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The 'Roman emperor' Sponsian is known only from an assemblage of coins allegedly found in Transylvania (Romania) in 1713. They are very unlike regular Roman coins in style and manufacture, with various enigmatic features including bungled legends and historically mixed motifs, and have long been dismissed as poorly made forgeries. Here we present non-destructive imaging and spectroscopic results that show features indicative of authenticity. Deep micro-abrasion patterns suggest extensive circulation-wear. Superficial patches of soil minerals bound by authigenic cement and overlain by oxidation products indicate a history of prolonged burial then exhumation. These observations force a re-evaluation of Sponsian as a historical personage. Combining evidence from the coins with the historical record, we suggest he was most likely an army commander in the isolated Roman Province of Dacia during the military crisis of the 260s CE, and that his crudely manufactured coins supported a functioning monetary economy that persisted locally for an appreciable period., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Pearson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In 2017, Polish Biobanking Network was established in Poland, within BBMRI.pl project titled "Organization of Polish Biobanking Network within the Biobanking and Biomolecular Resources Research Infrastructure BBMRI-ERIC" as a strategic scientific infrastructure concept. One of the key elements of the project was the verification of the current status of QMS in the Polish biobanking institutions and the implementation of common solutions. The main goal was to indicate the current QMS level and determine the starting points for QMS development for each biobank of the Polish Biobanking Network (PBN). Within 3 years, 35 audit visits were performed. The current status and the level of QMS implementation in each biobank were assessed. Five hundred and seventy recommendations were prepared. The data was analyzed using Fischer Exact test to determine whether or not a significant association was observed. Three areas of analysis were covered: (1) BBMRI.pl status, (2) QMS implementation level and (3) private/public party, respectively. The results were discussed within 15 areas. Concluding remarks showed that some differences were observed in the case of subgroups analysis. There is convergence in QMS within the biobanks where Tissue Banks are located. Moreover, some discrepancies between the QMS implementation level in BBMRI.pl Consortium biobanks and PBN biobanks are observed. Nevertheless, the consortium members are obliged to prepare other biobanks willing to enter the PBN as Members/Observers or which already are in the PBN, so that they can meet the requirements of the quality management system that will enable efficient management of biobanking processes in these units. That is why some actions within BBMRI.pl projects are organized to help the whole biobanking community in Poland implement the harmonized solution., 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 Matera-Witkiewicz, Krupińska, Sitek, Laskowski, Zagórska and Gleńska-Olender.)

Introduction: Advances in the acute treatment of myocardial infarction (AMI) substantially reduced in-hospital mortality, but the post-discharge prognosis is still unacceptable. The Managed Care in Acute Myocardial Infarction (MC-AMI) is a program of Poland's National Health Fund that aims at comprehensive post-AMI care to improve long-term prognosis. The aim of the study was to assess the effect of MC-AMI on all-cause mortality in one-year follow-up., Methods: MC-AMI includes acute MI treatment, complex revascularization, cardiac rehabilitation (CR), scheduled one-year outpatient follow-up, and prevention of sudden cardiac death. In this retrospective observational study performed in a province of Silesia, Poland, we analyzed 3893 MC-AMI participants, and compared them to 6946 patients in the control group. After propensity score matching, we compared two groups of 3551 subjects each. To assess the effect of MC-AMI and other variables on mortality, we preformed a Cox regression., Results: MC-AMI was related with mortality reduction by 38% in a 12-month observation period and the effect persisted even after. Multivariable Cox regression analysis revealed MC-AMI participation to be inversely associated with 1-year mortality (HR 0.52, 95%CI 0.42-0.65, p < 0.001). Besides that, older age (HR 1.47/10 y), ST-elevation AMI (HR 1.41), heart failure (HR 2.08), diabetes (HR 1.52), and dialysis (HR 2.38) were significantly associated with the primary endpoint. Among MC-AMI components, cardiac rehabilitation (HR 0.34) and strict outpatient care (HR 0.42) are the crucial factors affecting mortality reduction., Conclusions: Participation in MC-AMI reduced 1-year mortality by 38% and the effect persisted after the program had been completed.

