Randomized comparison between KTd and KRd induction therapy followed by maintenance therapy with K or observation in transplant-ineligible patients with newly diagnosed multiple myeloma.

Randomized comparison between KTd and KRd induction followed by second randomization to carfilzomib in transplant-ineligable patients with newly diagnosed multiple myeloma.

Biaxial flexural strength of 3D-printed 3Y-TZP zirconia using a novel ceramic printer.

OBJECTIVES: To compare the strength and reliability of 3D-printed 3Y-TZP zirconia manufactured with various printing orientations and staining. MATERIALS AND METHODS: A total of one-hundred cylindrical zirconia specimens were designed and fabricated using 3D printing and processed according to ISO 6872 standards. Of these specimens, 80 were 3D printed using the new ZIPRO-D (ZD) 3D ceramic printer. In this ZD group, 60 specimens were printed in a vertical orientation and were either stained after debinding (ZD1, x-orientation, n = 20) or not stained (ZD2, x-orientation, n = 20; ZD3, y-orientation, n = 20) and the remaining 20 specimens out of n = 80 were printed in a horizontal orientation (ZD4). Further 20 specimens out of the entire sample N = 100 were printed vertically with the CeraFab7500 3D ceramic printer (LC). All completed specimens were loaded until fracture using a universal testing machine. Biaxial flexural strengths and Weibull parameters were computed for the ZD groups and for the LC group. Group and sub-group effects were evaluated using Welch ANOVA (alpha = 0.05). RESULTS: The mean (standard deviation, SD) biaxial flexural strengths of vertically oriented ZD samples with (ZD1) and without (ZD2/ZD3) staining were 811 (197) and 850 (152) MPa, respectively (p > 0.05). The ZD4 (horizontally printed), 1107 (144) MPa, and LC (1238 (327)) MPa samples had higher mean (SD) flexural strengths than the ZD1-3 specimens. No difference was observed between the ZD4 and LC group (p > 0.05). Weibull moduli were between m = 4.6 (ZD1) and 9.1 (ZD4) in the ZD group and m = 3.5 in the LC group. CONCLUSIONS: All tested 3D-printed zirconia specimens exceeded the flexural strengths required for class 5 restorations according to ISO 6872 standards. While the flexural strengths of zirconia printed using the novel ZD device in the vertical orientation are lower than those of zirconia printed using the LC printer, the ZD printer shows at least comparable reliability. CLINICAL RELEVANCE: 3D-printing of zirconia is a new technology in dental application. Based on the presented strengths values, clinical application of 3D-printed zirconia for fixed dental protheses can be recommended.

Cellular senescence: Neither irreversible nor reversible.

Cellular senescence is a critical stress response program implicated in embryonic development, wound healing, aging, and immunity, and it backs up apoptosis as an ultimate cell-cycle exit mechanism. In analogy to replicative exhaustion of telomere-eroded cells, premature types of senescence-referring to oncogene-, therapy-, or virus-induced senescence-are widely considered irreversible growth arrest states as well. We discuss here that entry into full-featured senescence is not necessarily a permanent endpoint, but dependent on essential maintenance components, potentially transient. Unlike a binary state switch, we view senescence with its extensive epigenomic reorganization, profound cytomorphological remodeling, and distinctive metabolic rewiring rather as a journey toward a full-featured arrest condition of variable strength and depth. Senescence-underlying maintenance-essential molecular mechanisms may allow cell-cycle reentry if not continuously provided. Importantly, senescent cells that resumed proliferation fundamentally differ from those that never entered senescence, and hence would not reflect a reversion but a dynamic progression to a post-senescent state that comes with distinct functional and clinically relevant ramifications.

Effect of firing time and wall thickness on the biaxial flexural strength of 3D-printed zirconia.

OBJECTIVES: To evaluate the effect of accelerated firing on 3D-printed zirconia. METHODS: To check if formulae provided by ISO 6872 can be extended to thin samples, finite element analyses were carried out in advance of fabricating 3-mol% yttria-stabilized tetragonal zirconia polycrystal discs by milling and by 3D-printing. Four groups (n = 38 each) of 3D-printed specimens were produced with two nominal thicknesses (0.6 mm and 1.2 mm) and two firing strategies (long: 51 h, accelerated: 14.5 h). In the milled group (thickness 1.2 mm, n = 30), a standard firing program (9.8 h) was selected. Biaxial flexural strength tests were applied and mean strength, characteristic strength, and Weibull modulus were calculated for each group. Differences were analyzed using Welch ANOVA and Dunnett-T3 post-hoc tests. RESULTS: Maximum tensile stresses occurring during biaxial strength testing can be calculated according to ISO 6872 for thin samples with b > 0.3 mm. Variability of measured strengths values was smaller for milled zirconia compared with 3D-printed zirconia. The 1.2-mm-thick 3D-printed samples had significantly decreased strength after accelerated firing than after long firing. However, for the 0.6-mm-thick samples, comparable mean biaxial strength values of about 1000 MPa were measured for both firing protocols. SIGNIFICANCE: At the moment, long fabrication time for zirconia restorations is a major drawback of 3D-printing when compared with milling technology. This investigation showed that the strength of 0.6-mm-thick zirconia discs fabricated by 3D-printing was not impaired by accelerated firing. Thus, overnight firing of thin-walled 3D-printed zirconia restorations could be possible.

