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Pär Johansson,1 Ryo Jimbo,1 Yoshihito Naito,2 Per Kjellin,3 Fredrik Currie,3 Ann Wennerberg1 1Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden; 2Oral Implant Center, Tokushima University Hospital, Tokushima, Japan; 3Promimic AB, Stena Center, Göteborg, Sweden Abstract: Polyether ether ketone (PEEK) possesses excellent mechanical properties similar to those of human bone and is considered the best alternative material other than titanium for orthopedic spine and trauma implants. However, the deficient osteogenic properties and the bioinertness of PEEK limit its fields of application. The aim of this study was to limit these drawbacks by coating the surface of PEEK with nano-scaled hydroxyapatite (HA) minerals. In the study, the biological response to PEEK, with and without HA coating, was investigated. Twenty-four screw-like and apically perforated implants in the rabbit femur were histologically evaluated at 3 weeks and 12 weeks after surgery. Twelve of the 24 implants were HA coated (test), and the remaining 12 served as uncoated PEEK controls. At 3 weeks and 12 weeks, the mean bone–implant contact was higher for test compared to control (P

Deyar Jallal Hadi Mahmood, Ewa H Linderoth, Ann Wennerberg, Per Vult Von Steyern Department of Prosthetic Dentistry, Faculty of Odontology, Malmö University, Malmö, Sweden Aim: To investigate and compare the fracture strength and fracture mode in eleven groups of currently, the most commonly used multilayer three-unit all-ceramic yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) fixed dental prostheses (FDPs) with respect to the choice of core material, veneering material area, manufacturing technique, design of connectors, and radii of curvature of FDP cores. Materials and methods: A total of 110 three-unit Y-TZP FDP cores with one intermediate pontic were made. The FDP cores in groups 1–7 were made with a split-file design, veneered with manually built-up porcelain, computer-aided design-on veneers, and over-pressed veneers. Groups 8–11 consisted of FDPs with a state-of-the-art design, veneered with manually built-up porcelain. All the FDP cores were subjected to simulated aging and finally loaded to fracture. Results: There was a significant difference (P

Jonas Anderud,1,2 Peter Abrahamsson,2 Ryo Jimbo,1 Sten Isaksson,2 Erik Adolfsson,3 Johan Malmström,2 Yoshihito Naito,4 Ann Wennerberg1 1Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden; 2Maxillofacial Unit Halmstad, Region Halland, Halmstad, Sweden; 3Swedish Ceramic Institute, IVF, Mölndal, Sweden; 4Department of Oral and Maxillofacial Prosthodontics and Oral Implantology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan Abstract: The purpose of the study was to evaluate histologically, whether vertical bone augmentation can be achieved using a hollow ceramic space maintaining device in a rabbit calvaria model. Furthermore, the chemistry of microporous hydroxyapatite and zirconia were tested to determine which of these two ceramics are most suitable for guided bone generation. 24 hollow domes in two different ceramic materials were placed subperiosteal on rabbit skull bone. The rabbits were sacrificed after 12 weeks and the histology results were analyzed regarding bone-to-material contact and volume of newly formed bone. The results suggest that the effect of the microporous structure of hydroxyapatite seems to facilitate for the bone cells to adhere to the material and that zirconia enhance a slightly larger volume of newly formed bone. In conclusion, the results of the current study demonstrated that ceramic space maintaining devices permits new bone formation and osteoconduction within the dome. Keywords: hydroxyapatite, zirconia, guided bone regeneration, GBR, histology, membrane

