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Patients with hematologic malignancies can be immunocompromized because of their disease, anti-cancer therapy, and concomitant immunosuppressive treatment. Furthermore, these patients are usually older than 60 years and have comorbidities. For all these reasons they are highly vulnerable to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and have an increased risk of developing severe/critical Coronavirus disease 2019 (COVID-19) compared to the general population. Although COVID-19 vaccination has proven effective in reducing the incidence of severe/critical disease, vaccinated patients with lymphoma may not be protected as they often fail to develop a sufficient antiviral immune response. There is therefore an urgent need to address the management of patients with lymphoma and COVID-19 in the setting of the ongoing pandemic. Passive immunization with monoclonal antibodies against SARS-CoV-2 is a currently available complementary drug strategy to active vaccination for lymphoma patients, while monoclonal antibodies and antiviral drugs (remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir) have proven effective in preventing the progression to severe/critical COVID-19. In this narrative review we present the most recent data documenting the characteristics and outcomes of patients with concomitant lymphoma and COVID-19. Our ultimate goal is to provide practice-oriented guidance in the management of these vulnerable patients from diagnosis to treatment and follow-up of lymphoma. To this purpose, we will first provide an overview of the main data concerning prognostic factors and fatality rate of lymphoma patients who develop COVID-19; the outcomes of COVID-19 vaccination will also be addressed. We will then discuss current COVID-19 prophylaxis and treatment options for lymphoma patients. Finally, based on the literature and our multidisciplinary experience, we will summarize a set of indications on how to manage patients with lymphoma according to COVID-19 exposure, level of disease severity and former history of infection, as typically encountered in clinical practice.

Circulating tumor DNA (ctDNA) has become the most investigated analyte in blood. It is shed from the tumor into the circulation and represents a subset of the total cell-free DNA (cfDNA) pool released into the peripheral blood. In order to define if ctDNA could represent a useful tool to monitor hematologic malignancies, we analyzed 81 plasma samples from patients affected by different diseases. The results showed that: (i) the comparison between two different extraction methods Qiagen (Hilden, Germany) and Promega (Madison, WI) showed no significant differences in cfDNA yield, though the first recovered higher amounts of larger DNA fragments; (ii) cfDNA concentrations showed a notable inter-patient variability and differed among diseases: acute lymphoblastic leukemia and chronic myeloid leukemia released higher amounts of cfDNA than chronic lymphocytic leukemia, and diffuse large B-cell lymphoma released higher cfDNA quantities than localized and advanced follicular lymphoma; (iii) focusing on the tumor fraction of cfDNA, the quantity of ctDNA released was insufficient for an adequate target quantification for minimal residual disease monitoring; (iv) an amplification system proved to be free of analytical biases and efficient in increasing ctDNA amounts at diagnosis and in follow-up samples as shown by droplet digital PCR target quantification. The protocol has been validated by quality control rounds involving external laboratories. To conclusively document the feasibility of a ctDNA-based monitoring of patients with hematologic malignancies, more post-treatment samples need to be evaluated. This will open new possibilities for ctDNA use in the clinical practice.

The metachronic onset of diffuse large B-cell lymphoma (DLBCL) after classic Hodgkin lymphoma (cHL) is a rare event affecting patients’ outcomes. However, although several studies have investigated the prognostic role of this event, little is known about a hypothetical common origin of the two different neoplastic cells. Aims: To investigate a possible relationship between DLBCL and cHL, in this retrospective study of 269 patients with newly diagnosed cHL treated at Bari University Hospital (Italy) between 2007 and 2020, we analyzed data from 4 patients (3 male and 1 female) with cHL who subsequently developed DLBCL. Methods: Gene expression profile analysis, assessed by NanoString Lymphoma Subtype Assay, was performed to identify the cell of origin in the DLBCL cases, in addition to Hans’s algorithm. Results: Using Hans’s algorithm, all DLBCL cases showed a germinal center-B-Cell subtype. The gene expression profile evaluated by the NanoString Lymphoma Subtype Assay revealed two cases of the GCB molecular subtype, while the others were unclassified. After first-line chemotherapy, 1 patient achieved complete remission, 3 were non-responders (2 died of lymphoma within 6 months, whereas the other achieved complete remission after autologous and allogeneic stem cell transplantation and is still alive). Conclusions: The origin of the second neoplastic cell in patients with DLBCL with a previous history of cHL remains controversial, although the different immunophenotypic characteristics suggest that it may mainly arise de novo in a subject with a possible individual predisposition to develop lymphoid neoplasms.

