Publications by authors named "Thomas Schmidt"

853 Publications

A Simplified Method for Patterning Graphene on Dielectric Layers.

ACS Appl Mater Interfaces 2021 Jul 30. Epub 2021 Jul 30.

Department of Physics, Aberystwyth University, Aberystwyth SY23 3BZ, United Kingdom.

The large-scale formation of patterned, quasi-freestanding graphene structures supported on a dielectric has so far been limited by the need to transfer the graphene onto a suitable substrate and contamination from the associated processing steps. We report μm scale, few-layer graphene structures formed at moderate temperatures (600-700 °C) and supported directly on an interfacial dielectric formed by oxidizing Si layers at the graphene/substrate interface. We show that the thickness of this underlying dielectric support can be tailored further by an additional Si intercalation of the graphene prior to oxidation. This produces quasi-freestanding, patterned graphene on dielectric SiO with a tunable thickness on demand, thus facilitating a new pathway to integrated graphene microelectronics.
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http://dx.doi.org/10.1021/acsami.1c09987DOI Listing
July 2021

Comparative Repeat Profiling of Two Closely Related Conifers ( and ) Reveals High Genome Similarity With Only Few Fast-Evolving Satellite DNAs.

Front Genet 2021 12;12:683668. Epub 2021 Jul 12.

Institute of Botany, Technische Universität Dresden, Dresden, Germany.

In eukaryotic genomes, cycles of repeat expansion and removal lead to large-scale genomic changes and propel organisms forward in evolution. However, in conifers, active repeat removal is thought to be limited, leading to expansions of their genomes, mostly exceeding 10 giga base pairs. As a result, conifer genomes are largely littered with fragmented and decayed repeats. Here, we aim to investigate how the repeat landscapes of two related conifers have diverged, given the conifers' accumulative genome evolution mode. For this, we applied low-coverage sequencing and read clustering to the genomes of European and Japanese larch, (Lamb.) Carrière and (Mill.), that arose from a common ancestor, but are now geographically isolated. We found that both species harbored largely similar repeat landscapes, especially regarding the transposable element content. To pin down possible genomic changes, we focused on the repeat class with the fastest sequence turnover: satellite DNAs (satDNAs). Using comparative bioinformatics, Southern, and fluorescent hybridization, we reveal the satDNAs' organizational patterns, their abundances, and chromosomal locations. Four out of the five identified satDNAs are widespread in the genus, with two even present in the more distantly related and genera. Unexpectedly, the EulaSat3 family was restricted to and absent from , indicating its evolutionarily young age. Taken together, our results exemplify how the accumulative genome evolution of conifers may limit the overall divergence of repeats after speciation, producing only few repeat-induced genomic novelties.
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http://dx.doi.org/10.3389/fgene.2021.683668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312256PMC
July 2021

HIPEC-Induced Acute Kidney Injury: A Retrospective Clinical Study and Preclinical Model.

Ann Surg Oncol 2021 Jul 14. Epub 2021 Jul 14.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) is the treatment of choice for selected patients with peritoneal malignancies. HIPEC is accompanied by moderate-to-high patient morbidity, including acute kidney injury. The significance of nephrotoxic agents such as cisplatin versus hyperthermia in HIPEC-induced nephrotoxicity has not been defined yet.

Patients And Methods: A total of 153 patients treated with HIPEC were divided into groups with (AKI+) and without (AKI-) kidney injury. Laboratory parameters and data concerning patient demographics, underlying disease, surgery, complications, and HIPEC were gathered to evaluate risk factors for HIPEC-induced AKI. A preclinical mouse model was applied to assess the significance of cisplatin and hyperthermia in HIPEC-induced AKI, as well as protective effects of the cytoprotective agent amifostine.

Results: AKI occurred in 31.8% of patients undergoing HIPEC. Treatment with cisplatin-containing HIPEC regimens represented a major risk factor for HIPEC-related AKI (p < 0.001). Besides, angiotensin receptor blockers and increased preoperative creatinine and urea levels were independent risk factors for AKI after HIPEC. In a preclinical mouse model, intraperitoneal perfusion with cisplatin induced AKI, whereas hyperthermia alone, or in combination with cisplatin, did not induce or enhance renal injury. Amifostine failed to confer nephroprotective effects in a miniaturized HIPEC model.