Pär Johansson,1 Ryo Jimbo,1 Per Kjellin,2 Fredrik Currie,2 Bruno Ramos Chrcanovic,1 Ann Wennerberg1 1Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden; 2Promimic AB, Göteborg, Sweden Abstract: Polyether ether ketone (PEEK) is today frequently used as a biomaterial in different medical operations due to its excellent mechanical and chemical properties. However, the untreated surface of PEEK is bioinert and hydrophobic, and it does not osseointegrate in its pure form. The aim of this study was to evaluate a unique nano-modified surface of PEEK with respect to osseointegration. Forty-eight threaded, non-cutting PEEK implants were inserted bilaterally in the tibia of 24 rabbits. Half of the implants (n=24) were coated with nanocrystalline hydroxyapatite (test) and the remaining implants (n=24) were left uncoated (control). Half of the animals (n=12) were euthanized after 3 weeks of healing and the remaining (n=12) after 12 weeks. The implant retention was measured with a removal torque apparatus. Surface analysis was performed with interferometry, scanning electron microscopy, and X-ray photon spectroscopy to relate the removal torque to the applied surface. The test implants revealed a significantly higher retention after 3 weeks (P=0.05) and 12 weeks (P=0.028) compared to controls. The result of the present study proves that the addition of nanocrystalline hydroxyapatite coating to PEEK surfaces significantly increases its removal torque and biocompatibility. Keywords: polyether ether ketone, hydroxyapatite, removal torque, nanotopography

Abstract Intratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in patient cells. Here, we describe a machine learning approach, scTherapy, which leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors. Patient-specific treatments reveal a wide spectrum of co-inhibitors of multiple biological pathways predicted for primary cells from heterogenous cohorts of patients with acute myeloid leukemia and high-grade serous ovarian carcinoma, each with unique resistance patterns and synergy mechanisms. Experimental validations confirm that 96% of the multi-targeting treatments exhibit selective efficacy or synergy, and 83% demonstrate low toxicity to normal cells, highlighting their potential for therapeutic efficacy and safety. In a pan-cancer analysis across five cancer types, 25% of the predicted treatments are shared among the patients of the same tumor type, while 19% of the treatments are patient-specific. Our approach provides a widely-applicable strategy to identify personalized treatment regimens that selectively co-inhibit malignant cells and avoid inhibition of non-cancerous cells, thereby increasing their likelihood for clinical success.

Abstract Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.

Ann Wennerberg1,2, Silvia Galli2, Tomas Albrektsson2,31Department of Prosthodontics, Malmö University, Malmö, 2Department of Biomaterials, Gothenburg University, Gothenburg, 3Department of Materials Science and Technology, Malmö University, SwedenAbstract: This review summarizes the present documentation for the SLActive surface, a hydrophilic and nanostructured surface produced by Straumann Company in Switzerland, and covers the results from 15 in vitro, 17 in vivo, and 16 clinical studies. The SLActive surface is a development of the large grit-blasted and acid-etched SLA surface, and is further processed to a high degree of hydrophilicity. In general, the in vitro and in vivo studies of the SLActive surface demonstrate a stronger cell and bone tissue response than for the predecessor, the SLA surface, produced by the same company. However, in most studies, this difference disappears after 6–8 weeks. In the clinical studies, a stronger bone response was reported for the SLActive surface during the early healing phase when compared with the SLA surface. However, the later biological response was quite similar for the two surfaces and both demonstrated very good clinical results.Keywords: SLActive, surface, in vitro, in vivo, clinical results

Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.

Cannabis (Cannabis sativa) is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (-)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood. Here we report that CBD modulates type I interferon responses in human macrophages. Transcriptomics analysis shows that CBD treatment significantly attenuates cGAS-STING-mediated activation of type I Interferon response genes (ISGs) in monocytic THP-1 cells. We further showed that CBD treatment effectively attenuates 2'3-cGAMP stimulation of ISGs in both THP-1 cells and primary human macrophages. Interestingly, CBD significantly upregulates expression of autophagy receptor p62/SQSTM1. p62 is critical for autophagy-mediated degradation of stimulated STING. We observed that CBD treated THP-1 cells have elevated autophagy activity. Upon 2'3'-cGAMP stimulation, CBD treated cells have rapid downregulation of phosphorylated-STING, leading to attenuated expression of ISGs. The CBD attenuation of ISGs is reduced in autophagy deficient THP-1 cells, suggesting that the effects of CBD on ISGs is partially mediated by autophagy induction. Lastly, CBD decreases ISGs expression upon HIV infection in THP-1 cells and human primary macrophages, leading to increased HIV RNA expression 24 hours after infection. However, long term culture with CBD in infected primary macrophages reduced HIV viral spread, suggesting potential dichotomous roles of CBD in HIV replication. Our study highlights the immune modulatory effects of CBD and the needs for additional studies on its effect on viral infection and inflammation.