Alternative splicing (AS) has been shown to participate in prostate cancer development and progression; however, a link between AS and prostate cancer health disparities has been largely unexplored. Here we report on the cloning of a novel splice variant of FGFR3 that is preferentially expressed in African American (AA) prostate cancer. This novel variant ( FGFR3-S ) omits exon 14, comprising 123 nucleotides that encode the activation loop in the intracellular split kinase domain. Ectopic overexpression of FGFR3-S in European American (EA) prostate cancer cell lines (PC-3 and LNCaP) led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared with FGFR3-L (retains exon 14). The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and antiapoptotic activities, as well as a modest but significant gain in cell motility. Moreover, the FGFR3-S-conferred proliferative and motility gains were highly resistant to the pan-FGFR small-molecule inhibitor dovitinib and the antiapoptotic gain was insensitive to the cytotoxic drug docetaxel, which stands in marked contrast with dovitinib- and docetaxel-sensitive FGFR3-L. In an in vivo xenograft model, mice injected with PC-3 cells overexpressing FGFR3-S exhibited significantly increased tumor growth and resistance to dovitinib treatment compared with cells overexpressing FGFR3-L. In agreement with our in vitro and in vivo findings, a high FGFR3-S/FGFR3-L expression ratio in prostate cancer specimens was associated with poor patient prognosis. IMPLICATIONS: This work identifies a novel FGFR3 splice variant and supports the hypothesis that differential AS participates in prostate cancer health disparities., (©2019 American Association for Cancer Research.)

Many types of biomedical research projects depend on high-quality biological material with a data set attached. The Quality Management System (QMS) is focused on operational standards for all organizational activities to ensure that the described quality of each procedure, product, or service is guaranteed. The implementation of the QMS is necessary for the provision of both high quality and repeatability of processes in research laboratories. The current status of implementation of the QMS is determined according to the "Organisation of Polish Biobanking Network" within the project "Biobanking and Biomolecular Resources Research Infrastructure BBMRI-ERIC" supported by the Polish Ministry of Science and Higher Education-decision number DIR/WK/2017/01. According to the above, preliminary audits in six Polish institutions were conducted and reports with recommendations concerning the implementation and improvement of the QMS in Polish biobanks were prepared. During all audits, 13 QMS main areas were analyzed. All audited units belong to the BBMRI.pl consortium, which is responsible for the creation of the Polish Biobanking Network within the BBMRI-ERIC structure. Among all 13 analyzed areas, 27 deviations were identified. Eleven of them were implemented in all audited biobanks but defined as the areas for improvement , 16 of them were not implemented correctly or not implemented at all, respectively ( areas underlined to corrective procedures ).

Alternative splicing, the process of removing introns and joining exons of pre-mRNA, is critical for growth, development, tissue homeostasis, and species diversity. Dysregulation of alternative splicing can initiate and drive disease. Aberrant alternative splicing has been shown to promote the "hallmarks of cancer" in both hematological and solid cancers. Of interest, recent work has focused on the role of alternative splicing in prostate cancer and prostate cancer health disparities. We will provide a review of prostate cancer health disparities involving the African American population, alternative RNA splicing, and alternative splicing in prostate cancer. Lastly, we will summarize our work on differential alternative splicing in prostate cancer disparities and its implications for disparate health outcomes and therapeutic targets.

Atomic force microscopy (AFM) is being increasingly used to directly measure protein interactions in nearly physiological environments. Here, protocols for atomic force microscopy (AFM) for visualization of antigen-antibody complexes are presented. The technique is used to demonstrate complexes formed by rheumatoid arthritis patient antibodies with lipopolysaccharide (LPS) isolated from P. mirabilis (O3) strain S1959 and a synthetic antigen (LPS epitope of 6 N-alpha-(D-galacturonoyl)-L-lysine residues).

This corrects the article DOI: 10.1038/ncomms15921.

Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa.

