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Known concentrations of Staphylococcus aureus and Candida auris were applied on gloves and gowns then sampled with E-swabs and BBL liquid Amies swabs. The mean numbers of colony-forming units per milliliter (CFU/mL) obtained from culture of the 2 swab types were not different, suggesting that either can be used for recovery of these two pathogens from personal protective equipment.

Regulatory T cell (Treg) suppression of conventional T cells is a central mechanism that ensures immune system homeostasis. The exact time point of Treg emergence is still disputed. Furthermore, the time of Treg-mediated suppression mechanisms’ emergence has not been identified. It is not yet known whether Treg suppression mechanisms diverged from a single pathway or converged from several sources. We investigated the evolutionary history of Treg suppression pathways using various phylogenetic analysis tools. To ensure the conservation of function for investigated proteins, we augmented our study using nonhomology-based methods to predict protein functions among various investigated species and mined the literature for experimental evidence of functional convergence. Our results indicate that a minority of Treg suppressor mechanisms could be homologs of ancient conserved pathways. For example, CD73, an enzymatic pathway known to play an essential role in invertebrates, is highly conserved between invertebrates and vertebrates, with no evidence of positive selection (w = 0.48, p-value < 0.00001). Our findings indicate that Tregs utilize homologs of proteins that diverged in early vertebrates. However, our findings do not exclude the possibility of a more evolutionary pattern following the duplication degeneration–complementation (DDC) model. Ancestral sequence reconstruction showed that Treg suppression mechanism proteins do not belong to one family; rather, their emergence seems to follow a convergent evolutionary pattern.

This article presents the design, construction, and high-power test of two X -band radio frequency (RF) accelerating structures built as part of a collaboration between CERN and the Paul Scherrer Institute (PSI) for the compact linear collider (CLIC) study. The structures are a modified “tuning-free” variant of an existing CERN design and were assembled using Swiss free electron laser (SwissFEL) production methods. The purpose of the study is two-fold. The first objective is to validate the RF properties and high-power performance of the tuning-free, vacuum brazed PSI technology. The second objective is to study the structures’ high-gradient behavior to provide insight into the breakdown and conditioning phenomena as they apply to high-field devices in general. Low-power RF measurements showed that the structure field profiles were close to the design values, and both structures were conditioned to accelerating gradients in excess of 100 MV/m in CERN’s high-gradient test facility. Measurements performed during the second structure test suggest that the breakdown rate (BDR) scales strongly with the accelerating gradient, with the best fit being a power law relation with an exponent of 31.14. In both cases, the test results indicate that stable, high-gradient operation is possible with tuning-free, vacuum brazed structures of this kind.

Celem artykułu jest przedstawienie, na podstawie ustaleń historiografii, ewolucji najważniejszych ośrodków osadnictwa wołoskiego w rejonach Olimpu i Vermio. Umocniły się one w następstwie wędrówek ludności z obszaru Pindosu, w XVIII i XIX wieku. W przypadku Olimpu kulminacja migracji przypadła na drugą połowę XVIII wieku, a w rejonie Vermio na pierwsze trzy dekady XIX wieku. Ukształtowane wówczas enklawy osadnicze, związane z Livadi, Kato Vermio, Xirolivado, w kolejnych dekadach ulegały rozczłonkowaniu. Choć część ludności kontynuowała wcześniejszą działalność ekonomiczną i jeszcze w XIX wieku utrzymywała kontakty z „macierzystymi” osadami z Pindosu, większość uległa asymilacji z Grekami. Wołosi zasilali greckojęzyczne społeczności miejskie w Werii (Veroia), Naoussie i Katerini, rezygnowali z gospodarki transhumancyjnej i tradycyjnego języka oraz migrowali do Rumunii.