This study evaluates how eDNA information could be used within Environmental Impact Assessment (EIA). We developed an original model to simulate the conditions for which an eDNA signal detects, or does not detect, an impact on a targeted (receptor) species in a given project area. The simulation has four consecutive steps. First, a deterministic model simulated the dynamics of the receptor population and their eDNA fragment concentrations in the environment. Second, random distributions of receptor organisms and eDNA fragment quantities at steady-state were simulated within the project area. Then Simple Random Samplings were performed for both the receptor and eDNA. Third, post-sampling processes (eDNA extraction, amplification, analysis) were simulated to estimate the detection probability of the species from sample plan characteristics (size of sampling unit, number of samples collected). Fourth, we simulated an impact by modifying the growth, mortality and mobility (null, passive and active) parameters of the receptor species, then determined if an impact was detected. Detection probability curves were estimated for a range of sample volumes fitted with a Weibull cumulative distribution function. An F-like statistic compared detection curves before and after impact. Twelve scenarios were simulated. A statistically significant impact was detected with eDNA when receptor species growth rate was halved, but only in cases of null or passive mobility. When the receptor experienced both reduced growth and increased mortality rates, an impact was detected in all three mobility cases (null, passive and active). Our results suggest that an impact could be detected using eDNA if both the population dynamics of the receptor and the dynamics of DNA shed into the environment are known. These results indicate that caution should be exercised with eDNA data for EIA, but the proposed framework provides a valuable starting point to improve interpretation of indirect observation methods such as eDNA.

Current trends in the ceramic industry see an increasing interest on porcelain stoneware, by which is possible to produce large tiles and slabs. These products are manufactured by spray-dried powders, which have excellent technological properties but require high energy and water consumption. Dry-processed granulates allow to reduce such a consumption, but suffer from a different technological behavior. A solution to improve the environmental sustainability of ceramic tile-making is mixing powders prepared by the wet and the dry routes. The technological features of industrially manufactured mixed powders was investigated (rheological properties, compaction response and firing behavior) in order to point out advantages and possible pitfalls. Dry-processed and spray-dried granulates exhibit different distributions of size, shape and moisture that reflect on distinct rheological and compaction behaviors. Mixed powders show a more or less accentuated deviation from linearity between the end terms. This fact makes possible to add up to ∼50% dry granulates by keeping the technological properties close to current industrial bodies. Sparings of water, energy and CO2 emission for the milling and granulation stages are estimated for a mix 50% spray-dried and 50% dry-processed powders.

Background: The rapid spread of COVID‐19 forced many countries to adopt severe containment measures, transferring all didactic activities into virtual environments. However, the integration of technology in teaching may present difficulties, especially in some countries, such as Italy. Objectives: The present study analyzed how the two main factors of the Technology Acceptance Model (TAM), namely perceived usefulness and perceived ease of use, combined with online teaching self‐efficacy, were associated with the intention to use technology to teach. We posited a moderated moderation model in which perceived usefulness represented the main predictor, with self‐efficacy and perceived ease of use as moderators of intention to use technology to teach. Method: The model was tested through multiple regressions, using the PROCESS macro on SPSS 26 with a sample of 178 upper secondary school teachers in Italy. Results and conclusions: Regressions showed that each variable significantly predicted the intention to use technology. In addition, a moderation effect of self‐efficacy on the perceived usefulness of using technology was found for medium and high‐level of perceived ease of use of technology. Implications: The present study provides targeted implications for distance education policy and practice to promote its adoption (or the blended modality) in Italian upper schools. [ABSTRACT FROM AUTHOR] Copyright of Journal of Computer Assisted Learning is the property of Wiley-Blackwell 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.)

Supplementary Figure S6. Mean changes from baseline by study arm in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 symptom items.

Supplementary Appendix S1 Supplementary Appendix S2

PDF file - 23K, Proteins identified in MMECs upon HIF-1�siRNA and panobinostat treatment (MALDITOFF mass spectrometry).

PDF file - 114K, Lack of HIF-1alpha expression by BM macrophages in normoxia condition.

PDF file - 2376K, Panobinostat effect on MMECs in the presence of BM cells and proteomic analysis of MMECs upon treatment with HIF-1α·siRNA or panobinostat.

Supplementary Figure Legends

Supplementary Figure S5. Mean changes from baseline by study arm in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 global quality of life and functional scales.

Supplementary Figure S3. The waterfall plots of the best percentage change in the tumor burden from baseline evaluation in patients treated with CAPTEM (A) and FOLFIRI (B).

Supplementary Figure S8. The waterfall plots of the best percentage change in the tumor burden from baseline evaluation in patients treated with CAPTEM (left panels) and FOLFIRI (right panels) according to MGMT IHC expression and MGMT % methylation by Methyl-BEAMing.

