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Abstract Background Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10–15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker. Methods Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts. Results The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank). Conclusion PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort.

This paper describes the experiences of two teachers, Ms. Santiago and Mr. Jelenik, who participated in a comprehensive National Science Foundation-supported science, technology, engineering, and mathematics (STEM) professional learning experience. This comparative case study describes how Ms. Santiago and Mr. Jelenik leveraged the justice-oriented curriculum of a STEM professional learning opportunity to transform their identities as educators while influencing their instructional practices. The professional learning experience included access to a justice-oriented curriculum introduced through monthly content-focused experiences, regular faculty learning communities, and support from an expert onsite coach. Evidence of transformed identities and instructional practices is derived from semi-structured in-depth interviews and video recordings of classroom teaching and learning. Analysis of the interview data suggests that Ms. Santiago and Mr. Jelenik found the professional learning experience transformative and that the experience served as a pedagogical identity project. Evidence from the classroom videos suggests that Ms. Santiago and Mr. Jelenik's instructional practices shifted, becoming more justice-oriented and student-centered. Moreover, Ms. Santiago's practices shifted in a manner more aligned with an engaged teaching approach. We conclude that the comprehensive STEM professional learning experience served as a pedagogical identity project while positively influencing the instructional practices of Ms. Santiago and Mr. Jelenik. Implications for preservice and in-service teacher education are discussed.

This interdisciplinary investigation of the human remains of Balduin Helm, one of the most important abbots of the Fürstenfeld monastery, provides novel information on this historic individual. This is particularly interesting since Balduin, during the early 18th century, was involved in the renovation of this large Bavarian monastery. Metastatic prostate cancer was found as evidenced by multiple mixed osteolytic–osteoblastic bone lesions in all available vertebral bodies, fragments of both os coxae, and isolated metastases in skull bones. Distribution, radio- and histomorphology, and especially the immunohistochemical detection of prostate-specific antigens in those metastases definitively confirm this diagnosis. Further investigation, especially by stable isotope analysis, showed a balanced high-level diet with considerable contribution from animal protein and significant freshwater fish. These additional findings suggest a significant radiocarbon reservoir effect as an explanation for a “too old” radiocarbon date. Finally, the obviously high-level protein diet may have contributed to the tumorigenesis which caused the death of the abbot at an advanced age.

Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

PURPOSE: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response. PATIENTS AND METHODS: A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months. RESULTS: As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5-16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7-14.1) and 9.6 months (95% CI: 4.8-16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders. CONCLUSIONS: The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation.

Abstract Background Functional neurological disorder (FND) is a common neurological diagnosis that encapsulates a range of incapacitating clinical presentations. These include functional seizures, movement disorders, and sensory disturbances. Safe driving requires both cognitive skills and physical abilities, which may be impacted by FND symptoms. The primary objective of this study was to gain deeper insights into the challenges faced by people with FND when driving. Methods A qualitative study and interpretative phenomenological analysis were conducted. Individuals experiencing functional seizures and/or movement disorders completed both questionnaires and semi‐structured interviews about FND symptoms, driving behavior, and crashes. Results A total of 26 patients with FND participated in this study. Based on the interviews, four key themes were identified: (1) driving difficulties experienced by individuals with FND; (2) strategies utilized by people with FND to overcome difficulties experienced while driving; (3) barriers preventing driving challenges being addressed in this population; and (4) crashes and perceived dangerous driving events experienced by individuals with FND. All participants reported that driving a car provoked FND symptoms and this affected their driving ability. FND sufferers reported using a number of strategies such as limiting how far they drive and relying on advanced driver assistance system features to help manage their associated symptoms, such as fatigue and/or pain. Several participants reported crashes and perceived dangerous driving events since developing FND. Conclusion Individuals experiencing FND often employ self‐regulation techniques, yet the extent to which these methods enhance driving safety remains uncertain. The variable nature of the disorder makes judging an individual's driving risk particularly difficult. The themes emerging from the interviews highlighted the need for further empirical research to inform guidelines and best practice when determining the impact of FND on an individual's driving safety .