The Italian Republic Toward Political Changes in the Western Balkans Region at the Turn of 20th and 21st Centuries (1991–2001). National Interests and Euro-Atlantic Policy The article aims to show the main circumstances influencing the evolution of the Italian diplomatic attitude towards the post-Yugoslav and Albanian area from 1991 through 2001. Both the international and internal contexts are included (the change of international order after the collapse of communist regimes, relations with NATO and the European Union, and the weakening of the international position of Italy as the result of its internal political crisis in 1992–1994). Two mutually supportive elements can be distinguished within the Italian policy toward the Balkans. Traditionally, Italian diplomats were focused on bilateral and multilateral activities aiming at the protection of territorial security and economic interests, primarily in the Adriatic region. They criticized all international military intervention in the post-Yugoslav area. This attitude was partially changed in 1999, when Italy decided to take part in NATO’s air operation Allied Force against Yugoslavia, although many controversies regarding this action arose on the Italian political scene. The article is based on published diplomatic documents, scientific publications and the press.

In recent years, there has been a trend toward replacing petrochemical raw materials with so-called “bio” plastics, i.e. plastics from renewable sources. Herein, the susceptibility of degradation in the compost heap of three types of packaging polyesters, by means of PET and biobased PEF and PLA, with other thermoplastic polyesters with more methylene groups (three and six) bio—(PTF and PHF, respectively) and petrochemically-based (PTT and PHT, respectively) has been studied. Two series of polymer materials based on ethylene, propylene, and hexamethylene glycols and two diesters (dimethyl terephthalate and dimethyl 2,5-furandicarboxylate) were thus obtained and compared with “double green” PLA. Moreover, the assessment of the influence of the subsequent processing cycle (injection moulding) on the utilitarian properties of these materials, constitutes the analogy to the subsequent recycling cycle. The susceptibility to degradation was assessed in the context of changes in the structure (analyzed by FTIR and DSC), intrinsic viscosity, and mechanical performance. In addition, chromatographic analysis of the solutions of the analyzed samples in methanol was carried out in order to determine whether and what low-molecular compounds were released from the analyzed polyesters. It has been shown that furan-based polyesters have great potential to replace materials based on dimethyl terephthalate-based polyesters.

Recent discoveries shed light on molecular mechanisms responsible for classical Hodgkin lymphoma (HL) development and progression, along with features of Hodgkin – Reed and Sternberg cells (HRS). Here, we summarize current knowledge on characteristic molecular alterations in HL, as well as existing targeted therapies and potential novel treatments for this disease. We discuss the importance of cluster of differentiation molecule 30 (CD30) and the programmed cell death-1 protein (PD-1) and ligands (PD-L1/2), and other molecules involved in immune modulation in HL. We highlight emerging evidence indicating that the altered function of SWI/SNF-type chromatin remodeling complexes, PRC2, and other epigenetic modifiers, contribute to variations in chromatin status, which are typical for HL. We postulate that despite of the existence of plentiful molecular data, the understanding of HL development remains incomplete. We therefore propose research directions involving analysis of reverse signaling in the PD-1/PD-L1 mechanism, chromatin remodeling, and epigenetics-related alterations, in order to identify HL features at the molecular level. Such attempts may lead to the identification of new molecular targets, and thus will likely substantially contribute to the future development of more effective targeted therapies.

The article presents the results of strength tests of screw-nut threaded connections made of polymeric materials such as: ABS, PLA, PET-G and RGD720. In order to make physical models, three 3D printing techniques were used: Fused Deposition Modeling (FDM), Fused Filament Fabrication (FFF), and PolyJet. The tests took into account the stresses caused by the axial force generated when the bolt is screwed into the nut or other structural element. Due to the complexity of the issue, the presented studies are only a starting point for further research.

Zrównoważony rozwój od wielu lat stanowi kluczowy element strategii większości organizacji na świecie. Jego cele zostały przyjęte w rezolucji Zgromadzenia Ogólnego ONZ Przekształcamy nasz świat: Agenda na rzecz zrównoważonego rozwoju 2030. Ze względu na rolę i znaczenie leśnictwa i usług pocztowych w harmonizowaniu celów ekonomicznych, społecznych i środowiskowych za interesujące zagadnienie można uznać sposób ujawniania różnego rodzaju działań przez podmioty zaangażowane w tego typu działalność. Celem artykułu jest wskazanie zakresu ujawnianych informacji odnoszących się do celów zrównoważonego rozwoju przez podmioty prowadzące działalność leśną i pocztową. Założony cel został zrealizowany dzięki przeglądowi opracowań krajowych i zagranicznych oraz analizie treści dokumentów sporządzanych obowiązkowo i dobrowolnie. Na podstawie przeprowadzonego badania stwierdzono, że obowiązkowe ujawnienia dostarczają ograniczonych informacji na temat realizacji celów zrównoważonego rozwoju. Więcej informacji można uzyskać z ujawnień o charakterze dobrowolnym. Nie stwierdzono szczególnego prymatu wymiaru środowiskowego nad społecznym i odwrotnie.