Purpose: Marginal bone resorption (MBR) around dental implants may sometimes be a self-limiting condition due to balancing immunologic reactions against utilized materials rather than a progressive bacterial infection. Contrary to previous assumptions from ligature-induced experimental peri-implantitis studies, a recent 8-week experiment by the present authors showed that marginal ligatures trigger an inflammatory immune response, resulting in bone resorption around implants in the absence of plaque. The present study aimed to investigate whether this inflammatory/immunologic reaction attenuates or progresses toward implant failure after a longer healing time (12 weeks). Materials and Methods: Sterile silk ligatures were placed around the top of titanium (Ti) implants and compressed against the femoral cortical bone plate of six rabbits. A nonligated implant was used as a control. After 12 weeks of submerged healing, ground sections of implants and surrounding tissues were investigated with light microscopy. The marginal soft tissues were also analyzed using selected quantitative polymerase chain reaction (qPCR) markers. Results: Histologically, the ligatures were outlined by immune cells, including multinucleated giant cells (MNGCs), with adjacent fibrous encapsulation and resorbed peripheral bone that contrasted from the osseointegrated nonligated control implants. The difference in expression of qPCR markers was not significant, but > two-fold upregulation of markers CDIIb, IL1β, ARG1, NCF1, and CD4 and > twofold downregulation of CD8 indicated a mild, focal inflammatory/immune response against the ligatures compared to controls, with upregulation of M1 and M2 macrophages, neutrophils, and helper T-cells as well as downregulation of killer T cells. Further, the bone formation markers OC and ALPL were > two-fold downregulated (consistent with the lack of osseointegration of the ligatures) compared to control implants. Conclusions: Marginal silk ligatures trigger an inflammatory/immune response and aseptic bone resorption around implants. Compared to the previous 8-week study, the inflammatory reaction against the silk appears to attenuate with time, with only a mild persisting inflammation that may block osseointegration; instead, a fibrous tissue encapsulation-type reaction is maintained. This may explain why traditional ligature experiments have required regular exchange of ligatures for the bone resorption to progress. [ABSTRACT FROM AUTHOR]

Abstract The principle of drug sensitivity testing is to expose cancer cells to a library of different drugs and measure its effects on cell viability. Recent technological advances, continuous approval of targeted therapies, and improved cell culture protocols have enhanced the precision and clinical relevance of such screens. Indeed, drug sensitivity testing has proven diagnostically valuable for patients with advanced hematologic cancers. However, different cell types behave differently in culture and therefore require optimized drug screening protocols to ensure that their ex vivo drug sensitivity accurately reflects in vivo drug responses. For example, primary chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells require unique microenvironmental stimuli to survive in culture, while this is less the case for acute myeloid leukemia (AML) cells. Here, we present our optimized and validated protocols for culturing and drug screening of primary cells from AML, CLL, and MM patients, and a generic protocol for cell line models. We also discuss drug library designs, reproducibility, and quality controls. We envision that these protocols may serve as community guidelines for the use and interpretation of assays to monitor drug sensitivity in hematologic cancers and thus contribute to standardization. The read-outs may provide insight into tumor biology, identify or confirm treatment resistance and sensitivity in real time, and ultimately guide clinical decision-making.