Purpose: To determine a “gene/molecular fingerprint” of multiple myeloma endothelial cells and identify vascular mechanisms governing the malignant progression from quiescent monoclonal gammopathy of undetermined significance.Experimental Design: Comparative gene expression profiling of multiple myeloma endothelial cells and monoclonal gammopathy of undetermined significance endothelial cells with the Affymetrix U133A Arrays was carried out in patients at diagnosis; expression and function of selective vascular markers was validated by real-time reverse transcriptase-PCR, Western blot, and small interfering RNA analyses.Results: Twenty-two genes were found differentially expressed (14 down-regulated and eight up-regulated) at relatively high stringency in multiple myeloma endothelial cells compared with monoclonal gammopathy of undetermined significance endothelial cells. Functional annotation revealed a role of these genes in the regulation of extracellular matrix formation and bone remodeling, cell adhesion, chemotaxis, angiogenesis, resistance to apoptosis, and cell-cycle regulation. Validation was focused on six genes (DIRAS3, SERPINF1, SRPX, BNIP3, IER3, and SEPW1) not previously found to be functionally correlated to the overangiogenic phenotype of multiple myeloma endothelial cells in active disease. The small interfering RNA knockdown of BNIP3, IER3, and SEPW1 genes affected critical multiple myeloma endothelial cell functions correlated with the overangiogenic phenotype.Conclusions: The distinct endothelial cell gene expression profiles and vascular phenotypes detected in this study may influence remodeling of the bone marrow microenvironment in patients with active multiple myeloma. A better understanding of the linkage between plasma cells and endothelial cells in multiple myeloma could contribute to the molecular classification of the disease and thus pinpoint selective gene targets for more effective antiangiogenic treatments. (Clin Cancer Res 2009;15(17):5369–78)

Supplementary Figure S1 from Endothelial Differentiation of Hematopoietic Stem and Progenitor Cells from Patients with Multiple Myeloma

Supplementary Figures S1-S4; Supplementary Table S1.

PDF file - 133K, HIF-1alpha protein correlates with VEGFR-2, FGFR-2 and HGF.

PDF file - 17K, Real Time RT-PCR Primers.

PDF file - 166K, HIF-1alpha protein does not correlate with AKT, and VHL.

Supplementary Data from Gene Expression Profiling of Bone Marrow Endothelial Cells in Patients with Multiple Myeloma

Purpose: Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). In tumors, near angiogenesis, vasculogenesis contributes to the formation of the microvascular plexus that is important for diffusion. Here, we show that hematopoietic stem and progenitor cells (HSPC) of multiple myeloma (MM) patients are able to differentiate into cells with endothelial phenotype on exposure to angiogenic cytokines.Experimental Design: Circulating HSPCs were purified with an anti-CD133 antibody from patients with newly diagnosed MM before autologous transplantation and exposed to vascular endothelial growth factor (VEGF), fibroblast growth factor-2 and insulin-like growth factor in a 3-week culture.Results: HSPCs gradually lost CD133 expression and acquired VEGF receptor-2, factor VIII–related antigen, and vascular endothelial-cadherin expression. The expression pattern overlapped with paired MM endothelial cells (MMEC). During culture, cells adhered to fibronectin, spread, and acquired an endothelial cell shape. Differentiated HSPCs also became capillarogenic in the Matrigel assay with maximal activity at the third week of culture. Bone marrow biopsies revealed HSPCs inside the neovessel wall in patients with MM but not in those with monoclonal gammopathy of undetermined significance.Conclusions: In patients with MM, but not in those with monoclonal gammopathy of undetermined significance, HSPCs contribute to the neovessel wall building together with MMECs. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. Tentatively, we hypothesize that in HSPC cultures a multipotent cell population expressing low VEGF receptor-2 levels corresponds to the endothelial progenitor cell precursor and seems to be the MMEC precursor.

Supplementary Figure S2. Forest plots of overall survival by patient subgroups within the intention-to-treat population.

Purpose:To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with RAS-mutated, methyl-guanine methyltransferase (MGMT)-methylated metastatic colorectal cancer (mCRC).Patients and Methods:In this randomized, phase II trial, we enrolled patients with RAS-mutated, MGMT-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed MGMT methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A.Results:Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (n = 43) or arm B (n = 43). After a median follow-up of 30.5 months (interquartile range, 12.2–36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided P = 0.223). Progression-free survival and overall survival were 3.5 (2.0–5.0) and 9.5 (8.2–25.8) in arm A versus 3.5 (2.3–6.1) and 10.6 (8.5–20.8) in arm B [HR = 1.19 (0.82–1.72) and HR = 0.97 (0.58–1.61)], respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM.Conclusions:Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.

Supplementary Figure S1. Forest plots of progression-free survival by subgroups within the intention-to-treat population.

Supplementary Table S1. Efficacy and activity measures in intention-to-treat population.

Supplementary Figure S7. Mean changes from baseline by study arm in Functional Assessment of Cancer Therapy-Colorectal [FACT-C].

