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Agata Janikowska,1 Jens Soukup,2 Rainer U Pliquett,1 Rabah Abdel-Rahim1 1Department of Nephrology and Diabetology, Carl-Thiem Hospital, Cottbus, Germany; 2Clinic for Anesthesiology, Intensive Therapy and Palliative Medicine, Carl-Thiem Hospital, Cottbus, GermanyCorrespondence: Agata Janikowska, Tel +49 355 46 79592, Fax +49 355 46 2240, Email agata.janikowska@yahoo.comAbstract: We present 2 cases of severe Covid-19 with comorbidities (arterial hypertension, obesity, diabetes mellitus) treated with membrane-based therapeutic plasma exchanges in combination with a short-term high-dose immunosuppressive therapy. The therapy has been initiated in an attempt to alleviate the prevalent cytokine storm and to prevent intubation and invasive mechanical ventilation, when a long-term nasal oxygen therapy with a maximum flow rate of 8L/min was insufficient to achieve an adequate oxygenation. Even though patient 2 had to be intubated after the 4th cycle of plasmapheresis due to the exhaustion of the respiratory muscles and the subsequent acquired sepsis with a microbiological evidence of a mixed bacterial-fungal infection, both patients showed a good response to treatment, including improvement of laboratory and radiological findings. To our knowledge, this combination of therapeutic plasma exchange with a high-dose steroid therapy has not been reported previously.Keywords: Covid-19, plasmapheresis, immunosuppression, cytokine storm

Copyright of Otorhinolaryngology & Phoniatrics / Otorinolaryngologie a Foniatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Acute traumatic intervertebral disc herniation of the thoracic spine is a rather rare injury with only a few reported cases to date. In this manuscript, we present a case of a 58-year-old male patient who sustained a car accident-related high-energy trauma, resulting in a disc herniation of the thoracic spine. Furthermore, we also discuss the possible implications of late diagnosis of such condition. The patient was initially referred from the Emergency Department as a case of head contusion with a left upper limb paresis. Due to only minimal bony trauma visible on the initial spine CT scan, the neurological deficit was attributed to the cranial trauma. The diagnosis of a traumatic disc herniation was therefore established only after the rapid onset of paraparesis, which gradually progressed into paraplegia, and a following spine MRI scan. Despite the subsequent urgent spinal decompression, the neurological functions of the lower limbs were not restored. This manuscript addresses the indications for performing MRI scans in polytrauma patients with a CT-verified spine trauma. Although it may be complicated to perform routine MRI scans in all such patients in daily practice, it can certainly help diagnose such injuries earlier and thus prevent potential permanent neurological damage to the patients. [ABSTRACT FROM AUTHOR]

Copyright of Transfusiology & Haematology Today / Transfuze a Hematologie Dnes is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rosette-forming glioneuronal tumors (RGNTs) with FGFR1 tyrosine kinase domain internal tandem duplication (FGFR1 ITD) is exceedingly rare, with only a few cases reported in the literature. Hereby we present a case of a tumor with RGNT morphology occurring in area of septum pellucidum of 43-year-old male. The tumor showed FGFR1 ITD, no PIK3CA, PIK3R1 or NF1 alterations and inconclusive methylation profile with match for class of "low-grade glial/glioneuronal/neuroepithelial tumors". No areas characteristic of dysembryoplastic neuroepithelial tumor were identified. A brief review of literature on discrepancies between morphological diagnosis of RGNT and molecular profile of the entity is provided., (© 2024 Japanese Society of Neuropathology.)

Glioblastoma is the commonest primary malignant brain tumor, with a very poor prognosis and short overall survival. It is characterized by its high intra- and intertumoral heterogeneity, in terms of both the level of single-nucleotide variants, copy number alterations, and aneuploidy. Therefore, routine diagnosis can be challenging in some cases. We present a complicated case of glioblastoma, which was characterized with five cytogenomic methods: interphase fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, comparative genomic hybridization array and single-nucleotide polymorphism, targeted gene panel, and whole-genome sequencing. These cytogenomic methods revealed classical findings associated with glioblastoma, such as a lack of IDH and TERT mutations, gain of chromosome 7, and loss of chromosome 10. At least three pathological clones were identified, including one with whole-genome duplication, and one with loss of 1p and suspected loss of 19q. Deletion and mutation of the TP53 gene were detected with numerous breakends on 17p and 20q. Based on these findings, we recommend a combined approach to the diagnosis of glioblastoma involving the detection of copy number alterations, mutations, and aneuploidy. The choice of the best combination of methods is based on cost, time required, staff expertise, and laboratory equipment. This integrated strategy could contribute directly to tangible improvements in the diagnosis, prognosis, and prediction of the therapeutic responses of patients with brain tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Aghova, Lhotska, Lizcova, Svobodova, Hodanova, Janeckova, Vucinic, Gregor, Konecna, Kramar, Soukup, Netuka and Zemanova.)

Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular β-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Annotation of multiple regions of interest across the whole mouse brain is an indispensable process for quantitative evaluation of a multitude of study endpoints in neuroscience digital pathology. Prior experience and domain expert knowledge are the key aspects for image annotation quality and consistency. At present, image annotation is often achieved manually by certified pathologists or trained technicians, limiting the total throughput of studies performed at neuroscience digital pathology labs. It may also mean that simpler and quicker methods of examining tissue samples are used by non-pathologists, especially in the early stages of research and preclinical studies. To address these limitations and to meet the growing demand for image analysis in a pharmaceutical setting, we developed AnNoBrainer, an open-source software tool that leverages deep learning, image registration, and standard cortical brain templates to automatically annotate individual brain regions on 2D pathology slides. Application of AnNoBrainer to a published set of pathology slides from transgenic mice models of synucleinopathy revealed comparable accuracy, increased reproducibility, and a significant reduction (~ 50%) in time spent on brain annotation, quality control and labelling compared to trained scientists in pathology. Taken together, AnNoBrainer offers a rapid, accurate, and reproducible automated annotation of mouse brain images that largely meets the experts' histopathological assessment standards (> 85% of cases) and enables high-throughput image analysis workflows in digital pathology labs., Competing Interests: Declarations. Competing Interests: All authors that are/were employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may hold stocks and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. A subset of manuscript authors are inventors on a patent related to this work (patent application number: 34187-56244). All of this work/code is licensed under the MIT permissive free software license., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, 2024.)

Systemic acquired acclimation and resistance are vital physiological mechanisms, essential for plants to survive challenging conditions, including herbicide stress. Harmonizing this adaptation involves a series of complex communication pathways. Hydrogen peroxide (H 2 O 2 ) metabolism might play pivotal roles in orchestrating weeds' acclimation and defense responses. In the context of herbicide resistance, the interaction between H 2 O 2 and key stress signaling pathways is crucial in understanding weed physiology and developing effective management strategies. This dynamic interplay might significantly influence how weeds develop resistance to the various challenges posed by herbicides. Moreover, the production and eradication of H 2 O 2 can be highly compartmentalized, depending on the type of herbicide exposure. Till date there have been no studies aiming to explore/discuss these possibilities. Therefore, in this mini-review, our objective is to delve into the potentialities and recent advancements regarding H 2 O 2 -mediated signaling of transcriptomic changes during herbicide stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mouse neuronal CAD 5 cell line effectively propagates various strains of prions. Previously, we have shown that it can also be differentiated into the cells morphologically resembling neurons. Here, we demonstrate that CAD 5 cells chronically infected with prions undergo differentiation under the same conditions. To make our model more realistic, we triggered the differentiation in the 3D culture created by gentle rocking of CAD 5 cell suspension. Spheroids formed within 1 week and were fully developed in less than 3 weeks of culture. The mature spheroids had a median size of ~300 μm and could be cultured for up to 12 weeks. Increased expression of differentiation markers GAP 43, tyrosine hydroxylase, β-III-tubulin and SNAP 25 supported the differentiated status of the spheroid cells. The majority of them were found in the G0/G1 phase of the cell cycle, which is typical for differentiated cells. Moreover, half of the PrP C on the cell membrane was N-terminally truncated, similarly as in differentiated CAD 5 adherent cells. Finally, we demonstrated that spheroids could be created from prion-infected CAD 5 cells. The presence of prions was verified by immunohistochemistry, western blot and seed amplification assay. We also confirmed that the spheroids can be infected with the prions de novo. Our 3D culture model of differentiated CAD 5 cells is low cost, easy to produce and cultivable for weeks. We foresee its possible use in the testing of anti-prion compounds and future studies of prion formation dynamics., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Amaranthus retroflexus L. (redroot pigweed) is one of the most problematic weeds in maize, sugar beet, vegetables, and soybean crop fields in Europe. Two pigweed amaranth biotypes (R1 and R2) from the Czech Republic resistant to photosystem II (PSII)-inhibiting herbicides were analyzed in this study. This study aimed to identify the genetic mechanisms that underlie the resistance observed in the biotypes. Additionally, we also intended to establish the use of chlorophyll fluorescence measurement as a rapid and reliable method for confirming herbicide resistance in this weed species. Both biotypes analyzed showed high resistance factors in a dose-response study and were thus confirmed to be resistant to PSII-inhibiting herbicides. A sequence analysis of the D1 protein revealed a well-known Ser-Gly substitution at amino acid position 264 in both biotypes. Molecular docking studies, along with the wild-type and mutant D1 protein's secondary structure analyses, revealed that the S264G mutation did not reduce herbicide affinity but instead indirectly affected the interaction between the target protein and the herbicides. The current study identified the S264G mutation as being responsible for conferring herbicide resistance in the pigweed amaranth biotypes. These findings can provide a strong basis for future studies that might use protein structure and mutation-based approaches to gain further insights into the detailed mechanisms of resistance in this weed species. In many individuals from both biotypes, resistance at a very early stage (BBCH10) of plants was demonstrated several hours after the application of the active ingredients by the chlorophyll fluorescence method. The effective PS II quantum yield parameter can be used as a rapid diagnostic tool for distinguishing between sensitive and resistant plants on an individual level. This method can be useful for identifying herbicide-resistant weed biotypes in the field, which can help farmers and weed management practitioners develop more effective weed control tactics.

