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The circular economy approach has been introduced to the construction sector to design out waste, reduce carbon emissions and energy use in production of primary materials and achieve resource efficiency. 'Design for deconstruction' is increasingly important for a sustainable economy, especially for composite structure that is deemed as resource‐efficient in the first cycle of use. With this background, research has been conducted to facilitate the use of demountable composite beams in steel‐framed structures. This article presents the results of two 6 m full‐scale composite beam tests with prefabricated composite slabs. Demountable shear connectors were used, which have been newly developed within the frame of an EU project. The nominal degree of shear connection of the composite beam specimens was 0.37, which was slightly below the required 0.4 specified in EN1994‐1‐1 for welded shear studs. Based on the experimental observations, it can be demonstrated that (1) the tested demountable composite beam produced higher resistance but lower stiffness values than a comparable reference composite beam with welded shear studs; (2) the beam specimens showed a good plastic behaviour with high ductility despite the non‐ductile nature of the applied demountable shear connectors. Remarks on the demountability of the developed demountable composite beams are provided. [ABSTRACT FROM AUTHOR]

A Lego‐like steel‐framed structural system has been developed within the frame of an RFCS project, REDUCE, to facilitate 1) deconstruction of composite structures, 2) circularity at structure and element levels, and 3) serial production in construction by promoting a greater standardization of structural elements. The system utilizes innovative demountable shear connections for composite flooring solutions with precast concrete elements, and adjustable steel connections for use in both beam‐to‐beam and beam‐to‐column connections. The first use case of the structural system has been realized in the Petite Maison project which is a demonstration project for circularity and contributes to the event ESCH2022. Each construction element is linked to a digital database and remains available for future reuse, as a result of the plug‐and‐play, demountable and robust features of the developed system. This paper presents the proposed demountable system, the results from experiments and finite element analyses on the behaviour of shear connections, composite beams, and steel connections, and indicates the analysing methods for structural engineers to open a pathway for full implementation of the structures built into digital tools, fabrication, and construction. [ABSTRACT FROM AUTHOR]

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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or with TP53 defect, with BTK and phospholipase C gamma 2 (PLCG2) mutations representing the predominant mechanisms conferring secondary ibrutinib resistance. To understand the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment, an ultra‐deep next‐generation sequencing analysis of 30 recurrently mutated genes was performed on sequential samples of 20 patients, collected before and during single‐agent ibrutinib treatment. Mutations in the SF3B1, MGAand BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in posttreatment samples. Besides the canonical mutations, four novel BTK mutations and three previously unreported PLCG2 variants were identified. BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR and were detectable on average 10.5 months before clinical relapse. With a median follow‐up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease progression based on clinical and/or laboratory features. In conclusion, subclonal heterogeneity, dynamic clonal selection and various patterns of clonal variegation were identified with novel resistance‐associated BTK mutations in individual patients treated with ibrutinib. What's new? Although the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia, 20% of patients still show disease progression. Comprehensive characterisation of mechanisms underlying ibrutinib resistance and the related changes in the subclonal architecture induced by the selective pressure of the treatment may usher in new clinical advances. This time‐resolved ultra‐deep genomic scrutiny of mutation target genes reveals unique patterns of highly dynamic clonal variegation associated with BTK inhibition and identifies novel resistance‐associated BTK mutations in individual patients. Furthermore, evidence suggests that sensitive molecular monitoring of treatment response can facilitate the early detection of impending relapse. [ABSTRACT FROM AUTHOR]

The basic principle of the circular economy is to reduce or totally eliminate waste and carbon dioxide production with the help of a multiple, efficient usage of resources. The application of reusable structural elements plays an important role and can contribute essentially to a low‐carbon future. Within the European research project REDUCE (Grant Agreement number: 710040), composite beams and steel‐based flooring systems, which are demountable and reusable, have been developed and investigated. The experimental investigations showed that the structural behaviour of the newly developed shear connectors differs from the behaviour of the traditionally applied welded studs. Some behave in a non‐ductile way. In order to assess, how far the regulations of EN1994‐1‐1 for shear connections can still be applied, parametric studies have been conducted. The respective numerical models were developed with the use of the commercially available finite element software ABAQUS® and were validated against the experimental observations. The effects of the lack of ductility of the shear connectors on the structural behaviour of the entire composite beam was examined with different types of shear connectors, shear connector layouts and material grades. This contribution presents the underlying laboratory tests as well as the results of the supplementing numerical parameter studies. The outcome provides valuable information for future design guidance concerning the use of demountable shear connectors in composite beams. [ABSTRACT FROM AUTHOR]