The microstructural architecture of remodeled bone in the peri-implant region of screw implants plays a vital role in the distribution of strain energy and implant stability. We present a study in which screw implants made from titanium, polyetheretherketone and biodegradable magnesium-gadolinium alloys were implanted into rat tibia and subjected to a push-out test four, eight and twelve weeks after implantation. Screws were 4 mm in length and with an M2 thread. The loading experiment was accompanied by simultaneous three-dimensional imaging using synchrotron-radiation microcomputed tomography at 5 μm resolution. Bone deformation and strains were tracked by applying optical flow-based digital volume correlation to the recorded image sequences. Implant stabilities measured for screws of biodegradable alloys were comparable to pins whereas non-degradable biomaterials experienced additional mechanical stabilization. Peri-implant bone morphology and strain transfer from the loaded implant site depended heavily on the biomaterial utilized. Titanium implants stimulated rapid callus formation displaying a consistent monomodal strain profile whereas the bone volume fraction in the vicinity of magnesium-gadolinium alloys exhibited a minimum close to the interface of the implant and less ordered strain transfer. Correlations in our data suggest that implant stability benefits from disparate bone morphological properties depending on the biomaterial utilized. This leaves the choice of biomaterial as situational depending on local tissue properties.

Abstract Background The soft tissue around dental implants forms a barrier between the oral environment and the peri-implant bone and a crucial factor for long-term success of therapy is development of a good abutment/soft-tissue seal. Sol-gel derived nanoporous TiO2 coatings have been shown to enhance soft-tissue attachment but their effect on adhesion and biofilm formation by oral bacteria is unknown. Methods We have investigated how the properties of surfaces that may be used on abutments: turned titanium, sol-gel nanoporous TiO2 coated surfaces and anodized Ca2+ modified surfaces, affect biofilm formation by two early colonizers of the oral cavity: Streptococcus sanguinis and Actinomyces naeslundii. The bacteria were detected using 16S rRNA fluorescence in situ hybridization together with confocal laser scanning microscopy. Results Interferometry and atomic force microscopy revealed all the surfaces to be smooth (Sa ≤ 0.22 μm). Incubation with a consortium of S. sanguinis and A. naeslundii showed no differences in adhesion between the surfaces over 2 hours. After 14 hours, the level of biofilm growth was low and again, no differences between the surfaces were seen. The presence of saliva increased the biofilm biovolume of S. sanguinis and A. naeslundii ten-fold compared to when saliva was absent and this was due to increased adhesion rather than biofilm growth. Conclusions Nano-topographical modification of smooth titanium surfaces had no effect on adhesion or early biofilm formation by S. sanguinis and A. naeslundii as compared to turned surfaces or those treated with anodic oxidation in the presence of Ca2+. The presence of saliva led to a significantly greater biofilm biovolume but no significant differences were seen between the test surfaces. These data thus suggest that modification with sol-gel derived nanoporous TiO2, which has been shown to improve osseointegration and soft-tissue healing in vivo, does not cause greater biofilm formation by the two oral commensal species tested than the other surfaces.

Abstract Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments.

While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central for orchestration of both innate and adaptive immune responses against cancer. The role of P2X7R in anti-tumour immunity is complex and preclinical studies have described opposing roles of the P2X7R in regulating immune responses against tumours. Therefore, few P2X7R modulators have reached clinical testing in cancer patients. Here, we review the prognostic value of P2X7R in cancer, how P2X7R have been targeted to date in tumour models, and we discuss four aspects of how tumours skew immune responses to promote immune escape via the P2X7R; non-pore functional P2X7Rs, mono-ADP-ribosyltransferases, ectonucleotidases, and immunoregulatory cells. Lastly, we discuss alternative approaches to offset tumour immune escape via P2X7R to enhance immunotherapeutic strategies in cancer patients.

