 receptor-associated kinase 4 in MFN2-deficient cells. Our data suggest pro-inflammatory effects of MFN2 deficiency in human macrophages.
Magnetic resonance-guided laser interstitial laser therapy (MRgLITT) and radiofrequency ablation (RFA) represent two minimally invasive methods for the treatment of drug-refractory mesial temporal lobe epilepsy (mTLE). We performed a systematic review and a meta-analysis to compare outcomes and complications between MRgLITT, RFA, and conventional surgical approaches to the temporal lobe (i.e., anterior temporal lobe resection [ATL] or selective amygdalohippocampectomy [sAHE]). Forty-three studies (13 MRgLITT, 6 RFA, and 24 surgery studies) involved 554, 123, 1504, and 1326 patients treated by MRgLITT, RFA, ATL, or sAHE, respectively. Engel Class I (Engel-I) outcomes were achieved after MRgLITT in 57% (315/554, range = 33.3%–67.4%), RFA in 44% (54/123, range = 0%–67.2%), ATL in 69% (1032/1504, range = 40%–92.9%), and sAHE in 66% (887/1326, range = 21.4%–93.3%). Meta-analysis revealed no significant difference in seizure outcome between MRgLITT and RFA (Q = 2.74, p = .098), whereas ATL and sAHE were both superior to MRgLITT (ATL: Q = 8.92, p = .002; sAHE: Q = 4.33, p = .037) and RFA (ATL: Q = 6.42, p = .0113; sAHE: Q = 5.04, p = .0247), with better outcome in patients at follow-up of 60 months or more. Mesial hippocampal sclerosis (mTLE + hippocampal sclerosis) was associated with significantly better outcome after MRgLITT (Engel-I outcome in 64%; Q = 8.55, p = .0035). The rate of major complications was 3.8% for MRgLITT, 3.7% for RFA, 10.9% for ATL, and 7.4% for sAHE; the differences did not show statistical significance. Neuropsychological deficits occurred after all procedures, with left-sided surgeries having a higher rate of verbal memory impairment. Lateral functions such as naming or object recognition may be more preserved in MRgLITT. Thermal therapies are effective techniques but show a significantly lower rate of Engel-I outcome in comparison to ATL and sAHE. Between MRgLITT and RFA there were no significant differences in Engel-I outcome, whereby the success of treatment seems to depend on the approach used (e.g., occipital approach). MRgLITT shows a similar rate of complications compared to RFA, whereas patients undergoing MRgLITT may experience fewer major complications compared to ATL or sAHE and might have a more beneficial neuropsychological outcome.
Background: We hypothesized that lymph node dissection (LND) at salvage radical prostatectomy may be associated with lower cancer-specific mortality (CSM) and we tested this hypothesis.
Methods: We relied on surveillance, epidemiology, and end results (2004–2016) to identify all salvage radical prostatectomy patients. Categorical, as well as univariate and multivariate Cox regression models tested the effect of LND (LND performed vs. not), as well as at its extent (log-transformed lymph node count) on CSM.
Results: Of 427 salvage radical prostatectomy patients, 120 (28.1%) underwent LND with a median lymph node count of 6 (interquartile range [IQR], 3–11). According to LND status, no significant or clinically meaningful differences were recorded in PSA at diagnosis, stage and biopsy Gleason score at diagnosis, except for age at prostate cancer diagnosis (LND performed 63 vs. 68 years LND not performed, p < .001). LND status (performed) was an independent predictor of lower CSM (hazard ratio [HR] 0.47; p = .03). Similarly, lymph node count (log transformed) also independently predicted lower CSM (HR: 0.60; p = .01). After the 7th removed lymph node, the effect of CSM became marginal. The effect of N-stage on CSM could not be tested due to insufficient number of observations.
Conclusions: Salvage radical prostatectomy is rarely performed and LND at salvage radical prostatectomy is performed in a minority of patients. However, LND at salvage radical prostatectomy is associated with lower CSM. Moreover, LND extent also exerts a protective effect on CSM. These observations should be considered in salvage radical prostatectomy candidates.
Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached. Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.
Purpose: Dexamethasone (Dex) is the most common corticosteroid to treat edema in glioblastoma (GBM) patients. Recent studies identified the addition of Dex to radiation therapy (RT) to be associated with poor survival. Independently, Tumor Treating Fields (TTFields) provides a novel anti-cancer modality for patients with primary and recurrent GBM. Whether Dex influences the efficacy of TTFields, however, remains elusive. Methods: Human GBM cell lines MZ54 and U251 were treated with RT or TTFields in combination with Dex and the effects on cell counts and cell death were determined via flow cytometry. We further performed a retrospective analysis of GBM patients with TTFields treatment +/- concomitant Dex and analysed its impact on progression-free (PFS) and overall survival (OS). Results: The addition of Dex significantly reduced the efficacy of RT in U251, but not in MZ54 cells. TTFields (200 kHz/250 kHz) induced massive cell death in both cell lines. Concomitant treatment of TTFields and Dex did not reduce the overall efficacy of TTFields. Further, in our retrospective clinical analysis, we found that the addition of Dex to TTFields therapy did not influence PFS nor OS. Conclusion: Our translational investigation indicates that the efficacy of TTFields therapy in patients with GBM and GBM cell lines is not affected by the addition of Dex.
Objectives: To evaluate peri-implant tissue dimensions following nonsurgical (NS) and surgical therapy (S) employing different decontamination protocols of advanced ligature-induced peri-implantitis in dogs.
Material & Methods: Peri-implantitis defects (n = 5 dogs, n = 30 implants) were randomly and equally allocated in a split-mouth design to NS or S treatment using either an Er:YAG laser (ERL), an ultrasonic device (VUS), or plastic curettes + local application of metronidazole gel (PCM), respectively. Horizontal bone thickness (hBT) and soft tissue thickness (hMT) were measured at different reference points: (v0) at the marginal portion of the peri-implant mucosa (PM); (v1) at 50% of the distance from PM to bone crest (BC); (v2) at the BC; (v3) at the most coronal extension of the bone-to-implant contact. Vertical peri-implant tissue height was calculated from PM to BC.
Results: All of the treatment groups showed a gradual hMT increase from v0 to the v2 reference point, followed by a reduction from v2 to the v3 region. The S-VUS subgroup tended to be associated with higher hMT values at the v0 region than the NS-VUS subgroup (0.44 mm versus 0.31 mm). PM-BC distance varied from 2.22 to 2.83 mm in the NS group, and from 2.07 to 2.38 in the S group.
Conclusion: Vertical and horizontal peri-implant tissue dimensions were similar in different treatment groups.