In Poland storage of human biological samples takes place at most universities and scientific institutions conducting research projects in the field of biomedicine. The First International Biobanking Conference organized by the Ministry of Science and Higher Education in 2014 shed a light on the situation of Polish biobanking infrastructures. The country has around 40 large biorepositories, which store unique biological material such as whole brains, muscle fibers from patients with rare diseases, as well as thousands of samples from patients with lifestyle diseases. There are only two population-based biobanks working locally and several disease-oriented biobanks specializing mainly in oncological diseases. Consortium BBMRI.pl created plans for establishing a Polish Network of Biobanks, with national node which meets standards for biobanks and cooperation to guarantee development of biomedical sciences and international collaboration between Poland and other countries. The Polish network will enhance research activities, due to better visibility of samples and data that are stored in the national biobanking catalogue. However, it requires more than a comprehensive understanding of all benefits. The list of examples of benefits can be presented as follows: (i) a reduction of the duration and cost of clinical trials and subsequent time to market for anticancer drugs; (ii) more precise patient diagnosis and the associated impact on treatment and lower healthcare costs for providers, individuals, and the nation; (iii) improvements in research experiment time frames and data efficiencies; (iv) convergence to an industry standards for biospecimen quality; (v) optimization of capital infrastructure and IT technology.

Endothelins are a family of four endogenous peptides (ET-1, ET-2, ET-3, ET-4) secreted primarily in an inactive form by the endothelium. They are activated with the participation of converting enzyme. Numerous studies have described their pleiotropic biological activity. These peptides are involved, inter alia, in the regulation of processes such as cell proliferation, migration, angiogenesis and apoptosis. Their important role in the regulation of blood pressure, tissue perfusion (especially in the central nervous system), and myocardial systolic function is also known. Moreover, changes in transcriptional activity of endothelin and its receptors may be involved, with the participation of a number of signaling pathways, in carcinogenesis, and the pathogenesis of numerous diseases (heart, kidney, lung and skin disorders, especially with the component of fibrosis). Their role has been documented in the development of breast, prostatic, colorectal, ovarian, lung, kidney, and endometrial cancer, and in melanoma. In this article we present a brief description of the endothelin group and the participation of them and their receptors in carcinogenesis. We also try to show their role as prognostic and predictive factors in human malignant tumors. The article also refers to clinical trials on the use of preparations of endothelin receptor antagonists in the design of molecular therapeutic strategies in human malignancies.

Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (Tapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicer1, was positively correlated with the development of analgesic tolerance. The purpose of the present study was to test the hypothesis that miRNAs play a significant role in the development of analgesic tolerance as measured by thermal nociception. Dicer1 knockdown, miRNA profiling, bioinformatics, and confirmation of high value targets were used to test the proposition. Regionally targeted Dicer1 knockdown (via shRNA) had the anticipated consequence of eliminating the development of tolerance in C57BL/6J (B6) mice, thus supporting the involvement of miRNAs in the development of tolerance. MiRNA expression profiling identified a core set of chronic morphine-regulated miRNAs (miR's 27a, 9, 483, 505, 146b, 202). Bioinformatics approaches were implemented to identify and prioritize their predicted target mRNAs. We focused our attention on miR27a and its predicted target serpin peptidase inhibitor clade I (Serpini1) mRNA, a transcript known to be intricately involved in dendritic spine density regulation in a manner consistent with chronic morphine's consequences and previously found to be correlated with the development of analgesic tolerance. In vitro reporter assay confirmed the targeting of the Serpini1 3'-untranslated region by miR27a. Interestingly miR27a was found to positively regulate Serpini1 mRNA and protein levels in multiple neuronal cell lines. Lastly, Serpini1 knockout mice developed analgesic tolerance at a slower rate than wild-type mice thus confirming a role for the protein in analgesic tolerance. Overall, these results provide evidence to support a specific role for miR27a and Serpini1 in the behavioral response to chronic opioid administration (COA) and suggest that miRNA expression and mRNA targeting may underlie the neuroadaptations that mediate tolerance to the analgesic effects of morphine.