Objective: The course of sedation during drug-induced sleep endoscopy (DISE) depends on the application pattern of the sedative drug. The depth of sedation should imitate light and deep sleep as well. Moreover, there should be as many breathing cycles as possible available for observation during light and deep sedation. The aim of the study was to evaluate different rates of propofol application with respect to the achieved depth and length of the course of sedation., Methods: Sixty-three consecutive patients with obstructive sleep apnea and/or snoring undergoing DISE were randomly sedated by propofol perfusion at seven different application patterns: 14, 16, 18, 19, 20, 22 mg/kg/h (0.233, 0.267, 0.3, 0.317, 0.333, 0.367 mg/kg/min) per perfusor and individual bolus application 10 mg each. Sedation depth was monitored by BiSpectral Index™ (BIS). The influence of baseline parameters and the courses of sedation were analyzed., Results: The application rate was the only factor that influenced the depth of sedation. Basic parameters (gender, age, body mass index, apnea-hypopnea index) had no influence on the depth of sedation. The sedation depth was dependent on the rate of propofol application. Regimes at 14 and 16 mg/kg/h as well as bolus application did not reach BIS levels below 50 representing deep sleep. Propofol doses of more than 20 mg/kg/h led to rapid decreases of sedation levels below deep sleep niveau. Propofol rates between 18 and 20 mg/kg/h enable BIS levels below 50 representing deep sleep and providing enough breathing cycles for observation., Conclusion: Lower application rates of propofol provide slower courses of sedation and shallower depths of sedation. A rate of 14 mg/kg/h might be appropriate to reach a sedation plateau at light sleep. A rate of 18 mg/kg/h leads to a sedation, corresponding to deep sleep. The combination of both rates might be a suitable pattern for performing sedation-controlled DISE., Level of Evidence: 2: Randomized trial., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Background: Glioblastoma is a malignant and aggressive type of central nevous system malignancy characterized by many distinct biological features including extensive hypoxia. Hypoxia in glioblatoma associates with complex signaling patterns including activation of several pathways such as MAPK, PI3K-AKT/mTOR and IL-6/JAK/STAT3 with the master regulator HIF-1, which in turn drive particular tumor behaviors determining, in the end, treatment outcomes and patients fate. Thus, the present study was designed to investigate the expression of selected hypoxia related factors including STAT3 in a small set of long-term surviving glioma patients., Methods: The expression of selected hypoxia related factors including STAT3 was evaluated in a time series of formalin fixed paraffin embedded and cryopreserved glioma samples from repeatedly resected patients. In addition, comparative studies were also conducted on primary glioma cells derived from original patient samples, stabilized glioma cell lines and tumor-xenograft mice model. Obtained data were correlated with clinical findings too., Results: Glioblastoma samples of the analyzed patients displayed heterogeneity in the expression of hypoxia- related and EMT markers with most interesting trend being observed in pSTAT3. This heterogeneity was subsequently confirmed in other employed models (primocultures derived from glioblastoma tissue resections, cryopreserved tumor specimens, stabilized glioblastoma cell line in vitro and in vivo) and concerned, in particular, STAT3 expression which remained stable. In addition, subsequent studies on the role of STAT3 in the context of glioblastoma hypoxia demonstrated opposing effects of its deletion on cell viability as well as the expression of hypoxia and EMT markers., Conclusions: Our results suport the importance of STAT3 expression and activity in the context of hypoxia in malignant glioblastoma long-term surviving glioma patients while emphasizing heterogeneity of biological outcomes in varying employed tumor models., (© 2024. The Author(s).)

Chordoma is a rare malignant tumor with notochordal differentiation, usually affecting the axial skeleton of young patients. We report a case of a high-grade epithelioid tumor involving the synovium and soft tissues of the knee in a 74-year-old male patient. The preliminary biopsy was inconclusive, but a diagnosis of metastatic clear-cell carcinoma of unknown origin was suggested. However, imaging studies did not reveal any primary lesions. The resection specimen consisted of nests and sheets of oval to polygonal cells with discernible cell borders, clear or lightly amphophilic cytoplasm, and round to oval nuclei with occasional well-visible eosinophilic nucleoli. Rare atypical mitoses, necrotic areas, and bizarre nuclei were noted. The biopsy and resection specimens underwent a wide molecular genetic analysis which included methylation profiling. The DKFZ sarcoma classifier assigned the methylation class chordoma (dedifferentiated) with a calibrated score of 0.96, and additionally, a loss of SMARCB1 locus was noted in the copy number variation plot. To verify these findings, T-brachyury and SMARCB1 immunostaining was performed afterward, showing diffuse nuclear positivity and complete loss in the tumor cells, respectively. To assess the prevalence of T-brachyury immunopositivity among SWI/SNF-deficient tumors and to evaluate its specificity for poorly differentiated chordoma, we analyzed a series of 23 SMARCB1- or SMARCA4-deficient tumors, all of which were negative. After incorporating all the available data, including the absence of any morphological features of conventional chordoma, the case was diagnosed as poorly differentiated chordoma. As illustrated herein, the utilization of methylation profiling in the diagnostic process of some carefully selected unclassifiable soft tissue neoplasms may lead to an increased detection rate of such extremely rare soft tissue tumors and enable their better characterization., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background : Percutaneous vertebroplasty (PVP) and kyphoplasty (PKP) are established methods in the treatment of vertebral compression fractures (VCFs). In our manuscript, the target was to evaluate the efficacy of PVPs/PKPs and to determine the implications of potential periprocedural complications. Methods : 280 patients, specifically 194 women (69.3%) and 86 men (30.7%), were enrolled. We used the AO spine fractures classification and the Yeom classification to determine the subtype of cement leakage. Only single-level VCFs of the thoracic or lumbar spine were included. Visual analogue scale (VAS) was assessed preoperatively and regularly after the surgery. Vertebral compression ratio (VBCR) was used to determine postoperative vertebral body collapse. Results : We recorded 54 cases (19.3%) of cement leakage. There was a significant decrease in mean VAS scores (6.82-0.76 in PVPs, 7.15-0.81 in PKPs). The decrease in VBCR was greater in the VP group (4.39%; 84.21-79.82) compared to the KP group (1.95%; 74.36-72.41). Conclusions : No significant difference in the risk of cement leakage when comparing KPs and VPs was found. VPs and KPs provide rapid and significant pain relief in patients with VCFs. Clinically relevant complications of VPs and KPs are rare. Kyphoplasties prevent further vertebral body collapse more effectively compared to vertebroplasties.

Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rigid ryegrass ( Lolium rigidum Gaud.) is one of the most troublesome weeds in Moroccan and Tunisian cereal crop fields. In total, 19 rigid ryegrass field populations were randomly selected in northern wheat crop areas of Morocco and Tunisia to examine the patterns of herbicide resistance to acetolactate synthase (ALS)- and acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. Greenhouse experiments confirmed reduced sensitivity to ALS- and/or ACCase-inhibiting herbicides in all L. rigidum populations. The occurrence of target-site resistance (TSR) was tested using high-throughput genotyping. The advent of next-generation sequencing (NGS) has enabled easy identification of causal mutations and confirmed the presence of ALS and ACCase mutations at specific codons conferring TSR. Thirteen populations showed resistance to ALS-inhibiting herbicides associated with point mutations in positions Pro-197-Thr, Pro-197-Ser, Pro-197-Leu, Pro-197-Gln and Trp-574-Leu, while resistance to ACCase-inhibiting herbicides was detected in 18 populations in positions Asp-2078-Val, Trp-2027-Cys, Ile-1781-Leu, Gly-2096-Ala, and Ile-2041-Asn of the enzymes conferring TSR. Additionally, dose-response experiments with pyroxsulam applied after the inhibition of cytochrome P450 monooxygenase by malathion showed an increase in sensitivity in two out of seven highly resistant (HR) rigid ryegrass populations. This demonstrates the presence of non-target-site resistance (NTSR) in some ryegrass populations. Further evidence of NTSR was investigated in dose-response experiments with pyroxsulam, following pretreatment with the glutathione S -transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl), which partially reversed resistance in only a few individuals of two L. rigidum populations. Hence, our study confirms the existence of multiple and cross-resistance to ALS- and ACCase-inhibiting herbicides in L. rigidum from Morocco and Tunisia with both TSR and NTSR mechanisms. These results emphasize local resistance management as an important tool to detect and mitigate gene flow from rigid ryegrass populations where resistance has evolved., Competing Interests: Author AE is employed by Maghreb Phytotest SARL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 El-Mastouri, Košnarová, Hamouzová, Alimi and Soukup.)

Prions are responsible for a number of lethal neurodegenerative and transmissible diseases in humans and animals. Extracellular vesicles, especially small exosomes, have been extensively studied in connection with various diseases. In contrast, larger microvesicles are often overlooked. In this work, we compared the ability of large extracellular vesicles (lEVs) and small extracellular vesicles (sEVs) to spread prions in cell culture. We utilized CAD5 cell culture model of prion infection and isolated lEVs by 20,000×g force and sEVs by 110,000×g force. The lEV fraction was enriched in β-1 integrin with a vesicle size starting at 100 nm. The fraction of sEVs was partially depleted of β-1 integrin with a mean size of 79 nm. Both fractions were enriched in prion protein, but the lEVs contained a higher prion-converting activity. In addition, lEV infection led to stronger prion signals in both cell cultures, as detected by cell and western blotting. These results were verified on N2a-PK1 cell culture. Our data suggest the importance of lEVs in the trafficking and spread of prions over extensively studied small EVs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is the fourth most commonly diagnosed malignant condition in the world. Micro RNAs (miRNAs) as well as epithelial to mesenchymal transition (EMT) play an important role in the pathogenesis of CRC. We performed a comparative analysis of the expression of selected miRNA genes and EMT markers in bioptic samples from patients (n = 45) with primary CRC or metastatic (m)CRC to the regional lymph node using reverse transcription-quantitative PCR and IHC staining. Results: Out of all miRNA analyzed, the miR-17 expression was most significantly different and associated with lower risk of CRC spread to the lymph node. In addition, significant relationships were found between the tumor side localization and several miRNAs expressions (miR-9, miR-29b, miR-19a, miR-19b, miR-21, miR-106a, miR-20a and miR-17). In addition, of the examined EMT markers, only VEGFA expression correlated with tumor progression (tumor grade G2). In the examined set of patient samples and their matched healthy tissue, several specific molecular markers (miRNAs associated with EMT and tumor progression) were identified with a promising prognostic potential. Their further examination in larger patient cohorts is planned to validate the present data.