Conclusions: AKI is a frequent complication after HIPEC. The risk of renal injury is particularly high in patients treated with cisplatin-containing HIPEC regimens. Hyperthermic perfusion of the abdomen by itself does not seem to induce or aggravate HIPEC-induced renal injury.
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http://dx.doi.org/10.1245/s10434-021-10376-5DOI Listing
July 2021

Self-expanding Metal Stents for Anastomotic Leaks After Upper Gastrointestinal Cancer Surgery.

J Surg Res 2021 Jul 10;267:516-526. Epub 2021 Jul 10.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.

Background: Anastomotic leakage (AL) is a common and severe complication after upper gastrointestinal (UGI) surgery. Although evidence is scarce, endoscopic deployed self-expanding metal stents (SEMS) are well-established for the management of AL in UGI surgery. The present study aimed to evaluate the feasibility, effectiveness, and safety of SEMS in terms of success, mortality, and morbidity in patients with AL after UGI cancer surgery.

Materials And Methods: Patients with AL after primary UGI cancer surgery were retrospectively analyzed with regard to demographics, disease, surgical and endoscopic procedures, and complications. Stent treatment success was divided into technical, primary (within 72 hours of stent deployment), sustained (after 72 hours of stent deployment), and sealing success.

Results: In a total of 63 patients, 74 stents were used and 11 were deployed in endoscopic reinterventions. Stent deployment was successful in all patients. Primary and sustained success rates were 68.3% (n = 43) and 65.1% (n = 41), respectively. Of the primarily successfully treated patients, 87.8% remained successfully treated. If primary treatment was unsuccessful, it remained unsuccessful in 66.6% of the patients (P = 0.002). Final sealing of the leakage was observed in 65.1% of patients (n = 41). Longer stent shafts and wider stent end widths were correlated with successful stent treatment (P < 0.05).

Conclusion: SEMS are a safe and sufficient tool in the treatment of AL after UGI cancer surgery. Treatment success is improved with longer stent shafts and wider stent end widths. Switching to alternative treatments is strongly suggested if signs of persistent leakage are present beyond 72 hours after stent placement, as this is highly indicative of sustained stent failure.
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http://dx.doi.org/10.1016/j.jss.2021.06.007DOI Listing
July 2021

Translocated microbiome composition determines immunological outcome in treated HIV infection.

Cell 2021 Jul 7;184(15):3899-3914.e16. Epub 2021 Jul 7.

Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL 33124, USA.

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.
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http://dx.doi.org/10.1016/j.cell.2021.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316372PMC
July 2021

Liquid Pressure Determination in Polymer Electrolyte Fuel Cells.

ACS Appl Mater Interfaces 2021 Jul 8;13(29):34003-34011. Epub 2021 Jul 8.

Electrochemistry Laboratory, Paul Scherrer Institut (PSI), Villigen 5232, Switzerland.

Extending the operating range of fuel cells to higher current densities is limited by the ability of the cell to remove the water produced by the electrochemical reaction, avoiding flooding of the gas diffusion layers. It is therefore of great interest to understand the complex and dynamic mechanisms of water cluster formation in an operando fuel cell setting as this can elucidate necessary changes to the gas diffusion layer properties with the goal of minimizing the number, size, and instability of the water clusters formed. In this study, we investigate the cluster formation process using X-ray tomographic microscopy at 1 Hz frequency combined with interfacial curvature analysis and volume-of-fluid simulations to assess the pressure evolution in the water phase. This made it possible to observe the increase in capillary pressure when the advancing water front had to overcome a throat between two neighboring pores and the nuanced interactions of volume and pressure evolution during the droplet formation and its feeding path instability. A 2 kPa higher breakthrough pressure compared to static capillary pressure versus saturation evaluations was observed, which suggests a rethinking of the dynamic liquid water invasion process in polymer electrolyte fuel cell gas diffusion layers.
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http://dx.doi.org/10.1021/acsami.1c04560DOI Listing
July 2021

How I do it: endoscopic endonasal approach to the orbital apex.