In a recent paper, Levy, Gadd, Kerridge, and Komesaroff attempt to defend the ethicality of homeopathy by attacking the utilitarian ethical framework as a basis for medical ethics and by introducing a distinction between evidence-based medicine and modern science. This paper demonstrates that their argumentation is not only insufficient to achieve that goal but also incorrect. Utilitarianism is not required to show that homeopathic practice is unethical; indeed, any normative basis of medical ethics will make it unethical, as a defence of homeopathic practice requires the rejection of modern natural sciences, which are an integral part of medical ethics systems. This paper also points out that evidence-based medicine lies at the very core of modern science. Particular arguments made by Levy et al. within the principlist medical ethics normative system are also shown to be wrong.

Purpose: African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality compared with European American (EA) men. In addition to socioeconomic influences, biologic factors are believed to play a critical role in prostate cancer disparities. We investigated whether population-specific and -enriched miRNA-mRNA interactions might contribute to prostate cancer disparities., Experimental Design: Integrative genomics was used, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis, and functional validation, to map miRNA-mRNA interactions associated with prostate cancer disparities., Results: We identified 22 AA-specific and 18 EA-specific miRNAs in prostate cancer versus patient-matched normal prostate, and 10 "AA-enriched/-depleted" miRNAs in AA prostate cancer versus EA prostate cancer comparisons. Many of these population-specific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed EGFR (or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs and miRNA-mRNA pairings. Novel miRNA-mRNA pairings were validated by qRT-PCR, Western blot, and/or IHC analyses in prostate cancer specimens. Loss/gain of function assays performed in population-specific prostate cancer cell lines confirmed miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ITPR2, and miR-34a/PPP2R2A as critical miRNA-mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA prostate cancer cells., Conclusions: Our data suggest that AA-specific/-enriched miRNA-mRNA pairings may play a critical role in the activation of oncogenic pathways in AA prostate cancer. Our findings also suggest that miR-133a/MCL1, miR-513c/STAT1, and miR-96/FOXO3A may have clinical significance in the development of novel strategies for treating aggressive prostate cancer., (©2015 American Association for Cancer Research.)

Functional expression of voltage-gated Na(+) channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.

Background: The academic half-day (AHD) curriculum is an alternative to the traditional noon conference in graduate medical education, yet little is known regarding its effect on knowledge acquisition and resident satisfaction., Objective: We investigated the association between the 2 approaches for delivering the curriculum and knowledge acquisition, as reflected by the Internal Medicine In-Training Examination (IM-ITE) scores and assessed resident learning satisfaction under both curricula., Methods: The Cleveland Clinic Internal Medicine Residency Program transitioned from the noon conference to the AHD curriculum in 2011. Covariates for residents enrolled from 2004 to 2011 were age; sex; type of medical degree; United States Medical Licensing Examination Step 1, 2 Clinical Knowledge; and IM-ITE-1 scores. We performed univariable and multivariable linear regressions to investigate the association between covariates and IM-ITE-2 and IM-ITE-3 scores. Residents also were surveyed about their learning satisfaction in both curricula., Results: Of 364 residents, 112 (31%) and 252 (69%) were exposed to the AHD and the noon conference curriculum, respectively. In multivariable analyses, the AHD curriculum was associated with higher IM-ITE-3 (regression coefficient, 4.8; 95% confidence interval 2.9-6.6) scores, and residents in the AHD curriculum had greater learning satisfaction compared with the noon conference cohort (Likert, 3.4 versus 3.0; P  =  .003)., Conclusions: The AHD curriculum was associated with improvement in resident medical knowledge acquisition and increased learner satisfaction.