Purpose: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative., Materials and Methods: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected., Results: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011)., Conclusions: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tumor consistency is considered to be a critical factor for the surgical removal of meningiomas and its preoperative assessment is intensively studied. A significant drawback in the research of predictive methods is the lack of a clear shared definition of tumor consistency, with most authors resorting to subjective binary classification labeling the samples as "soft" and "hard." This classification is highly observer-dependent and its discrete nature fails to capture the fine nuances in tumor consistency. To compensate for these shortcomings, we examined the utility of texture analysis to provide an objective observer-independent continuous measure of meningioma consistency., Methods: A total of 169 texturometric measurements were conducted using the Brookfield CT3 Texture Analyzer on meningioma samples from five patients immediately after the removal and on the first, second, and seventh postoperative day. The relationship between measured stiffness and time from sample extraction, subjectively assessed consistency grade and histopathological features (amount of collagen and reticulin fibers, presence of psammoma bodies, predominant microscopic morphology) was analyzed., Results: The stiffness measurements exhibited significantly lower variance within a sample than among samples (p = 0.0225) and significant increase with a higher objectively assessed consistency grade (p = 0.0161, p = 0.0055). A significant negative correlation was found between the measured stiffness and the time from sample extraction (p < 0.01). A significant monotonic relationship was revealed between stiffness values and amount of collagen I and reticulin fibers; there were no statistically significant differences between histological phenotypes in regard to presence of psammoma bodies and predominant microscopic morphology., Conclusions: We conclude that the values yielded by texture analysis are highly representative of an intrinsic consistency-related quality of the sample despite the influence of intra-sample heterogeneity and that our proposed method can be used to conduct quantitative studies on the role of meningioma consistency., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Omics techniques, including genomics, transcriptomics, proteomics, and metabolomics have smoothed the researcher's ability to generate hypotheses and discover various agronomically relevant functions and mechanisms, as well as their implications and associations. With a significant increase in the number of cases with resistance to multiple herbicide modes of action, studies on herbicide resistance are currently one of the predominant areas of research within the field of weed science. High-throughput technologies have already started revolutionizing the current molecular weed biology studies. The evolution of herbicide resistance in weeds (particularly via non-target site resistance mechanism) is a perfect example of a complex, multi-pathway integration-induced response. To date, functional genomics, including transcriptomic and metabolomic studies have been used separately in herbicide resistance research, however there is a substantial lack of integrated approach. Hence, despite the ability of omics technologies to provide significant insights into the molecular functioning of weeds, using a single omics can sometimes be misleading. This mini-review will aim to discuss the current progress of transcriptome-based and metabolome-based approaches in herbicide resistance research, along with their systematic integration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sen, Bhattacharya, Bharati, Hamouzová and Soukup.)

HoxB13 is a transcription factor involved in defining of posterior endodermal derivatives, including prostate and rectum. While it is used as a marker of prostatic adenocarcinoma, it has not been studied systematically in neuroendocrine neoplasms. Thus, we performed HoxB13 immunohistochemistry in tissue microarrays and the whole sections of 232 neuroendocrine neoplasms. These included 34 paragangliomas (PGs), 20 cauda equina neuroendocrine tumors (CENETs), 123 well-differentiated neuroendocrine tumors (WDNETs), and 55 neuroendocrine carcinomas (NECs). WDNETs were additionally analyzed with SATB2, and colorectal WDNETs with CDX2 and serotonin immunohistochemistry. In total, HoxB13 immunoreactivity was observed in 95% (19/20) CENETs, 10.6% (13/123) WDNETs, and 12.9% (7/54) NECs. No PGs were positive. Large intestine WDNETs expressed HoxB13 in 68.4% (13/19); five negative tumors originated in cecum and one in rectum. In rectum, 92.9% (13/14) WDNETs expressed HoxB13. HoxB13 was 92.9% sensitive and 100% specific, showing 100% positive predictive value for the rectal origin of WDNET. In NECs, HoxB13 was positive in 15.4% (2/13) GIT tumors and 80% (4/5) prostatic NECs, but in none of urinary bladder NECs (0/8). SATB2 was positive in 17.1% (21/123) WDNETs, including 78.9% (15/19) of colorectal WDNETs, 71.4% (5/7) appendiceal WDNETs, and 2.9% (1/34) small intestine WDNETs. All 4 SATB2-negative large bowel tumors originated in the cecum. When both markers combined, HoxB13+/SATB2+ immunoprofile was seen exclusively in rectal WDNETs (positive predictive value 100%), while HoxB13-/SATB2+ immunoprofile was highly suggestive of the appendiceal origin (positive predictive value 71.4%). Therefore, HoxB13 can be useful as an immunohistochemical marker of rectal WDNETs and prostatic NECs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We report a case of a 73-year-old male with rheumatoid arthritis presenting with acute abdominal and back pain and rapidly developing multiorgan failure. A positive blood culture (Staphylococcus aureus, Candida species) followed by transoesophageal sonography established a diagnosis of mitral valve infective endocarditis. At the autopsy, the heart examination revealed fibrinous pericarditis and multiple small vegetations on the mitral valve. The mitral valve itself showed no significant damage. Surprisingly, the histological examination of the mitral valve showed granulomatous inflammation with central fibrinoid necrosis and peripheral palisade of histiocytes, with occasional giant cells and lymphocytic inflammatory infiltrate - findings consistent with a rheumatoid nodule. Infective vegetations were overlying the nodule. Due to its relative frequency, a possibility of cardiac involvement by rheumatoid arthritis and its potential infective complications should be considered in patients with appropriate history and clinical symptoms.

This study evaluated the clinical success rate of guided tissue regeneration (GTR) for treating advanced periodontal disease in a large canine cohort. A total of 112 GTR procedures performed from 2003-2021 were retrospectively evaluated, including pre- and post-treatment (3-12 months) periodontal probing depths of 104 treated teeth, dental radiographs of 73 treated teeth, and both diagnostic modalities in 64 treated teeth. Probing depth, radiographically apparent bone height, bone graft material, barrier membrane material, and tooth extraction adjacent to the GTR site were investigated as factors affecting success. Vertical bone defects were evaluated separately from furcation defects. GTR was clinically successful, defined as objective improvement in probing depth, objective decrease in radiographic vertical bone defect, and subjective radiographic gain in bone height in 90.3% of vertical bone defects. Success was significantly associated with the magnitude of initial probing depth and the type of barrier membrane used. GTR was clinically successful, defined as objective improvement in furcation probing and subjective radiographic improvement of the bone in the furcation in 22.2% of furcation defects. When F3 lesions were excluded, GTR was successful in 64.3% of furcation defects. GTR is an appropriate treatment to maintain teeth in the oral cavity of dogs with proper client counseling and patient selection, but it is most likely to be successful in vertical defects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Soukup, Rendahl and Goldschmidt.)

