Histone deacetylase inhibition (HDACi) has been suggested as a promising approach to bolster TLR-mediated induction of antimicrobial peptides such as human β-defensin 2 (hBD2). In inflammatory bowel ...disease (IBD), Crohn's disease (CD) patients display an attenuated expression of hBD2 as compared to ulcerative colitis (UC). Here, we aimed to study if combining HDACi with the therapeutic E. coli Nissle 1917 (EcN), a strong hBD2 inducer, might be a feasible strategy to further modify protective immune responses. Monolayer epithelial cell lines versus cultured human biopsies from healthy controls and CD and UC patients showed diverse effects. In mono-cell systems, we observed a strong NF-kB-dependent enhancement of TLR- but also IL1β-mediated hBD2 induction after HDACi. In contrast, multicellular colonic biopsy culture showed the opposite result and HDACi was associated with an abolished TLR-mediated hBD2 induction in all tested patient groups. Of note, CD patients showed an attenuated induction of hBD2 by E. coli Nissle as compared to UC. We conclude that the role of HDACs in hBD2 regulation is context-dependent and likely modified by different cell types. Differential induction in different IBD entities suggests different clinical response patterns based on still unknown hBD2-associated mechanisms.
Healing of gastrointestinal ulcers after Hemospray application was reported in literature. The pathophysiological mechanism of action of hemostatic powders is not elucidated so far. A prospective ...animal model was performed to evaluate the effect of Hemospray application on the healing process of artificially induced ulcers of the upper and lower gastrointestinal tract. In 10 pigs, 20 ulcers were created in each the upper and the lower gastrointestinal tract by endoscopic mucosal resection. 50% of the pigs were immediately treated with Hemospray application, the others were not treated. Ulcer size was measured endoscopically on day 0, 2, and 7. On day 7 the ulcers were histopathological evaluated for capillary ingrowth and the thickness of the collagen layer. After 7 days the sizes of the ulcers decreased significantly (stomach: - 22.8% with Hemospray application, - 19% without Hemospray application; rectum: - 50.8% with Hemospray application, - 49.5% without Hemospray application; p = 0.005-0.037), but without significant difference between both groups. This study shows no significant effect of the hemostatic powder Hemospray on ulcer healing in the upper and lower gastrointestinal tract compared with untreated controls, neither harmful nor beneficial. However, some trends merit further trials in patients and may indicate a possible mechanism of accelerated mucosal healing.
Ultrasound is one of the most important imaging techniques in clinical medicine with unique advantages. Skills in ultrasound imaging are very usefull for physicians including novices and thus also ...mandated by the Task Force "National Competence-Based Learning Objectives for Undergraduate Medical Education" (NKLM) in Germany and as well as by the German Ultrasound Society (Deutsche Gesellschaft für Ultraschall in der Medizin, DEGUM). Since ultrasound is best learned hands-on in very small supervised groups, we developed and implemented a comprehensive ultrasound-curriculum for all undergraduate medical students of our faculty using a peer-teaching concept.
We used Kern's six-step model of curricular development comprising (1) problem identification and general needs assessment, (2) needs assessment of the targeted learners, (3) goals and objectives, (4) educational stategies, (5) implementation, and (6) evaluation and feedback.
The developed curriculum covers basic ultrasound of the abdomen and the throat, eFAST (Extended Focused Assessment with Sonography for Trauma), lung-ultrasound, FEEL (Focused Echocardiography in Emergency Life Support) and compression duplex sonography of the thigh deep vein system. All 5th year medical students receive a 90 min lecture on ultrasound basics by a faculty member and then a 12.5 h hands-on course divided into three sessions with one student tutor for every 4 students. The students are provided with a script (PDF-File) that covers all the learning goals, including example images of pathologies. The student tutors are trained during a 1 week ultrasound course and a 21-day rotation through seven different ultrasound laboratories. In addition, they undergo a standardized 1.5 day didactical training. Prior to the implementation for all students, the overall course was tested on 27 volunteer students. These students rated (on a 6-point Likert scale from 1 = excellent to 6 = very poor) the satisfaction with the student tutors and the faculty members as 1.4 ± .9 (mean ± stddev) and 1.3 ± .5 respectively.
A comprehensive ultrasound curriculum for all undergraduate medical students using a peer-teaching concept is feasible. Further studies are needed to evaluate in detail the learning outcomes for students and student tutors.
Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. The accumulation of neoplastic B-cells is primarily caused by ...prolonged life-span of these cells due to deregulation of apoptosis, and only marginally due to a higher proliferation rate. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little is known about the complex regulation of this process. Therefore, more detailed research is required to understand the complicated mechanisms and regulatory processes of apoptosis in neoplastic B lymphocytes.
Amongst all currently used drugs in the field of cancer therapy, the most prominent group of agents which induce DNA, damage both directly or indirectly. Intuitively DNA should not be a perfect ...target for relatively unspecific small molecular weight drugs. However, the current understanding is that not damage per se but cellular response to DNA damage induced by antitumor agents is responsible for their specific targeted effect towards cancer cells in comparison to the normal cells. DNA damaging chemotherapeutics include compounds with diferent activities namely: directly or indirectly induce DNA strand breaks, covalently modify DNA bases, change the chromatin structure and topology by inhibiting chromatin-modifying enzymes. In this special issue of Current Medicinal Chemistry entitled...
The occurrence and spread of multidrug-resistant bacteria is a prominent health concern. To curb this urgent threat, new innovative strategies pursuing novel antimicrobial agents are of the utmost ...importance. Here, we unleashed the antimicrobial activity of human neutrophil peptide-4 (HNP-4) by tryptic digestion. We identified a single 11 amino acid long fragment (HNP-4
1
–
11
) with remarkable antimicrobial potential, exceeding that of the full length peptide on both mass and molar levels. Importantly, HNP-4
1
–
11
was equally bactericidal against multidrug-resistant and non-resistant strains; a potency that was further enhanced by N- and C-terminus modifications (acetylation and amidation, respectively). These observations, combined with negligible cytotoxicity not exceeding that of the full length peptide, presents proteolytic digestion of innate host-defense-peptides as a novel strategy to overcome the current health crisis related to antibiotic-resistant bacteria.
The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as ...well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals.
EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).
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