Acta Neurochir (Wien) 2021 Jul 6. Epub 2021 Jul 6.

Department of Skull Base Surgery, Clinica Bio Bio, Avenida Alessandri 3515, Concepción, Chile.

Background: The endoscopic endonasal approach provides an option to approach the medial and inferior orbital apex, with less manipulation of intraorbital structures.

Method: We described the advantages, complications, caveats, and indications of the endoscopic endonasal approach to the orbital apex. An intraorbital extraconal cavernous malformation is shown as example.

Conclusion: The endoscopic endonasal approach is a good corridor to the medial and inferior orbital apex, providing good exposure and little manipulation of the intraorbital contents.
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http://dx.doi.org/10.1007/s00701-021-04900-5DOI Listing
July 2021

Granulin: An Invasive and Survival-Determining Marker in Colorectal Cancer Patients.

Int J Mol Sci 2021 Jun 16;22(12). Epub 2021 Jun 16.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany.

Background: Granulin is a secreted, glycosylated peptide-originated by cleavage from a precursor protein-which is involved in cell growth, tumor invasion and angiogenesis. However, the specific prognostic impact of granulin in human colorectal cancer has only been studied to a limited extent. Thus, we wanted to assess the expression of granulin in colorectal cancer patients to evaluate its potential as a prognostic biomarker.

Methods: Expressional differences of granulin in colorectal carcinoma tissue ( = 94) and corresponding healthy colon mucosa were assessed using qRT-PCR. Immunohistochemistry was performed in colorectal cancer specimens ( = 97), corresponding healthy mucosa ( = 47) and colorectal adenomas ( = 19). Subsequently, the results were correlated with histopathological and clinical patients' data. HCT-116 cells were transfected with siRNA for invasion and migration assays.

Results: Immunohistochemistry and qRT-PCR revealed tumoral over expression of granulin in colorectal cancer specimens compared to corresponding healthy colon mucosa and adenomas. Tumoral overexpression of granulin was associated with a significantly impaired overall survival. Moreover, downregulation of granulin by siRNA significantly diminished the invasive capacities of HCT-116 cells in vitro.

Conclusion: Expression of granulin differs in colorectal cancer tissue, adenomas and healthy colon mucosa. Furthermore, granulin features invasive and migrative capabilities and overexpression of granulin correlates with a dismal prognosis. This reveals its potential as a prognostic biomarker and granulin could be a worthwhile molecular target for individualized anticancer therapy.
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http://dx.doi.org/10.3390/ijms22126436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235441PMC
June 2021

Boswellic Acids Show In Vitro Activity against .

Molecules 2021 Jun 15;26(12). Epub 2021 Jun 15.

Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Pharma Campus-Corrensstrasse 48, D-48149 Münster, Germany.

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from resin. 11-keto-β-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against axenic amastigotes along with five further boswellic acid derivatives. 3--acetyl-11-keto-β-boswellic acid (AKBA) showed the strongest activity with an IC value of 0.88 µM against axenic amastigotes but was inactive against intracellular amastigotes in murine macrophages.
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http://dx.doi.org/10.3390/molecules26123651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232742PMC
June 2021

Antiprotozoal -Triterpene Alkaloids from L.

Antibiotics (Basel) 2021 Jun 10;10(6). Epub 2021 Jun 10.

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany.

