Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma ...mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
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•Kras/Trp53 mutant tumors lack CD8+ T cells and resist chemo- and immunotherapies•Immunogenic chemotherapy elicits tumor T cell infiltration and controls cancer growth•Tumor control requires CD8+ T cells, TLR4+ cells, and drug actions on cancer cells•T cell influx sensitizes tumors to checkpoint inhibition and durably controls cancer
There is an urgent need to expand the proportion of patients that respond to immune checkpoint therapy. Using clinically relevant genetic mouse models and a combination of immunogenic drugs to trigger T cell infiltration into tumors, Pittet and colleagues are able to make unresponsive tumors sensitive to checkpoint blockade therapy.
In this randomized trial involving women without the polycystic ovary syndrome undergoing IVF, there was no significant difference in the rate of ongoing pregnancy or live birth between a strategy of ...freezing all embryos versus fresh transfer.
This paper presents an overview of the theories and computer implementation aspects of phase field models (PFM) of fracture. The advantage of PFM over discontinuous approaches to fracture is that PFM ...can elegantly simulate complicated fracture processes including fracture initiation, propagation, coalescence, and branching by using only a scalar field, the phase field. In addition, fracture is a natural outcome of the simulation and obtained through the solution of an additional differential equation related to the phase field. No extra fracture criteria are needed and an explicit representation of a crack surface as well as complex track crack procedures are avoided in PFM for fracture, which in turn dramatically facilitates the implementation. The PFM is thermodynamically consistent and can be easily extended to multi-physics problem by ‘changing’ the energy functional accordingly. Besides an overview of different PFMs, we also present comparative numerical benchmark examples to show the capability of PFMs.
•Development in phase field models and the computer implementation is reviewed.•The theories on phase field modeling are systematically summarized.•Representative numerical examples are presented for different fracture problems.
Objective: To determine the temporal gene expression profile associated with the early healing events during osseointegration in a human model.
Material and methods: Nine solid screw‐type cylindrical ...titanium implants, 4 mm long and 2.8 mm wide, with a chemically modified surface (SLActive) were surgically inserted in the retromolar area of nine human volunteers. The devices were removed using a trephine following 4, 7 and 14 days of healing. The tissue surrounding the implant was harvested, total RNA was extracted and microarray analysis was carried out to identify the differences in the transcriptome between days 4, 7 and 14.
Results: Gene ontology (GO) analysis of the temporal transcriptional changes was characteristic of a maturing, osteogenic process over the course of the study (4–14 days). At day 4, a gene expression profile associated with proliferation and immuno‐inflammatory processes was predominant. However, by day 14, by far the most predominant mechanisms were associated with skeletogenesis, with the GO categories of skeletal system development, bone development and ossification being predominant, with the majority of changes occurring between days 7 and 14. Furthermore, the biological processes of angiogenesis and neurogenesis were also predominant by day 14. In terms of signal transduction, I‐κB kinase/NF‐κB cascade was predominant at day 4, whereas TGF‐β/BMP, Wnt and Notch signalling were all associated with the osteogenic process over the duration of the study. Furthermore, Ras and Rho protein signal transduction was regulated throughout the osseointegration process.
Conclusion: The temporal transcriptional changes during osseointegration involve the expression of proliferation and immuno‐inflammatory response associated genes during the early stages of osseointegration, which are ultimately replaced by genes associated with the biological processes of skeletogenesis, angiogenesis and neurogenesis. The early immuno‐inflammatory changes appear to be regulated via the I‐κB kinase/NF‐κB cascade, whereas the later osteogenesis‐related mechanisms are regulated by TGF‐β/BMP, Notch and Wnt signaling.
To cite this article:
Ivanovski S, Hamlet S, Salvi GE, Huynh‐Ba G, Bosshardt DD, Lang NP, Donos N. Transcriptional profiling of osseointegration in humans. Clin. Oral Impl. Res. 22, 2011; 273–281. doi: 10.1111/j.1600‐0501.2010.02112.x
Bacterial pathogens have evolved intricate mechanisms to evade the human immune system, including the production of immunomodulatory enzymes. Streptococcus pyogenes serotypes secrete two ...multi-modular endo-β-N-acetylglucosaminidases, EndoS and EndoS2, that specifically deglycosylate the conserved N-glycan at Asn297 on IgG Fc, disabling antibody-mediated effector functions. Amongst thousands of known carbohydrate-active enzymes, EndoS and EndoS2 represent just a handful of enzymes that are specific to the protein portion of the glycoprotein substrate, not just the glycan component. Here, we present the cryoEM structure of EndoS in complex with the IgG1 Fc fragment. In combination with small-angle X-ray scattering, alanine scanning mutagenesis, hydrolytic activity measurements, enzyme kinetics, nuclear magnetic resonance and molecular dynamics analyses, we establish the mechanisms of recognition and specific deglycosylation of IgG antibodies by EndoS and EndoS2. Our results provide a rational basis from which to engineer novel enzymes with antibody and glycan selectivity for clinical and biotechnological applications.
This paper studies elasto-plastic large deformation behaviour of thin shell structures using the isogeometric computational approach with the main focus on the efficiency in modelling the ...multi-patches and arbitrary material formulation. In terms of modelling, we employ the bending strip method to connect the patches in the structure. The incorporation of bending strips allows to eliminate the strict demand of the C1 continuity condition, which is postulated in the Kirchhoff-Love theory for thin shell, and therefore it enables us to use the standard multi-patch structure even with C0 continuity along the patch boundaries. Furthermore, arbitrary nonlinear material models such as hyperelasticity and finite strain plasticity are embedded in the shell formulation, from which a unified thin shell formulation can be achieved. In terms of analysis, the Bézier decomposition concept is used to retain the local support of the traditional finite element. The performance of the presented approach is verified through several numerical benchmarks.