Background: Although the American Board of Internal Medicine (ABIM) certification is valued as a reflection of physicians' experience, education, and expertise, limited methods exist to predict performance in the examination., Purpose: The objective of this study was to develop and validate a predictive tool based on variables common to all residency programs, regarding the probability of an internal medicine graduate passing the ABIM certification examination., Methods: The development cohort was obtained from the files of the Cleveland Clinic internal medicine residents who began training between 2004 and 2008. A multivariable logistic regression model was built to predict the ABIM passing rate. The model was represented as a nomogram, which was internally validated with bootstrap resamples. The external validation was done retrospectively on a cohort of residents who graduated from two other independent internal medicine residency programs between 2007 and 2011., Results: Of the 194 Cleveland Clinic graduates used for the nomogram development, 175 (90.2%) successfully passed the ABIM certification examination. The final nomogram included four predictors: In-Training Examination (ITE) scores in postgraduate year (PGY) 1, 2, and 3, and the number of months of overnight calls in the last 6 months of residency. The nomogram achieved a concordance index (CI) of 0.98 after correcting for over-fitting bias and allowed for the determination of an estimated probability of passing the ABIM exam. Of the 126 graduates from two other residency programs used for external validation, 116 (92.1%) passed the ABIM examination. The nomogram CI in the external validation cohort was 0.94, suggesting outstanding discrimination., Conclusions: A simple user-friendly predictive tool, based on readily available data, was developed to predict the probability of passing the ABIM exam for internal medicine residents. This may guide program directors' decision-making related to program curriculum and advice given to individual residents regarding board preparation.

The subject of the research were samples of overgrown adenoids removed by adenoidectomy 56 children, including 30 boys and 26 girls, exposure and unexposure from passive smoking, living in the administrative area of Chorzów. The statistic characteristic of Fe and Mn occurrence is presented in the thesis. The studies were carried out on the changes of Fe and Mn and other elements, (B, Al, La, Cd, Co, Cr, Cu, Ni, Pb, Zn, As, Se, Hg, V, Be, Mo, Sn, V, Ti, Sb, Bi, TI, Zr, Ca, Mg, Na, Ba, Sr, Li) respectively. The elemental composition of adenoids was determined with ICP-AES method (Inductively Coupled Plasma - Atomic Emission Spectroscopy). The studies on Fe and Mn occurrence in adenoids showed the presence of its higher concentrations in exposure boys (Fe - 116.13 microg/g; Mn - 0.70 microg/g), in comparison with exposure girls from passive smoking (93.06 microg/g; Mn - 0.57 microg/g).

The aim of this study was investigation influence sex and place living (industrial region or village) to concentration of: Ca, K, Mg and Na in pharyngeal tonsils (n = 84) from children exposed and unexposed to tobacco smoke and analysis kind of interactions between trace elements. Determination of these elements contents were performed by ICP-AES. It was found higher concentrations of Ca and Na in pharyngeal tonsils from boys (389 microg//g) and girls (356 microg/g) unexposed to tobacco smoke to comparison to expose to ETS boys (304 microg/g) and girls (298 microg/g). Higher concentrations of Ca and Na was found in this samples from children unexposed on ETS, living in industrial area to comparison to unexposed to ETS children living in village region. Higher concentration of K and Mg was found in exposed to ETS girls and boys in comparison to unexposed to ETS children, and higher level of these metals were found in exposed to tobacco smoke children living in industrial region and village.

This project is aimed to estimate the effect of passive smoke on the levels of selected trace elements (Ca, Mg, K, Na) in pharyngeal tonsils of children in several group of age (2-5 years, 6-9 years, 10-15 years). This trace elements were determined using ICP-AES method. It was concluded that the exposure to the cigarette smoke in pharyngeal tonsils is a factor producing the changes in the levels of essential elements: geometric mean of Ca was the highest in pharyngeal tonsils of children in 10-15 years old unexposure to ETS (410 microg/g). The least level of Ca - 281 microg/g was observed in this samples in the same group of age, but in children exposure by ETS. High levels of K was observed in pharyngeal tonsils of children exposure to passive smoking in all of group of age to comparison to unexposure by ETS. The greatest content - 27479 microg/g was in pharyngeal tonsils in exposure to ETS in 6-9 years old was observed, but the least - 16478 microg/g in 10-15 years old. Change of content of Mg was from 764 to 784 microg/g in samples from children exposure by ETS to comparison 720-744 microg/g in children unexposure by ETS. High level of Na was observed in pharyngeal tonsils from children exposure to ETS in all of group of age to comparison to unexposure. This study showed that the kind of interaction dependent on age and exposed by ETS. The changes of given elements were different for children passive smoking and no passive smoking in several group of age.