Malaria and human African trypanosomiasis (HAT; sleeping sickness) are life-threatening tropical diseases caused by protozoan parasites. Due to limited therapeutic options, there is a compelling need for new antiprotozoal agents. In a previous study, O-tigloylcyclovirobuxeine-B was recovered from a . L. (common box; Buxaceae) leaf extract by bioactivity-guided isolation. This -cycloartane alkaloid was identified as possessing strong and selective in vitro activity against the causative agent of malaria tropica, (). The purpose of this study is the isolation of additional alkaloids from . L. to search for further related compounds with strong antiprotozoal activity. In conclusion, 25 alkaloids were obtained from . L., including eight new natural products and one compound first described for this plant. The structure elucidation was accomplished by UHPLC/+ESI-QqTOF-MS/MS and NMR spectroscopy. The isolated alkaloids were tested against and (), the causative agent of East African sleeping sickness. To assess their selectivity, cytotoxicity against mammalian cells (L6 cell line) was tested as well. Several of the compounds displayed promising in vitro activity against the pathogens in a sub-micromolar range with concurrent high selectivity indices (SI). Consequently, various alkaloids from . L. have the potential to serve as a novel antiprotozoal lead structure.
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http://dx.doi.org/10.3390/antibiotics10060696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228141PMC
June 2021

Distal Bile Duct Cancer: Radical (R0 >1 mm) Resection Achieves Favorable Survival.

Ann Surg 2021 Jun 18. Epub 2021 Jun 18.

Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Objective: Evaluation of the outcome after resection for distal bile duct cancer (DBC) with focus on the impact of microscopic histopathological resection status R0 (>1 mm) vs R1 (≤1 mm) vs R1 (direct).

Summary Background Data: DBC is a rare disease for which oncologic resection offers the only chance of cure.

Methods: Prospectively collected data of consecutive patients undergoing pancreaticoduodenectomy for DBC were analyzed. Histopathological resection status was classified according to the Leeds protocol for pancreatic cancer (PDAC; R0 >1 mm margin clearance vs. R1 ≤1 mm vs. R1 direct margin involvement).

Results: A total of 196 patients underwent pancreaticoduodenectomy for DBC. Microscopic complete tumor clearance (R0>1 mm) was achieved in 113 patients (58%). Median overall survival (OS) of the entire cohort was 37 months (5- and 10-year OS rate: 40% and 31%, respectively). After R0 resection, median OS increased to 78 months with a 5-year OS rate of 52%. Negative prognostic factors were age >70 years (p < 0.0001, hazard ratio 2.48), intraoperative blood loss >1000 ml (p=0.0009, HR 1.99), pN1 and pN2 status (p=0.0052 and p=0.0006, HR2.14 and 2.62, respectively) and American Society of Anesthesiologists score >II (p=0.0259, HR 1.61).

Conclusions: This is the largest European single-center study of surgical treatment for DBC and the first to investigate the prognostic impact of the revised PDAC resection status definition in DBC. The results show that this definition is valid in DBC and that "true" R0 resection (>1 mm) is a key factor for excellent survival. In contrast to PDAC, there was no survival difference between R1 (≤1 mm) and R1 (direct).
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http://dx.doi.org/10.1097/SLA.0000000000005012DOI Listing
June 2021

GUNC: detection of chimerism and contamination in prokaryotic genomes.

Genome Biol 2021 Jun 13;22(1):178. Epub 2021 Jun 13.

Structural and Computational Biology Unit, European Molecular Biology Laboratory, 69117, Heidelberg, Germany.

Genomes are critical units in microbiology, yet ascertaining quality in prokaryotic genome assemblies remains a formidable challenge. We present GUNC (the Genome UNClutterer), a tool that accurately detects and quantifies genome chimerism based on the lineage homogeneity of individual contigs using a genome's full complement of genes. GUNC complements existing approaches by targeting previously underdetected types of contamination: we conservatively estimate that 5.7% of genomes in GenBank, 5.2% in RefSeq, and 15-30% of pre-filtered "high-quality" metagenome-assembled genomes in recent studies are undetected chimeras. GUNC provides a fast and robust tool to substantially improve prokaryotic genome quality.
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http://dx.doi.org/10.1186/s13059-021-02393-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201837PMC
June 2021

Insights into Reaction Kinetics in Confined Space: Real Time Observation of Water Formation under a Silica Cover.

J Am Chem Soc 2021 Jun 7;143(23):8780-8790. Epub 2021 Jun 7.