Nuclear factor kappa B ( NFKB) plays an important role in multiple myeloma ( MM), and bortezomib affects this pathway. We retrospectively analysed the effect of the NFKB1 −94ins/del ATTG polymorphism on the survival of 295 MM patients treated at a single centre. The median progression-free survival ( PFS) was 790 (659-921) d in patients with NFKB1 homozygous insertion genotype (I/I, n = 99) and 624 (515-733) d in deletion-carriers (I/D&D/D, n = 196, P = 0·013). In multivariate analysis, I/I carriers showed a favourable PFS compared to I/D&D/D with a hazard ratio of 0·622 (0·457-0·847), P = 0·003, in addition to international staging system ( ISS) score, fluorescence in situ hybridization ( FISH) risk score, age and bortezomib treatment. I/I patients benefited more from bortezomib treatment [ PFS 902 (703-1101) and 580 (343-817), P = 0·008] than I/D&D/D patients [ PFS 659 (487-831) and 488 (323-653), P = 0·531]; in addition the beneficial effect of low ISS score was not observed in the I/D&D/D group [ PFS 639 (454-824) and 650 (458-842), P = 0·226], while it was clear in I/I patients [ PFS 1140 (803-1477) and 580 (408-752), P < 0·001]. We conclude that homozygous carriers of the insertion allele of the NFKB1 −94ins/del ATTG polymorphism have a better prognosis and probably benefit more from bortezomib treatment than MM patients carrying the deletion allele. [ABSTRACT FROM AUTHOR]

Abstract: There is an increasing body of evidence that suggests that genes involved in cell fate decisions and pattern formation during development also play a key role in the continuous cell fate decisions made by adult tissue stem cells. Here we show that prolonged in vitro culture (14 days) of murine bone marrow lineage negative cells in medium supplemented with three early acting cytokines (stem cell factor, Flk-2/Flt-3 ligand, thrombopoietin) and with immobilized Notch ligand, Jagged-1, resulted in robust expansion of serially transplantable hematopoietic stem cells with long-term repopulating ability. We found that the absolute number of marrow cells was increased ∼8 to 14-fold in all cultures containing recombinant growth factors. However, the frequency of high quality stem cells was markedly reduced at the same time, except in cultures containing growth factors and Jagged-1-coated Sepharose-4B beads. The absolute number of hematopoietic cells with long-term repopulating ability was increased ∼10 to 20-fold in the presence of multivalent Notch ligand. These results support a role for combinatorial effects by Notch and cytokine-induced signaling pathways in regulating hematopoietic stem cell fate and to a potential role for Notch ligand in increasing cell numbers in clinical stem cell transplantation. [Copyright &y& Elsevier]