Histological identification of dispersed glioma cells in small biopsies can be challenging, especially in tumours lacking the IDH1 R132H mutation or alterations in TP53. We postulated that immunohistochemical detection of proteins expressed preferentially in gliomas (EGFR, MEOX2, CD34) or during embryonal development (SOX11, INSM1) can be used to distinguish reactive gliosis from glioma. Tissue microarrays of 46 reactive glioses, 81 glioblastomas, 34 IDH1-mutant diffuse gliomas, and 23 gliomas of other types were analysed. Glial neoplasms were significantly more often ( p < 0.001, χ 2 ) positive for EGFR (34.1% vs. 0%), MEOX2 (49.3% vs. 2.3%), SOX11 (70.5% vs. 20.4%), and INSM1 (65.4% vs. 2.3%). In 94.3% (66/70) of the glioblastomas, the expression of at least two markers was observed, while no reactive gliosis showed coexpression of any of the proteins. Compared to IDH1-mutant tumours, glioblastomas showed significantly higher expression of EGFR, MEOX2, and CD34 and significantly lower positivity for SOX11. Non-diffuse gliomas were only rarely positive for any of the five markers tested. Our results indicate that immunohistochemical detection of EGFR, MEOX2, SOX11, and INSM1 can be useful for detection of glioblastoma cells in limited histological samples, especially when used in combination.

Solitary fibrous tumors (SFTs) may show unusual morphologies, and in such circumstances, an unexpected immunoprofile can be misleading. Following an index case of myxoid meningeal SFT with a neuroendocrine immunoprofile, we decided to assess a neuroendocrine profile in SFTs from various locations. The cohort of 9 meningeal and 28 extrameningeal SFTs was evaluated for CNS WHO grade (G1-G3) and 4-tiered Demicco risk stratification. Immunohistochemical detection of synaptophysin, chromogranin, INSM1, CD56, and CD57 was performed in each case and semiquantitatively assessed (0: no expression; 1+: <10% positive; 2+: 11-50%; and 3+: >51%); whole sections (meningeal SFTs) or tissue microarray (extrameningeal SFTs) were used for immunohistochemistry. The cohort included 13 men and 24 women. Meningeal SFTs included 5 WHO G1, 3 WHO G2, and 1 WHO G3 tumors. Extrameningeal SFTs included 21 low-risk, 4 intermediate-risk, and 2 high-risk tumors. INSM1 immunoreactivity was observed in 12 of 37 cases (32%; 8 cases 1+, 3 cases 2+, and 1 case 3+); synaptophysin was positive in 6 of 35 cases (19%; 5 cases 1+ and 1 case 2+); CD56 was positive in 20 of 37 cases (54%; 16 cases 1+, 3 cases 2+, and 1 case 3+); and CD57 was expressed in 14 of 36 cases (39%; 5 cases 1+, 4 cases 2+, and 5 cases 3+). Chromogranin positivity was not observed. No significant association was observed between expression of neuroendocrine markers and tumor grade, Demicco risk group or meningeal and extrameningeal location. Extrapleural SFTs showed a tendency for positivity of INSM1 (P = .014, χ2) and CD57 (P = .017, χ2) compared to pleural SFTs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Both musculoskeletal gossypibomas and chronic expanding hematomas have been rarely reported; the reports that do exist are usually case reports. Our objective is to demonstrate problematic imaging diagnostics of an unusual presentation mimicking a malignant lesion. We report the case of a 47-year-old man who underwent bone graft harvesting from the iliac crest for spinal fusion due to scoliosis at 18 years of age, and 29 years later, he developed a growing, painful tumor at the original donor site (a bone defect in the iliac crest). It was challenging to differentiate a hematoma from a malignant tumor based solely on clinical and radiological workup, including an ultrasound-guided needle biopsy focused on viable tissue. The definitive diagnosis of a gossypiboma with a chronic expanding hematoma was based on histopathological assessment after wide surgical resection-a chronic expanding hematoma with multiple foamy macrophages and giant cells engulfing foreign material (original surgical hemostatic sponge).

Glioblastoma multiforme (GBM) belongs to most aggressive and invasive primary brain tumor in adults whose prognosis and survival remains poor. Potential new treatment modalities include targeting the cytoskeleton. In our study, we demonstrated that repurposed drug flubendazole (FLU) significantly inhibits proliferation and survival of GBM cells. FLU exerted its effect by affecting microtubule structure and our results also suggest that FLU influences tubulins expression to a certain degree. Moreover, FLU effects decreased activation of STAT3 and also partially inhibited its expression, leading to upregulation of p53 signaling pathway and subsequent cell cycle arrest at G2/M phase as well as caspase-dependent cell death in GBM cells. These results suggest FLU as a promising agent to be used in GBM treatment and prompting further testing of its effects on GBM., (© 2023. The Author(s).)