Domestic dogs have been central to life in the North American Arctic for millennia. The ancestors of the Inuit were the first to introduce the widespread usage of dog sledge transportation technology to the Americas, but whether the Inuit adopted local Palaeo-Inuit dogs or introduced a new dog population to the region remains unknown. To test these hypotheses, we generated mitochondrial DNA and geometric morphometric data of skull and dental elements from a total of 922 North American Arctic dogs and wolves spanning over 4500 years. Our analyses revealed that dogs from Inuit sites dating from 2000 BP possess morphological and genetic signatures that distinguish them from earlier Palaeo-Inuit dogs, and identified a novel mitochondrial clade in eastern Siberia and Alaska. The genetic legacy of these Inuit dogs survives today in modern Arctic sledge dogs despite phenotypic differences between archaeological and modern Arctic dogs. Together, our data reveal that Inuit dogs derive from a secondary pre-contact migration of dogs distinct from Palaeo-Inuit dogs, and probably aided the Inuit expansion across the North American Arctic beginning around 1000 BP.

Objectives: The purpose of this pilot study is to compare gene expression in mucosa around dental implants with zirconia abutment to titanium and investigate presence of particles in mucosa samples and on implant heads. Material and Methods: Ten patients with a single implant supported prosthesis connected to zirconia or titanium abutments were invited at the five-year control. A clinical examination and a survey on experience of function and appearance were conducted. A mucosa biopsy taken in close vicinity to the implant were analysed by real-time polymerase chain reaction (qPCR) and presence of particles in a scanning electron microscope/energy-dispersive X-ray spectroscope (SEM/EDX). Cytological smear samples were collected and analysed through inductively coupled plasma mass spectrometry (ICP-MS) to investigate presence of particles on implant heads. Results: In total, 9 patients participated in the study, five with titanium abutments and four with zirconia abutments. All patients were satisfied with function and aesthetics. Titanium and iron particles were detected in mucosa biopsies. The ICP - MS analysis demonstrated presence of zirconia and titanium. Several proinflammatory genes were upregulated in the zirconia abutment group. Conclusions: Around zirconia abutments a slight increase in proinflammatory response and amount of wear particles was seen as compared to titanium. Wear particles of titanium were present in all soft tissue samples, however zirconia particles only in the samples from implants heads/mucosa with zirconia abutments.

Biodegradable magnesium (Mg) alloys can revolutionize osteosynthesis, because they have mechanical properties similar to those of the bone, and degrade over time, avoiding the need of removal surgery. However, they are not yet routinely applied because their degradation behavior is not fully understood.In this study we have investigated and quantified the degradation and osseointegration behavior of two biodegradable Mg alloys based on gadolinium (Gd) at high resolution.Mg-5Gd and Mg-10Gd screws were inserted in rat tibia for 4, 8 and 12 weeks. Afterward, the degradation rate and degradation homogeneity, as well as bone-to-implant interface, were studied with synchrotron radiation micro computed tomography and histology. Titanium (Ti) and polyether ether ketone (PEEK) were used as controls material to evaluate osseointegration.Our results showed that Mg-5Gd degraded faster and less homogeneously than Mg-10Gd. Both alloys gradually form a stable degradation layer at the interface and were surrounded by new bone tissue. The results were correlated to in vitro data obtained from the same material and shape. The average bone-to-implant contact of the Mg-xGd implants was comparable to that of Ti and higher than for PEEK. The results suggest that both Mg-xGd alloys are suitable as materials for bone implants.

High-resolution monitoring of rivers becomes important because more frequent and severe flooding and drought events are expected in the future, caused by climate change. Some key hydrometric variables (water surface elevation, bathymetry, and water surface velocity) can be acquired at high spatial resolution and in a contactless and noninvasive way using Unoccupied Aerial Systems (UAS). This paper presents a large publicly available UAS hydrometric dataset surveyed within a 10 km stretch of Rönne Å in Sweden from 28 August to 1 September 2023. The data were acquired using UAS radar altimetry for water surface elevation mapping, UAS water penetrating radar and UAS sonar for bathymetric mapping, and UAS Doppler radar for surface velocity monitoring. All data are divided into three processing levels: the raw data (Level 1), processed point data (Level 2), and point data referenced to a reference river centerline/reference cross section line (Level 3). In-situ ground truth and legacy UAS hydrometry payload data are included for comparison and validation. Good consistency indicates that the new UAS hydrometry payloads provide satisfactory datasets. [ABSTRACT FROM AUTHOR]