Fracture Resistance of 3D-Printed Occlusal Veneers Made from 3Y-TZP Zirconia.

The aim of this paper was to evaluate the fracture resistance of 3D-printed zirconia occlusal veneers (OVs) of different thicknesses and supported by different abutment materials. Materials and Methods: The standard OV of a natural molar was prepared and digitized using a laboratory 3D scanner. The resulting digital tooth abutment was milled either using cobalt-chromium (CoCr) or a fiber-reinforced composite (FRC). All the abutments were digitized and standardized OVs (30° tilt of all the cusps) designed with 0.4 mm, 0.6 mm, or 0.8 mm wall thicknesses. The OVs were fabricated using either the Programill PM7 milling device (Ivoclar Vivadent, PM) or one of two 3D zirconia printers, Cerafab 7500 (Lithoz, LC) or Zipro-D (AON, ZD). The ZD samples were only tested on CoCr abutments. The completed OVs were luted to their abutments and subjected to artificial aging, consisting of thermocycling and chewing simulation before fracture testing with a steel sphere (d = 8 mm) as an antagonist with three contact points on the occlusal OV surface. Besides the total fracture resistance Fu,tot, the lowest contact force Fu,cont leading to the local fracture of a cusp was of interest. The possible effects of the factors fabrication approach, wall thickness, and abutment material were evaluated using ANOVA (α = 0.05; SPSS Ver.28). Results: The total fracture resistance/contact forces leading to failure ranged from Fu,tot = 416 ± 83 N/Fu,cont = 140 ± 22 N for the 0.4 mm OVs fabricated using LC placed on the FRC abutments to Fu,tot = 3309 ± 394 N (ZD)/Fu,cont = 1206 ± 184 N (PM) for the 0.8 mm thick OVs on the CoCr abutments. All the factors (the fabrication approach, abutment material, and OV wall thickness) had an independent effect on Fu,tot as well as Fu,cont (p < 0.032). In pairwise comparisons for Fu,tot of the OVs luted to the CoCr abutments, the ZD samples statistically outperformed the LC- and PM-fabricated teeth irrespective of the thickness (p < 0.001). Conclusions: Within the limitations of this study, the printed occlusal veneers exhibited comparable fracture resistances to those of the milled variants. However, more resilient abutments (FRC as a simulation of dentine) as well as a thinner wall thickness led to reduced OV fracture resistance, suggesting that 0.4 mm thick zirconia OVs should not be unreservedly used in every clinical situation.

Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.

From fibres to adhesives: evolution of spider capture threads from web anchors by radical changes in silk gland function.

Spider webs that serve as snares are one of the most fascinating and abundant type of animal architectures. In many cases they include an adhesive coating of silk lines-so-called viscid silk-for prey capture. The evolutionary switch from silk secretions forming solid fibres to soft aqueous adhesives remains an open question in the understanding of spider silk evolution. Here we functionally and chemically characterized the secretions of two types of silk glands and their behavioural use in the cellar spider, Pholcus phalangioides. Both being derived from the same ancestral gland type that produces fibres with a solidifying glue coat, the two types produce respectively a quickly solidifying glue applied in thread anchorages and prey wraps, or a permanently tacky glue deployed in snares. We found that the latter is characterized by a high concentration of organic salts and reduced spidroin content, showing up a possible pathway for the evolution of viscid properties by hygroscopic-salt-mediated hydration of solidifying adhesives. Understanding the underlying molecular basis for such radical switches in material properties not only helps to better understand the evolutionary origins and versatility of ecologically impactful spider web architectures, but also informs the bioengineering of spider silk-based products with tailored properties.

QoL during KTd or KRd induction followed by K maintenance or observation in transplant noneligible patients with newly diagnosed multiple myeloma: Longitudinal and cross-sectional analysis of the randomized AGMT 02 study.

Understanding the impact of induction and maintenance therapy on patients' quality of life (QoL) is important for treatment selection. This study aims to compare patient-reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL-C 30 and QOL-MY20 questionnaires in the AGMT-02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health-related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross-sectional comparisons indicated a "slight" superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross-sectional comparisons revealed a "slight" improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with "slight" or "moderate" impairments in several QoL scales compared with the observation group.

Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer.

DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities. SIGNIFICANCE: We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology. This article is featured in Selected Articles from This Issue, p. 384.