Fritz-Haber Institute of the Max-Planck Society, Faradayweg 4-6, 14195 Berlin, Germany.

We offer a comprehensive approach to determine how physical confinement can affect the water formation reaction. By using free-standing crystalline SiO bilayer supported on Ru(0001) as a model system, we studied the water formation reaction under confinement in situ and in real time. Low-energy electron microscopy reveals that the reaction proceeds via the formation of reaction fronts propagating across the Ru(0001) surface. The Arrhenius analyses of the front velocity yield apparent activation energies () of 0.32 eV for the confined and 0.59 eV for the nonconfined reaction. DFT simulations indicate that the rate-determining step remains unchanged upon confinement, therefore ruling out the widely accepted transition state effect. Additionally, HO accumulation cannot explain the change in for the confined cases studied because its concentration remains low. Instead, numerical simulations of the proposed kinetic model suggest that the H adsorption process plays a decisive role in reproducing the Arrhenius plots.
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http://dx.doi.org/10.1021/jacs.1c03197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297729PMC
June 2021

Improving mosquito control strategies with population genomics.

Trends Parasitol 2021 May 29. Epub 2021 May 29.

Pest and Environmental Adaptation Research Group, School of BioSciences, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia.

Mosquito control strategies increasingly apply knowledge from population genomics research. This review highlights recent applications to three research domains: mosquito invasions, insecticide resistance evolution, and rear and release programs. Current research trends follow developments in reference assemblies, either as improvements to existing assemblies (particularly Aedes) or assemblies for new taxa (particularly Anopheles). With improved assemblies, studies of invasive and rear and release target populations are better able to incorporate adaptive as well as demographic hypotheses. New reference assemblies are aiding comparisons of insecticide resistance across sister taxa while helping resolve taxon boundaries amidst frequent introgression. Anopheles gene drive deployments and improved Aedes genome assemblies should lead to a convergence in research aims for Anopheles and Aedes in the coming years.
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http://dx.doi.org/10.1016/j.pt.2021.05.002DOI Listing
May 2021

L.: Antitrypanosomal Activity and Active Constituents against .

Molecules 2021 May 27;26(11). Epub 2021 May 27.

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany.

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from L. (common Sage, Lamiaceae) possesses high activity against , causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against , in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group.
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http://dx.doi.org/10.3390/molecules26113226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199030PMC
May 2021

Teaching Pathology in an Integrated Preclinical Medical School Curriculum and Adaptations to COVID-19 Restrictions.

Acad Pathol 2021 Jan-Dec;8:23742895211015337. Epub 2021 May 19.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

The coronavirus disease 2019 (COVID-19) pandemic has had a major impact on education at all age levels, including professional schools and health professions programs. We describe the experience of adapting preclinical medical school courses within an integrated curriculum to virtual instruction. A major feature of two of the courses were pathology small groups adapted from pathology courses in the previous medical school curriculum. These small groups were designed to use facilitated groups of 8 to 10 students. With a sudden change to virtual learning, these small groups were shifted to large group virtual sessions. In general, the conversion went well, with ongoing optimization of the format of the large group sessions mainly occurring over the first several sessions. End-of-course student evaluations were generally positive, but with a preference toward returning to live sessions in the future. Scores on 5 multiple choice examinations in the spring 2020 course were essentially identical in mean, standard deviation, and distribution to examinations in the previous 2 years of the course that had similar layout and topic organization. We discuss the challenges and successes of the switch to virtual instruction and of teaching pathology content within an integrated medical school curriculum.
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http://dx.doi.org/10.1177/23742895211015337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138288PMC
May 2021

A Simple Assessment of Information Security Awareness in Hospital Staff Across Five Danish Regions.

Stud Health Technol Inform 2021 May;281:635-639

Biomedical Informatics, University of Pennsylvania, Phila., PA, USA.