Background: Volatile anesthetics are used more commonly for sedation in the intensive-care-unit (ICU). However, evidence for long-term use remains low. We therefore conducted a randomized-controlled trial comparing sevoflurane with intravenous sedation with particular focus on efficacy and safety., Methods: In this prospective, randomized-controlled phase-IIb monocentric clinical-trial ICU patients requiring at least 48 h of sedation were randomized to receive sevoflurane (S) or propofol/midazolam (P). Sedation quality was monitored using the Richmond-Agitation-Sedation-Scale. Following termination of sedation, the time to spontaneous breathing and extubation, opioid consumption, hemodynamics, ICU and hospital length of stay (LOS) and adverse events were recorded., Results: 79 patients were eligible to randomization. Sedation quality was comparable between sevoflurane (n = 39) and propofol (n = 40). However, the use of sevoflurane lead to a reduction in time to spontaneous breathing (26 min vs. 375 min, P < 0.001). Patients sedated with propofol had lower opioid requirements (remifentanil:400 μg/h vs. 500 μg/h, P = 0.007; sufentanil:40 μg/h vs. 30 μg/h, P = 0.007) while hemodynamics, LOS or the occurrence of adverse events did not differ., Conclusion: ICU patients sedated with sevoflurane >48 h may return to spontaneous breathing faster, while the quality of sedation is comparable to a propofol-based sedation regime. Sevoflurane might be considered to be safe for long-term sedation in this patient population, while being non-inferior compared to propofol., Competing Interests: Declaration of Competing Interest Jens Soukup and Patrick Kellner received speakers' fee and reimbursement of expenses for scientific lectures referring to analgosedation as well as inhalative sedation of intensive care patients from Sedana Medical (Danderyd, Sweden). Jens Soukup also from Abbott GmbH & Co KG (Wiesbaden, Germany) and Baxter (Unterschleißheim, Germany). All other authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Phox2B is a transcription factor responsible for chromaffin cell phenotype. Although it is used routinely for diagnosis of neuroblastoma, previous reports concerning its utility in the diagnosis of neuroendocrine neoplasms have been conflicting. We assessed Phox2b immunoreactivity in different neuroendocrine neoplasms. Tissue microarrays or whole sections of 36 paragangliomas (PGs), 91 well-differentiated neuroendocrine tumours of different organs (WDNETs), 31 neuroendocrine carcinomas (NECs), and 6 olfactory neuroblastomas (ONBs) were stained with Phox2B antibody (EP312) and GATA3. The percentage of positive cells and intensity was analysed using H-score. Phox2B immunoreactivity was seen in 97.2% (35/36) PGs, 11% (10/91) WDNETs, 9.7% (3/31) NECs, and 16.7% (1/6) ONBs. PGs were significantly more often positive (p < 0.001, χ 2 ) than other neuroendocrine tumours, showing highest H-score (mean 144.9, SD ± 75.1) and percentage of positive cells (median 81.3%, IQR 62.5-92.5%). Compared to Phox2B-positive WDNETs, PGs showed significantly higher H-score (median 145 vs 7.5, p < 0.001) and percentage of positive cells (median 82.5% vs 4.5%, p < 0.001). Phox2B positivity was 97.2% sensitive and 89% specific for the diagnosis of PG. GATA3 was 100% sensitive and 88% specific for the diagnosis of PG. When combined, any Phox2B/GATA3 coexpression was 97.1% sensitive and 99.1% specific for the diagnosis of paraganglioma. Widespread Phox2B immunoreactivity is a highly characteristic feature of PGs and it can be used as an additional marker in differential diagnosis of neuroendocrine tumours., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The continuous use of herbicides for controlling weeds has led to the evolution of resistance to all major herbicidal modes of action globally. Every year, new cases of herbicide resistance are reported. Resistance is still in progress in many species, which must be stopped before it becomes a worldwide concern. Several herbicides are known to cause stressful conditions that resemble plant abiotic stresses. Variation in intracellular calcium (Ca 2+ ) concentration is a primary event in a wide range of biological processes in plants, including adaptation to various biotic and abiotic stresses. Ca 2+ acts as a secondary messenger, connecting various environmental stimuli to different biological processes, especially during stress rejoindering in plants. Even though many studies involving Ca 2+ signalling in plants have been published, there have been no studies on the roles of Ca 2+ signalling in herbicide stress response. Hence, this mini-review will highlight the possible sensing and molecular communication via Ca 2+ signals in weeds under herbicide stress. It will also discuss some critical points regarding integrating the sensing mechanisms of multiple stress conditions and subsequent molecular communication. These signalling responses must be addressed in the future, enabling researchers to discover new herbicidal targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hamouzová, Sen, Bharati, Košnarová, Chawdhery, Roy and Soukup.)

Background: We present the case of a patient with a rare synovial sarcoma (SS) of the tibial nerve. So far, only 4 cases of patients with SS originating from the tibial nerve have been described in the literature, and our patient is only the second patient whose limb was saved during treatment. Synovial sarcomas are malignant mesenchymal tumors, i.e., tumors arising from connective tissue. Synovial sarcomas account for 5-10% of all soft tissue sarcomas. However, the name synovial sarcoma is misleading, because the tumor does not originate from synovial cells, but rather from primitive mesenchymal cells. The name most likely originated from the localization around the large joints on the limbs, more often on the lower ones, in the area of the knee joints. We point out the aspects of correct and quick diagnosis and subsequent treatment, which has very important effect on the patient's prognosis. Primary less radical excision without prior biopsy verification leads to a higher risk of local recurrence, even if a proper reexcision was performed immediately after biopsy verification of the sarcoma., Case Presentation: A woman born in 1949 began to suffer at the end of 2020 with escalating pain under the left inner ankle with a projection to the sole and fingers. Her personal, family work and social history were insignificant. After the initial neurological examination, the patient was sent for an ultrasound examination of the ankle, which showed a lobular mass measuring 50 × 22 × 16 mm and according magnetic resonance imaging, the finding appeared to be a suspicious neurinoma of the tibial nerve. The tumor was surgically excised, without prior biopsy verification: a 50 × 20 mm tumor was dissected in the distal part of the tarsal canal, which grew through the structure of the tibial nerve and in some places into the surrounding area and appeared intraoperatively as a neurofibroma. But histologically the tumor was classified as monophasic synovial sarcoma. The patient was indicated for a wide reexcision of the skin with the subcutaneous tissue of size 91 × 20 × 15 mm. Now the patient is being treated with external radiotherapy to the tumor bed and she is able to walk., Conclusion: This report draws attention to a rare type of malignant nerve tumor, which both clinically and radiologically can mimic benign peripheral nerve sheath tumors. Synovial sarcoma should be considered in very painful resistances, typically located around the joints of the lower limbs, the growth of which can be slow. Because the size of the tumor is a negative prognostic factor, it is necessary to make a timely diagnosis using MR imaging and a biopsy with histological examination and to start treatment quickly. Surgical treatment should take place only after a biopsy with histological examination of the tumor so that it is sufficiently radical and does not have to undergo an additional reoperation, as happened in the case of our patient., (© 2023. The Author(s).)