Introduction : The selective Bcl-2 inhibitor venetoclax has shown promising therapeutic potential in multiple myeloma, particularly in cases associated with t(11;14) IGH::CCND1 translocation. However, the efficacy of venetoclax in myeloma patients with the t(6;14) IGH::CCND3 translocation remains less investigated. Methods: In this study, we conducted a retrospective analysis to investigate the efficacy of venetoclax-based therapy in relapsed/refractory myeloma patients with t(6;14) translocation. The treatment courses of three patients, that included previous therapies and responses to venetoclax, were assessed. Clinical data, laboratory results, and adverse events were analyzed to evaluate treatment outcomes. Results: Our findings demonstrated remarkable therapeutic responses in three consecutive patients with t(6;14) translocation-associated myeloma who received venetoclax-based therapy. Patient 1, a lenalidomide-bortezomib-daratumumab and alkylator treatment refractory patient, achieved sustained stringent complete remission (sCR) after combining carfilzomib-dexamethasone with venetoclax, which was his best response ever. Similarly, Patient 2, refractory to frontline bortezomib-thalidomide-dexamethasone therapy, attained CR following a transition to bortezomib-dexamethason-venetoclax treatment. Patient 3, who was immunomodulatory (IMID)-intolerant, showed a highly favorable response to venetoclax-dexamethasone therapy after his first relapse following autologous stem cell transplantation. No significant adverse effects were observed in any of the patients. Discussion: Our study provides compelling preliminary evidence for the efficacy of venetoclax in t(6;14) translocation-associated myeloma. The outcomes observed in our patients suggest that venetoclax-based therapy holds substantial promise as an effective treatment option for this specific genetic subgroup. Furthermore, the similarities in treatment response between t(11;14) and t(6;14) translocation subgroups highlight the importance of personalized approaches targeting specific genetic abnormalities to optimize therapeutic outcomes., Competing Interests: GM received research funding and honoraria from AbbVie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ceglédi, Csukly, Fekete, Kozma, Szemlaky, Andrikovics and Mikala.)

Classical myeloproliferative diseases can be divided into Philadelphia chromosome-positive chronic myeloid leukemia and Philadelphia chromosome-negative myeloproliferative neoplasm. The driver mutations of the latter occur in the Janus kinase 2 or calreticulin genes. The coincidence of Philadelphia chromosome-negative and -positive myeloproliferative neoplasms in the same patient is exceptionally rare in the literature. During the long-term follow-up of our 120 patients with chronic myeloid leukemia, we investigated the clinical data of patients in whom Philadelphia chromosome-negative myeloproliferative disease was also confirmed. Philadelphia chromosome was detected by classical cytogenetic methods and/or fluorescence in situ hybridization. The amount of BCR-ABLI fusion RNA was monitored by quantitative real-time polymerase chain reaction. Mutations in the Janus kinase 2 and calreticulin genes were detected by quantitative allele-specific polymerase chain reaction and fragment analysis. The dynamics of disease development were inferred from the change in the amount of mutant clones over time and from the clinical data. We identified four cases carrying both Philadelphia chromosome and Janus kinase 2/calreticulin gene mutation. In some cases, competition between the clones, in other cases their co-occurrence in a common clone was observed. Isolated thrombocytosis at the time of diagnosis or persisting thrombocytosis during targeted therapy with good molecular response may call attention to the possibility of the co-occurrence of the two diseases. Co-occurrence of Philadelphia chromosome-positive and -negative myeloproliferative neoplasms is more frequent than the literature suggests. If the disease has an unusual appearance, the association of the two myeloproliferative dieseases may be suspected.

One characteristic type of the common somatic mutations causing myeloproliferative neoplasias is the frameshift mutation of the calreticulin gene that leads to proteins of abnormal structure. The pathologic protein induces novel cell biological processes that are fundamental to the onset and maintenance of myeloproliferative diseases. In this review, an insight is provided into these processes, aiding better understanding of the underlining pathobiological processes and eventually to more effective therapy in the future.

Despite the introduction of novel agents, multiple myeloma remains incurable for most patients, necessitating further therapeutic options. Venetoclax, a selective BCL-2 inhibitor, had shown promising results in patients with translocation t(11;14), but questions remain open about its optimal use. We have contacted all Hungarian haematology centers for their experience treating t(11;14) myeloma patients with venetoclax. 58 patients were reported. 37 received venetoclax in the relapsed/refractory setting with few or no other therapeutic options available. 21 patients started venetoclax as salvage after failing to achieve satisfactory response to first line therapy. In the relapsed/refractory setting objective response rate (ORR) was 94%, median progression-free survival (PFS) 10.0 months and median overall survival (OS) 14.6 months. In reinduction patients, ORR was 100%, median PFS and OS were not reached. Importantly, we found no adverse effect of high risk features such as deletion 17p or renal failure, in fact renal failure ameliorated in 42% of the cases, including three patients who became dialysis independent. Our study also reports the highest number of plasma cell leukemia cases successfully treated with venetoclax published in literature, with refractory plasma cell leukemia patients achieving a median PFS of 10.0 and a median OS of 12.2 months., 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 Szita, Mikala, Kozma, Fábián, Hardi, Alizadeh, Rajnics, Rejtő, Szendrei, Váróczy, Nagy, Illés, Vályi-Nagy, Masszi and Varga.)