Information Security Awareness among employees in healthcare has become an essential part in safeguarding health information systems against cyber-attacks and data breaches. We present three simple security awareness questions that can be included in larger surveys gauging other aspects of information systems. The questions have been tested in a national Danish survey to evaluate correlations among medical profession, computer proficiency, experience, and place of employment. We find that dissatisfaction with system usability is strongly linked with reduced information security awareness, and that clinical professions have different responses to security concerns.
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http://dx.doi.org/10.3233/SHTI210248DOI Listing
May 2021

Pseudo-Cerebrospinal Fluid Leaks of the Anterior Skull Base: Algorithm for Diagnosis and Management.

J Neurol Surg B Skull Base 2021 Jun 8;82(3):351-356. Epub 2019 Nov 8.

Department of Otorhinolaryngology, Universidad de Concepción, Concepción, Chile.

 Pseudo-cerebrospinal fluid (CSF) leaks are a rare cause of unilateral, watery rhinorrhea. We proposed a step-wise approach to evaluate these cases.  It involves a single-center retrospective cohort study.  The setting is that of a tertiary academic medical center.  Ten patients with diagnosis of pseudo-CSF leak over a 21-year period were evaluated using our proposed algorithm that includes computed tomography, magnetic resonance imaging, nasal endoscopy, β-2 transferrin, intrathecal fluorescein, and surgical exploration of the anterior cranial base.  The occurrence of intracranial infection and resolution of the symptoms were evaluated at a mean follow-up of 94.4 months.  Eight patients had history of skull base fracture or surgery. In all patients computed tomography, magnetic resonance imaging, and nasal endoscopy did not show signs of CSF leak. Beta-2 transferrin testing was performed in five patients, being negative in all of them. Intrathecal fluorescein was performed in seven patients, being negative in five and inconclusive in two. Surgical exploration was performed in five patients, definitively ruling out CSF leak. Six patients were treated with intranasal ipratropium, resolving the symptoms in all cases.  The presented algorithm provides a step-wise approach for patients with unilateral watery rhinorrhea, allowing to safely ruling out CSF leak.
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http://dx.doi.org/10.1055/s-0039-3399519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133806PMC
June 2021

treeclimbR pinpoints the data-dependent resolution of hierarchical hypotheses.

Genome Biol 2021 May 17;22(1):157. Epub 2021 May 17.

Department of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich, Zurich, 8057, Switzerland.

treeclimbR is for analyzing hierarchical trees of entities, such as phylogenies or cell types, at different resolutions. It proposes multiple candidates that capture the latent signal and pinpoints branches or leaves that contain features of interest, in a data-driven way. It outperforms currently available methods on synthetic data, and we highlight the approach on various applications, including microbiome and microRNA surveys as well as single-cell cytometry and RNA-seq datasets. With the emergence of various multi-resolution genomic datasets, treeclimbR provides a thorough inspection on entities across resolutions and gives additional flexibility to uncover biological associations.
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http://dx.doi.org/10.1186/s13059-021-02368-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127214PMC
May 2021

Outcome after surgical resection of multiple recurrent retroperitoneal soft tissue sarcoma.

Eur J Surg Oncol 2021 Aug 4;47(8):2189-2200. Epub 2021 May 4.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Introduction: Local recurrences (LR) and distant metastases (DM) are common in retroperitoneal soft tissue sarcoma (RPS). Longer time to recurrence and resection of the recurrent lesion have been identified as beneficial prognostic factors for overall survival (OS) upon first tumor relapse. However, prognostic factors concerning OS upon subsequent recurrences are scarcely defined. In this study, we aimed to identify prognostic factors for post-relapse outcome in multiple recurrent RPS.

Methods: Patients undergoing resection of primary and recurrent RPS at the University Hospital Heidelberg were retrospectively analyzed. Multivariable Cox regression analyses were performed to identify predictors of overall, LR- and DM-free survival. Subgroup analyses were performed for liposarcoma and leiomyosarcoma patients.