Knowing how much people travel is essential for transport planning. Empirical mobility traces collected from call detail records (CDRs), location-based social networks (LBSNs), and social media data have been used widely to study mobility patterns. However, these data suffer from sparsity, an issue that has largely been overlooked. In order to extend the use of these low-cost and accessible data, this study proposes a mobility model that fills the gaps in sparse mobility traces from which one can later synthesise travel demand. The proposed model extends the fundamental mechanisms of exploration and preferential return to synthesise mobility trips. The model is tested on sparse mobility traces from Twitter. We validate our model and find good agreement on origin-destination matrices and trip distance distributions for Sweden, the Netherlands, and São Paulo, Brazil, compared with a benchmark model using a heuristic method, especially for the most frequent trip distance range (1–40 km). Moreover, the learned model parameters are found to be transferable from one region to another. Using the proposed model, reasonable travel demand values can be synthesised from a dataset covering a large enough population of very sparse individual geolocations (around 1.5 geolocations per day covering 100 days on average).

We report the results of a DREAM challenge designed to predict relative genetic essentialities based on a novel dataset testing 98,000 shRNAs against 149 molecularly characterized cancer cell lines. We analyzed the results of over 3,000 submissions over a period of 4 months. We found that algorithms combining essentiality data across multiple genes demonstrated increased accuracy; gene expression was the most informative molecular data type; the identity of the gene being predicted was far more important than the modeling strategy; well-predicted genes and selected molecular features showed enrichment in functional categories; and frequently selected expression features correlated with survival in primary tumors. This study establishes benchmarks for gene essentiality prediction, presents a community resource for future comparison with this benchmark, and provides insights into factors influencing the ability to predict gene essentiality from functional genetic screens. This study also demonstrates the value of releasing pre-publication data publicly to engage the community in an open research collaboration.

The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P

Abstract The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.

Biodegradable magnesium (Mg) implants are emerging as a potential game changer in implant technology in situations where the implant temporarily supports the bone thereby avoiding secondary surgery for implant removal. However, the consequences of the alteration in the degradation rate to bone healing and the localization of degradation and alloying products in the long term remain unknown. In this study, we present the long-term osseointegration of three different biodegradable Mg alloys, Mg-10Gd, Mg-4Y-3RE and Mg-2Ag, which were implanted into rabbit femur for 6 and 9 months. In addition, we have investigated the effect of blood pre-incubation on the in vivo performance of the aforementioned alloys. Using high-resolution synchrotron radiation based micro computed tomography, the bone implant contact (BIC), bone volume fraction (BV/TV) and implant morphology were studied. The elemental traces have been characterized using micro X-ray fluorescence. Qualitative histological evaluation of the surrounding bone was also performed. Matured bone formed around all three implant types and Ca as well as P which represent parts of the degradation layer were in intimate contact with the bone. Blood pre-incubation prior to implantation significantly improved BIC in Mg-2Ag screws at 9 months. Despite different implant degradation morphologies pointing toward different degradation dynamics, Mg-10Gd, Mg-4Y-3RE and Mg-2Ag induced a similar long-term bone response based on our quantified parameters. Importantly, RE elements Gd and Y used in the alloys remained at the implantation site implying that they might be released later on or might persist in the implantation site forever. As the bone formation was not disturbed by their presence, it might be concluded that Gd and Y are non-deleterious. Consequently, we have shown that short and mid-term in vivo evaluations do not fully represent indicators for long-term osseointegration of Mg-based implants. [ABSTRACT FROM AUTHOR]