Purpose: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.Experimental Design: HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis–related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.Conclusions: The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance. Clin Cancer Res; 20(4); 847–58. ©2013 AACR.

PDF file - 403K, HIF-1alpha protein negative MMECs are sensitive to the antiangiogenic effect of bortezomib and lenalidomide.

Supplementary Figure S4. Compliance to quality of life questionnaires (number of patients completing baseline assessments and the assessments at designated time points). Panel A: EORTC QLQ-C30. Panel B: FACT-C

Internet usage is a salient developmental factor in adolescents’ lives. Although relevant correlates of internet use have been documented earlier, there is a lack of information on lower socioeconomic status groups. This is important, as these adolescents have increased risk for negative online experiences. The current survey aimed to explore internet use and parental involvement amongst adolescents from areas of socio-economic disadvantage in 30 urban schools across five European countries. A total of 2,594 students participated, of whom 90% were 14-16 years. Virtually all adolescents of socioeconomic disadvantage had internet access, with 88.5% reporting spending more than two hours per day online, often on apps such as Instagram, Snapchat, and YouTube. Almost one-third of adolescents did not talk with their parents about their internet use and almost two-thirds indicated that their parents were only a little or not interested in their internet use. A consistent finding across countries was that girls more often talked with their parents about their internet use and more often reported that their parents were interested in their internet use than boys. The results suggest that parents have an important task in explicitly showing interest in their adolescents’ internet use, with special attention needed for boys.

Minimal/measurable residual disease (MRD) monitoring is progressively changing the management of hematologic malignancies. The possibility of detecting the persistence/reappearance of disease in patients in apparent clinical remission offers a refined risk stratification and a treatment decision making tool. Several molecular techniques are employed to monitor MRD, from conventional real-time quantitative polymerase chain reaction (RQ-PCR) to next generation sequencing and digital droplet PCR (ddPCR), in different tissues or compartments through the detection of fusion genes, immunoglobulin and T-cell receptor gene rearrangements or disease-specific mutations. RQ-PCR is still the gold standard for MRD analysis despite some limitations. ddPCR, considered the third-generation PCR, yields a direct, absolute, and accurate detection and quantification of low-abundance nucleic acids. In the setting of MRD monitoring it carries the major advantage of not requiring a reference standard curve built with the diagnostic sample dilution and of allowing to reduce the number of samples below the quantitative range. At present, the broad use of ddPCR to monitor MRD in the clinical practice is limited by the lack of international guidelines. Its application within clinical trials is nonetheless progressively growing both in acute lymphoblastic leukemia as well as in chronic lymphocytic leukemia and non-Hodgkin lymphomas. The aim of this review is to summarize the accumulating data on the use of ddPCR for MRD monitoring in chronic lymphoid malignancies and to highlight how this new technique is likely to enter into the clinical practice.

Over the last years, the share of E-commerce has increased in all market segments and the European e-commerce market has become the largest market in the world. In the digital economy, the leading role of e-commerce is to achieve the goals of sustainable development, to ensure flexibility and adaptability of the management system. This study investigates patterns in e-commerce activities and their impact on energy efficiency for a group of 29 European countries by using a unique panel dataset spanning the years 2011–2019 collected from EUROSTAT. The empirical approach involves the specification of a difference one-step GMM estimation method. Our results suggest that e-commerce has the potential to facilitate more sustainable production processes and consumption patterns and ensure more circularity.

Sialylation is the terminal addition of sialic acid to underlying glycans and plays a prominent role in cell adhesion and immune regulation. Sialylated structures found on adhesion molecules, such as CD49d, mediate the interactions between cancer cells and the microenvironment, facilitating metastatic seeding in target organs. Chronic lymphocytic leukemia (CLL) is a clonal B-cell malignancy characterized by the accumulation of CD5- positive B cells in the peripheral blood, bone marrow and lymph nodes. CLL cells proliferate mainly in the lymph node “proliferation centers”, where the microenvironment provides pro-survival signals. Thus, migration and homing into these protective niches play a crucial role in CLL biology. In recent years, therapeutic strategies aiming at inducing the egress of CLL cells from the lymph nodes and bone marrow into the circulation have been highly successful. In this study, the sialylation status of 79 untreated and 24 ibrutinibtreated CLL patients was characterized by flow cytometry. Moreover, the effect of sialic acid removal on migration was tested by a transwell assay. Finally, we examined the sialylation status of CD49d by Western blot analysis. We found that CLL cells are highly sialylated, particularly those characterized by an “activated” immune phenotype. Notably, sialylation regulates CLL migration through the post-translational modification of CD49d. Finally, we showed that therapeutic agents that induce CLL mobilization from their protective niches such as ibrutinib, modulate the levels of sialic acids. We propose that sialylation is an important regulator of CLL trafficking and may represent a novel target to further improve CLL therapy.