Increased focus on the practical components of Danish health care education and greater coherence between theory and practice have been persistently identified as major issues requiring quality improvement. Policy initiatives to standardize education in eight health professional bachelor’s programs, including greater theory-practice coherence, prompted us to explore the types of educational practices highlighted by clinical supervisors to strengthen coherence between theory and practice. Thirty-one qualitative interviews were conducted with clinical supervisors in nursing, physiotherapy, occupational therapy, nutrition and health programs, biomedical laboratory science, midwifery, radiography, and psychomotor therapy. Data were thematically analyzed in a sociology of knowledge framework. We found that theoretical knowledge had a higher status in the programs. The imbalance may have negative consequences, whereby theoria activities in the practical part of the programs may, in unintended and subtle ways, increase in dominance. The intrinsic qualities of clinical practice are, therefore, at risk of being downplayed.

Precambrian sedimentary successions exposed worldwide record microbial deposits within both marine and continental strata. The Camaquã Basin records the transition from the Ediacaran to Cambrian periods in strata that comprise marine to lacustrine environments. The Camaquã Basin fossils comprise microbial mats and organic-walled microfossils in very close association. Carbonaceous laminae are common within the siltstone and mudstone layers and represent remarkably well-preserved Ediacaran microbial mats. These mats occurred along shallow marine through deep and shallow lake settings. The excellent preservation of these structures seems to be the product of calm hydrodynamic conditions and floodings. These hydrodynamic undisturbed environments allowed microbial mat growth. Besides, episodic floodings brought clay particles, which deposits guaranteed isolation from organic decomposition of mats. In general, the siltstones and mudstones record microbially induced sedimentary structures (MISS) that are typical from Ediacaran strata, such as wrinkle marks and elephant skin structures. Our research revealed that the occurrence of these structures is not limited to marine settings, as common in records from this period, but also present in lacustrine environments. Field studies were combined with optical and scanning electron microscopy plus energy-dispersive X-ray spectroscopy (SEM-EDS) analyses to demonstrate the vast occurrence of microbial mats along the deposits that registered the Camaquã Basin development. Geochemical data (whole-rock and total organic carbon (TOC) analyses) contribute to improving sedimentological descriptions, bringing light regarding the depositional environment where these microbial communities have developed. The excellent preservation state of organic matter on these marine and lacustrine siliciclastic sequences represents an impressive record in a Proto-Gondwana basin.

BackgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).MethodsPeripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses.ResultsIncreased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1.ConclusionsOur data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.

Behavioral health services access for justice- and child welfare-involved youth is limited despite significant need. Structural interventions to address limited access are nascent. Technology can advance access, but few interventions focus on system-impacted youth and their mental health needs and challenges. This article describes the development, process, and initial outcomes of the Youth Justice and Family Well-Being Technology Collaborative (JTC) that was formed to leverage technology within and across public health and justice-related systems to promote increased behavioral health services access. Cross-system considerations are identified for public health, court, and other key stakeholders to successfully integrate technology into practice to expand access to these critical services.

Background The aim of this study was to investigate whether bioactive adrenomedullin (bio-ADM) and interleukin-6 (IL-6) are related to acute kidney injury (AKI) and severe illness in COVID-19 patients. Methods 153 patients with COVID-19 admitted to the emergency department (ED) were included. Blood samples were collected from each patient at admission. Bio-ADM and IL-6, as well as DPP3 and routinely measured markers were evaluated regarding the endpoints AKI (22/128 hospitalized patients) and a composite endpoint of admission to intensive care unit and/or in-hospital death (n = 26/153 patients). Results Bio-ADM and IL-6 were significantly elevated in COVID-19 patients with AKI compared to COVID-19 patients without AKI (each p