Cauda equina neuroendocrine tumors (CENETs) are neoplasms of uncertain histogenesis with overlapping features between those of paragangliomas (PGs) and visceral neuroendocrine tumors (NETs). We have explored their biological relationship to both subsets of neuroendocrine neoplasms. The clinical and radiological features of a cohort of 23 CENETs were analyzed. A total of 21 cases were included in tissue microarrays, along with a control group of 38 PGs and 83 NETs. An extensive panel of antibodies was used to assess epithelial phenotype (cytokeratins, E-cadherin, EpCAM, Claudin-4, EMA, CD138), neuronal and neuroendocrine features (synaptophysin, chromogranin A, INSM1, neurofilaments, NeuN, internexin-α, calretinin), chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase), and possible histogenesis (Sox2, T-brachyury, Oct3/4, Sox10). The cohort included 5 women (22%) and 18 men (78%). The average age at the time of surgery was 48.3 years (range from 21 to 80 years). The average diameter of the tumors was 39.27 mm, and invasion of surrounding structures was observed in 6/21 (29%) tumors. Follow-up was available in 16 patients (median 46.5 months). One tumor recurred after 19 months. No metastatic behavior and no endocrine activity were observed. Compared to control groups, CENETs lacked expression of epithelial adhesion molecules (EpCAM, CD138, E-cadherin, Claudin-4), and at the same time, they lacked features of chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase). We observed no loss of SDHB. Cytokeratin expression was present in all CENETs. All the CENETs showed variable cytoplasmic expression of T-brachyury and limited nuclear expression of Sox2. These findings support the unique nature of the neoplasm with respect to NETs and PGs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pitx2 is a transcription factor responsible for establishment of the right-left axis and development of the gut and pituitary. In mouse embryos, Pitx2 is expressed in the greater curvature of the stomach and midgut. Previously, Pitx2 was studied in pituitary neuroendocrine tumours but not in other NETs. Pitx2 expression was immunohistochemically assessed in whole sections and tissue microarrays in a cohort of 224 neuroendocrine neoplasms, and was analysed in 29 cases. The cohort included 18 cauda equina NETs, 38 paragangliomas, 98 cases of primary visceral NETs from different organs, 23 metastases of visceral NETs and 47 neuroendocrine carcinomas (NECs). Pitx2 expression was observed in 29.5% (29 of 98) NETs and 14.9% (7 of 47) NECs, but was not observed in any paraganglioma or cauda equina NET. Pitx2 was observed only in tumours of midgut-derived organs, including the small intestine (100%, 20 of 20), appendix (88.9%, eight of nine) and large intestine (9.1%, one of 11 - only caecal NET). The NETs of remaining locations were negative. Pitx2 was 96.7% sensitive and 100% specific for NETs of midgut origin. In NECs, Pitx2 positivity was observed in goblet cell adenocarcinoma (75%, three of four), medullary thyroid carcinoma (42.9, three of seven) and one Merkel cell carcinoma (25%, one of four). In metastatic NETs, Pitx2 was observed in all the tumours originating in the small intestine (n = 17) or caecum (n = 1). No positivity was observed in tumours from other locations (four pancreas, one lung). We observed no correlation between immunoreactivity and mRNA expression. Thus, Pitx2 immunohistochemistry can be helpful in assessing the midgut origin of NETs., (© 2022 John Wiley & Sons Ltd.)

Although herbicides have been successfully used for controlling weeds, their continuous use has developed in the evolution of resistance to all major herbicide modes of action worldwide. Reports suggest that the members of Poaceae family are more prone to developing herbicide resistance than other families. In plants, epigenetic mechanisms play critical roles by increasing their stress-adaptive potential in a rapidly changing environment. Epigenetic mechanisms involve alteration of the expression of genetic elements, but without any changes in the DNA sequence. Although the possible roles of epigenetic mechanisms in contributing to survival and fitness under various stresses are well documented in model plants and crops, their contribution to herbicide resistance in weeds is still in its infancy. A few studies with herbicides have shown differential expression of DNA methyltransferases, histone methyltransferases and DNA demethylases in response to the herbicides; however, no further studies were conducted. In the case of herbicide stress, exploring how these epigenetic processes affect the gene expression pattern in individual plants subjected to recurrent selection would be exciting. Hence, our mini-review will focus on the potential contributions of epigenetic mechanisms to the adaptive responses of grass-weedy species to herbicide stress. A better understanding of these epigenetic changes will add novel perceptions to our knowledge of herbicide resistance evolution in weeds enabling the development of herbicides with novel targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sen, Hamouzová, Košnarová, Roy and Soukup.)

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KT has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); KK has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); AF has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); FMB has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); ZM has received honoraria for lectures and consultations and he also functions as medical director at CytoSorbents Europe (Berlin, Germany). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three highlighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC 50 around 10 μM. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)