The hoard found in 2003 during archaeological excavations in Perespa in the Tomaszów Lubelski district, Lublin voivodeship, despite its small size (46 coins), and thanks to its assured completeness, gives the opportunity to study the structure of the rural Polish monetary market in the middle of the 16th century, the role of coins from individual mints and foreign coinage. The location and context of the hoard also provide an opportunity to relate it to the results of research on the monetization of villages and the role of cash rents in the transformations of the rural economy in the early modern era. A high technical level coin counterfeit from the Perespa hoard deserves A separate reflection as it suggests that it was the product of an official mint.

Adoptive transfer, persistence, and migration of autologous control gene-marked T cells.

10D1F interacts with linear peptides from the HER3 domain II dimerization interface

Serum chemistry and cytokine levels in control animals.

10D1P demonstrates potent in vivo tumor growth inhibition in multiple xenograft tumor models

10D1F does not show rapid internalization in HER3 expressing cancer cell lines but activates ADCC

PDF file - 11K, List of antibodies used in the study

Supplementary Methods with References, Supplementary Figure Legends, and list of Supplementary Tables

Supplemental Table 2 - Summary of protein and gene expression data of HER family molecules, and their ligands, for the cancer cell lines used in this study

PDF file - 790K, Absence of morphological changes in organs of MMTV-neu mice treated with Curaxin-137 from 4 to 14 weeks of age.

Genetic engineering of T cells for adoptive transfer by introducing a tumor-targeting chimeric antigen receptor (CAR) is a new approach to cancer immunotherapy. A challenge for the field is to define cell surface molecules that are both preferentially expressed on tumor cells and can be safely targeted with T cells. The orphan tyrosine kinase receptor ROR1 is a candidate target for T-cell therapy with CAR-modified T cells (CAR-T cells) because it is expressed on the surface of many lymphatic and epithelial malignancies and has a putative role in tumor cell survival. The cell surface isoform of ROR1 is expressed in embryogenesis but absent in adult tissues except for B-cell precursors and low levels of transcripts in adipocytes, pancreas, and lung. ROR1 is highly conserved between humans and macaques and has a similar pattern of tissue expression. To determine if low-level ROR1 expression on normal cells would result in toxicity or adversely affect CAR-T cell survival and/or function, we adoptively transferred autologous ROR1 CAR-T cells into nonhuman primates. ROR1 CAR-T cells did not cause overt toxicity to normal organs and accumulated in bone marrow and lymph node sites, where ROR1-positive B cells were present. The findings support the clinical evaluation of ROR1 CAR-T cells for ROR1+ malignancies and demonstrate the utility of nonhuman primates for evaluating the safety of immunotherapy with engineered T cells specific for tumor-associated molecules that are homologous between humans and nonhuman primates. Cancer Immunol Res; 3(2); 206–16. ©2014 AACR.

PDF file - 175K, Table 1. Concentration of Curaxin-137 (muM) in mouse plasma and tissues (mean +/-SD in muM, n=4) 10 weeks after start of treatment (14 weeks of age) Table 2. Histopathological findings in old animals in each of treatment group (two mice per group)

Gating strategy for ROR1-expressing B cells in the lymph node.