Results: 201 patients with primary disease, 101 patients with first, 66 patients with second and 43 patients with third LR as well as 75 patients with DM were analyzed. More than 12 months to recurrence and resection of recurrence were associated with improved OS after resection of first and second LR (5-year OS for first/second LR; resection: 64%/62%, no resection: 20%/46%). Gross macroscopic incomplete resection of first (p < 0.001), second (p = 0.001), and third recurrences (p < 0.001) was an independent prognostic factor for poor OS.

Conclusion: Development of LR and DM is frequent in RPS. Once a tumor relapsed, patients benefit from tumor resection not only in case of first, but also in case of subsequent recurrences.
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http://dx.doi.org/10.1016/j.ejso.2021.04.040DOI Listing
August 2021

C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia.

Oncogene 2021 Jul 6;40(29):4746-4758. Epub 2021 May 6.

Institute for Biochemistry, Westfälische-Wilhelms-Universität, Münster, Germany.

Transcription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPβ. C/EBPβ-inhibitory STLs affect the expression of a large number of MYB-regulated genes, suggesting that the cooperation of MYB and C/EBPβ broadly shapes the transcriptional program of AML cells. We show that expression of GFI1, a direct MYB target gene, is controlled cooperatively by MYB, C/EBPβ, and co-activator p300, and is down-regulated by C/EBPβ-inhibitory STLs, exemplifying that they target the activity of composite MYB-C/EBPβ-p300 transcriptional modules. Ectopic expression of GFI1, a zinc-finger protein that is required for the maintenance of hematopoietic stem and progenitor cells, partially abrogated STL-induced myelomonocytic differentiation, implicating GFI1 as a relevant target of C/EBPβ-inhibitory STLs. Overall, our data identify C/EBPβ as a pro-leukemogenic factor in AML and suggest that targeting of C/EBPβ may have therapeutic potential against AML.
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http://dx.doi.org/10.1038/s41388-021-01800-xDOI Listing
July 2021

Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts.

J Clin Invest 2021 Jun;131(11)

Department of Medicine, Columbia University, New York, New York, USA.

Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.
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http://dx.doi.org/10.1172/JCI146987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159701PMC
June 2021

Systematic simplification of the Anaerobic Digestion Model No. 1 (ADM1) - Laboratory experiments and model application.

Bioresour Technol 2021 Aug 6;333:125104. Epub 2021 Apr 6.

Biochemical Conversion Department, Deutsches Biomasseforschungszentrum gemeinnützige GmbH, Torgauer Straße 116, 04347 Leipzig, Germany; Faculty of Agricultural and Environmental Sciences, Chair of Waste and Resource Management, University of Rostock, Justus-von-Liebig-Weg 6, 18059 Rostock, Germany.

Due to a limited number of available measurements on agricultural biogas plants, established process models, such as the Anaerobic Digestion Model No. 1 (ADM1), are rarely applied in practise. To provide a reliable basis for model-based monitoring and control, different model simplifications of the ADM1 were implemented for process simulation of semi-continuous anaerobic digestion experiments using agricultural substrates (maize silage, sugar beet silage, rye grain and cattle manure) and industrial residues (grain stillage). Individual model structures enable a close depiction of biogas production rates and characteristic intermediates (ammonium nitrogen, propionic and acetic acid) with equal accuracy as the original ADM1. The impact of different objective functions and standard parameter values on parameter estimates of first-order hydrolysis constants and microbial growth rates were evaluated. Due to the small number of required model parameters and suitable system characteristics, simplified model structures show clear advantages for practical application on agricultural biogas plants.
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http://dx.doi.org/10.1016/j.biortech.2021.125104DOI Listing
August 2021

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents.

J Med Chem 2021 05 26;64(9):6397-6409. Epub 2021 Apr 26.

Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.