In contrast to solid tumours, the genetic background of acute myeloid leukemia (AML) is characterized by a relatively low number of alterations per sample (average 3-5 mutations similarly to paediatric malignancies). Although the mutational background is rather heterogeneous, the detection of genetic alterations has diagnostic, prognostic and therapeutic relevance. We investigated cytogenetic and most commonly occurring molecular genetic alterations, and their co-occurrence in 830 AML patients diagnosed and treated in our institute between 2001 and 2019. Results from the recently introduced next generation sequencing for seven AML patients are also presented. Both methods (previously performed standard PCR-based tests and NGS) achieved the same results for commonly occurring mutations, but NGS technique was capable to identify further, rarely occurring mutations which bear diagnostic and prognostic importance according to the recent European LeukemiaNet recommendations. The introduction of NGS techniques to routine laboratory diagnostic applications is a required step following international expertise.

Nuclear factor kappa B (NFKB) plays an important role in multiple myeloma (MM), and bortezomib affects this pathway. We retrospectively analysed the effect of the NFKB1 -94ins/delATTG polymorphism on the survival of 295 MM patients treated at a single centre. The median progression-free survival (PFS) was 790 (659-921) d in patients with NFKB1 homozygous insertion genotype (I/I, n = 99) and 624 (515-733) d in deletion-carriers (I/D&D/D, n = 196, P = 0·013). In multivariate analysis, I/I carriers showed a favourable PFS compared to I/D&D/D with a hazard ratio of 0·622 (0·457-0·847), P = 0·003, in addition to international staging system (ISS) score, fluorescence in situ hybridization (FISH) risk score, age and bortezomib treatment. I/I patients benefited more from bortezomib treatment [PFS 902 (703-1101) and 580 (343-817), P = 0·008] than I/D&D/D patients [PFS 659 (487-831) and 488 (323-653), P = 0·531]; in addition the beneficial effect of low ISS score was not observed in the I/D&D/D group [PFS 639 (454-824) and 650 (458-842), P = 0·226], while it was clear in I/I patients [PFS 1140 (803-1477) and 580 (408-752), P < 0·001]. We conclude that homozygous carriers of the insertion allele of the NFKB1 -94ins/delATTG polymorphism have a better prognosis and probably benefit more from bortezomib treatment than MM patients carrying the deletion allele., (© 2014 John Wiley & Sons Ltd.)

Background: Additional chromosome abnormalities (ACAs), mutations of the BCR-ABL tyrosine kinase domain (TKD) and BCR-ABL splice variants may cause resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoid leukemia (ALL)., Methods: Karyotyping and BCR-ABL TKD mutation screening were performed in 71 imatinib-resistant CML patients and 6 Ph+ ALL patients. A total of 56 out of these 77 patients received second-generation TKI., Results: ACAs were present in 30 of 65 imatinib-resistant patients (46%). In 27 of 74 imatinib-resistant patients (36%), 15 different BCR-ABL TKD mutations were detected. Mutations were found in 25% of chronic-phase patients (12/47), 33% of accelerated-phase patients (5/15), 71% of blast crisis CML patients (5/7) and 100% of ALL patients. In nilotinib-resistant patients, Y253H, T315I and F359I/V mutations were detected; in dasatinib-resistant patients, L248M, E279K and T315I mutations were detected. T315I was found more frequently in patients on dasatinib than on imatinib therapy. The presence of ACAs predicted shorter survival during first- and second-generation TKI therapy, while TKD mutations only influenced survival during second-generation TKI therapy., Conclusion: For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis., (Copyright © 2011 S. Karger AG, Basel.)