10D1F demonstrates superior inhibition of cancer cell line proliferation by potently inhibiting downstream signaling through the PI3K pathway in additional cancer cell lines

10D1F parental antibody, 10D1P, binds with high affinity and specificity to a species-conserved epitope on HER3, and Class 1 and Class 2 HER3 antibodies show different HER3 binding profiles in presence and absence of NRG1

In recent years, HER3 has increasingly been implicated in the progression of a variety of tumor types and in acquired resistance to EGFR and HER2 therapies. Whereas EGFR and HER2 primarily signal through the MAPK pathway, HER3, as a heterodimer with EGFR or HER2, potently activates the PI3K pathway. Despite its critical role, previous attempts to target HER3 with neutralizing antibodies have shown disappointing efficacy in the clinic, most likely due to suboptimal and indirect mechanisms of action that fail to completely block heterodimerization; for example, tumors can escape inhibition of ligand binding by upregulating ligand-independent mechanisms of HER3 activation. We therefore developed 10D1F, a picomolar affinity, highly specific anti-HER3 neutralizing antibody that binds the HER3 heterodimerization interface, a region that was hitherto challenging to raise antibodies against. We demonstrate that 10D1F potently inhibits both EGFR:HER3 and HER2:HER3 heterodimerization to durably suppress activation of the PI3K pathway in a broad panel of tumor models. Even as a monotherapy, 10D1F shows superior inhibition of tumor growth in the same cell lines both in vitro and in mouse xenograft experiments, when compared with other classes of anti-HER3 antibodies. This includes models demonstrating ligand-independent activation of heterodimerization as well as constitutively activating mutations in the MAPK pathway. Possessing favorable pharmacokinetic and toxicologic profiles, 10D1F uniquely represents a new class of anti-HER3 neutralizing antibodies with a novel mechanism of action that offers significant potential for broad clinical benefit.10D1F is a novel anti-HER3 antibody that uniquely binds the receptor dimerization interface to block ligand-dependent and independent heterodimerization with EGFR/HER2 and thus more potently inhibits tumor growth than existing anti-HER3 antibodies.

Supplemental Table 3 - Toxicological data showing no adverse effects of 10D1F on the indicated hematological and biochemistry parameters in multiple rodent models

Supplemental Table 1 - Summary of the published functional mechanisms of action for anti-HER3 neutralizing antibodies in development

Summary Background PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. Methods In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. Findings Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. Interpretation Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. Funding Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA). Translation For the Portuguese translation of the Article see Supplementary Materials section.

Key Points Pembrolizumab improved health-related quality of life over brentuximab vedotin in patients with relapsed/refractory cHLPembrolizumab should be considered the preferred treatment option for relapsed/refractory cHL post-ASCT or in patients ineligible for ASCT, Visual Abstract, KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (>90%) and through week 24 (>80%) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31]; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74]; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT.

Celem artykułu jest przedstawienie okoliczności, które doprowadziły do odpływu ludności wołoskiej z rejonu gór Pindos, który jest uznawany za jeden z tradycyjnych obszarów osadnictwa Wołochów. Migracje te trwały przez dziesiątki lat, w większości odbywały się w ramach Turcji osmańskiej, ale poszczególne rodzin udawały się także poza jej granice, przeważnie do Europy środkowo-wschodniej. Wędrówki były powodowane przez pogarszający się stan bezpieczeństwa, związany z działalnością band rozbójniczych i turbulencje polityczno-militarne w europejskiej części Turcji. Motywy wędrówek miały także charakter ekonomiczny. Początkowo migrowały rodziny, żyjące z działalności handlowej i rzemieślniczej. Stopniowo z Pindosu zaczęły odpływać poszczególne klany, które szukały nowych pastwisk i miejsc osadnictwa. W rezultacie kilkusetletnich migracji, wołoscy osadnicy rozproszyli się po wyżynno-górzystych rejonach Tesalii, Tracji, Macedonii, Bośni. Osiedlali się w także miastach w Austrii, Serbii, Grecji, Bułgarii i Rumunii.

Felsőzsolca-Nagyszilváson az 1999–2000 között folyó feltárások során a 27. sírból előkerült egy hosszú ideig meghatározhatatlan 14–15. századi, baltikumi származásúnak vélt pénz. A sírban más melléklet nem volt, így keltezése is bizonytalan lábakon állt. Közel húsz év elteltével derült fény a pénz származási helyére az első ilyen veret ugyanis csak 2013-ban került elő Lengyelországban, Piotrówka erődjében. Napjainkig mindössze hat veretet ismerünk a típusból.