Herein, relationships between the structures of 1-aminoethyl-substituted chromenes and their antimalarial activities were thoroughly investigated. At first, the methyl moiety in the side chain was removed to eliminate chirality. The hydrogenation state of the benzopyran system, the position of the phenolic OH moiety, and the distance of the basic amino moiety toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol (IC = 10 nM), 1-benzopyran-7-ol (IC = 38 nM), and the aminoalcohol (IC = 17 nM) displayed antiplasmodial activity with IC values below 50 nM. To identify the mechanism of action, inhibition of three key enzymes by was investigated. was not able to reduce the number of in erythrocytes of mice. This low in vivo activity was explained by fast clearance from blood plasma combined with rapid biotransformation of . Three main metabolites of were identified by liquid chromatography-mass spectrometry (LC-MS) methods.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00483DOI Listing
May 2021

Fe-Enrichment effect on the composition and performance of Fe-based O-reduction electrocatalysts.

Phys Chem Chem Phys 2021 Apr;23(15):9147-9157

Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.

Pt-group metal (PGM)-free catalysts of the Me-N-C type based on abundant and inexpensive elements have gained importance in the field of oxygen reduction reaction (ORR) electrocatalysis due to their promising ORR-activities. Their insufficient stability, however, has fueled the interest in obtaining an in-depth understanding of their composition, which requires highly sensitive techniques compatible with their low metal contents (typically <5 wt%). In the particular context of iron-based materials, 57Fe-Mössbauer spectroscopy is often used to provide such compositional information, but requires (partially) 57Fe-enriched precursors. As a consequence, the extrapolation of conclusions drawn from Mössbauer measurements on 57Fe-enriched catalysts to equivalent materials with the standard isotope distribution relies on the assumption that the metal precursor's isotopic profile does not affect the catalysts' composition and ORR-activity. To verify this hypothesis, in this study we prepared two series of Fe-based catalysts using distinctively different synthesis approaches and various relative contents of 57Fe-enriched precursors, and observed that the extent of the latter parameter significantly affected the catalysts' ORR-activity. This effect was successfully correlated with the Fe-speciation of the catalysts inferred from the characterization of these samples with Mössbauer and X-ray absorption spectroscopies. Ultimately, these results highlight the crucial importance of verifying the consistency of the catalysts' activity and composition upon comparing standard and 57Fe-enriched samples.
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http://dx.doi.org/10.1039/d1cp00707fDOI Listing
April 2021

[Safe combined division of the splenic vein and the pancreas in distal pancreatectomy].

Chirurg 2021 May 19;92(5):478. Epub 2021 Apr 19.

Klinik für Allgemeine, Viszerale und Transplantationschirurgie, Universität Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Deutschland.

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http://dx.doi.org/10.1007/s00104-021-01402-zDOI Listing
May 2021

Autoreactive Peripheral Blood T Helper Cell Responses in Bullous Pemphigoid and Elderly Patients With Pruritic Disorders.

Front Immunol 2021 25;12:569287. Epub 2021 Mar 25.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated with recombinant BP180 proteins (NH- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.
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http://dx.doi.org/10.3389/fimmu.2021.569287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027500PMC
June 2021

Seroprevalence and correlates of SARS-CoV-2 neutralizing antibodies from a population-based study in Bonn, Germany.

Nat Commun 2021 04 9;12(1):2117. Epub 2021 Apr 9.

Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

To estimate the seroprevalence and temporal course of SARS-CoV-2 neutralizing antibodies, we embedded a multi-tiered seroprevalence survey within an ongoing community-based cohort study in Bonn, Germany. We first assessed anti-SARS-CoV-2 immunoglobulin G levels with an immunoassay, followed by confirmatory testing of borderline and positive test results with a recombinant spike-based immunofluorescence assay and a plaque reduction neutralization test (PRNT). Those with a borderline or positive immunoassay result were retested after 4 to 5 months. At baseline, 4771 persons participated (88% response rate). Between April 24 and June 30, 2020, seroprevalence was 0.97% (95% CI: 0.72-1.30) by immunoassay and 0.36% (95% CI: 0.21-0.61) when considering only those with two additional positive confirmatory tests. Importantly, about 20% of PRNT+ individuals lost their neutralizing antibodies within five months. Here, we show that neutralizing antibodies are detectable in only one third of those with a positive immunoassay result, and wane relatively quickly.
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http://dx.doi.org/10.1038/s41467-021-22351-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035181PMC
April 2021
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