•Unified thin shell formulation allowing arbitrary mateiral nonlinearity.•Multi-patch shell structure applicable.•C1 continuity at patch boundaries by bending strip method.•Bézier decomposition concept to retain local support of the traditional FE.
Due to the negative impacts the dye may have on aquatic habitats and human health, it is often found in industrial effluent and poses a threat to public health. Hence, to solve this problem, this ...study developed magnetic adsorbents that can remove synthetic dyes like methylene blue. The adsorbent, in the form of beads, consists of a polymer blend of chitosan, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, and superparamagnetic iron oxide nanoparticles (average size of 19.03 ± 4.25 nm). The adsorption and desorption of MB from beads were carried out at pH values of 7 and 3.85, respectively. At a concentration of 9 mg/L, the loading capacity and the loading amount of MB after 5 days peaked at 29.75 ± 1.53% and 297.48 ± 15.34 mg/g, respectively. Meanwhile, the entrapment efficiency of MB reached 29.42 ± 2.19% at a concentration of 8 mg/L. The cumulative desorption capacity of the adsorbent after 13 days was at its maximum at 7.72 ± 0.5%. The adsorption and desorption kinetics were evaluated.
Objectives: To compare the gene expression profile of osseointegration associated with a moderately rough and a chemically modified hydrophilic moderately rough surface in a human model.
Material and ...methods: Eighteen solid screw‐type cylindrical titanium implants, 4 mm long and 2.8 mm wide, with either a moderately rough (SLA) or a chemically modified moderately rough (SLActive) surface were surgically inserted in the retromolar area of nine human volunteers. The devices were removed using a trephine following 4, 7 and 14 days of healing. The tissue surrounding the implant was harvested, total RNA was extracted and microarray analysis was carried out to identify the differences in the transcriptome between the SLA and SLActive surfaces at days 4, 7 and 14.
Results: There were no functionally relevant gene ontology categories that were over‐represented in the list of genes that were differentially expressed at day 4. However, by day 7, osteogenesis‐ and angiogenesis‐associated gene expression were up‐regulated on the SLActive surface. Osteogenesis and angiogenesis appeared to be regulated by BMP and VEGF signalling, respectively. By day 14, VEGF signalling remains up‐regulated on the SLActive surface, while BMP signalling was up‐regulated on the SLA surface in what appeared to be a delayed compensatory response. Furthermore, neurogenesis was a prominent biological process within the list of differentially expressed genes, and it was influenced by both surfaces.
Conclusions: Compared with SLA, SLActive exerts a pro‐osteogenic and pro‐angiogenic influence on gene expression at day 7 following implant insertion, which may be responsible for the superior osseointegrative properties of this surface.
To cite this article:
Donos N, Hamlet S, Lang NP, Salvi GE, Huynh‐Ba G, Bosshardt DD, Ivanovski S. Gene expression profile of osseointegration of a hydrophilic compared with a hydrophobic microrough implant surface. Clin. Oral Impl. Res. 22, 2011; 365–372.
Bacteria produce a remarkably diverse range of glycoside hydrolases to metabolize glycans from the environment as a primary source of nutrients, and to promote the colonization and infection of a ...host. Here we focus on EndoE, a multi-modular glycoside hydrolase secreted by Enterococcus faecalis, one of the leading causes of healthcare-associated infections. We provide X-ray crystal structures of EndoE, which show an architecture composed of four domains, including GH18 and GH20 glycoside hydrolases connected by two consecutive three α-helical bundles. We determine that the GH20 domain is an exo-β-1,2-N-acetylglucosaminidase, whereas the GH18 domain is an endo-β-1,4-N-acetylglucosaminidase that exclusively processes the central core of complex-type or high-mannose-type N-glycans. Both glycoside hydrolase domains act in a concerted manner to process diverse N-glycans on glycoproteins, including therapeutic IgG antibodies. EndoE combines two enzyme domains with distinct functions and glycan specificities to play a dual role in glycan metabolism and immune evasion.
Introduction: The COVID-19 pandemic has been affecting the lives of millions of people globally. Patients recovering from COVID-19 are facing, not only the symptom of long COVID, but also ...psychological problems, such as sleep disturbance. This study aims to assess the proportion of COVID-19 recovered adult patients that suffer from insomnia and associated factors in Vietnam. Methods: A cross-sectional study was performed between January and March 2022 among patients who have recovered from a COVID-19 infection. Data were collected based on a self-administered questionnaire that included sociodemographic and standardized questionnaires from the Hospital Anxiety and Depression Scale (HADS), the Perceived stress scale (PSS) and the dependent variable using Insomnia Severity Index (ISI). Multivariable logistic regression was conducted to explore factors associated with the patients' insomnia disorder. Results: A total of 325 participants were included in this analysis, 34.5% of participants had insomnia. According to multivariable logistic regression, participants who were equal to and over 50 years of age, feeling alienated from others, and were not supported by families or relatives, reported significantly higher levels of insomnia disorders over those aged under 50 years, having closer ties with family and had received support from family or relatives. Besides, respondents who recorded mental health problems that included anxiety, depression and stress were more likely to get insomnia disorders than those without mental health symptoms (OR 2.7, 95% CI 1.1-6.6) (OR 4.5, 95% CI 2.3-8.9) (OR 2.3, 95% CI 1.1-5.3), respectively, all p < 0.05. Conclusion: There was a remarkable rate of COVID-19 recovered patients experiencing insomnia disorders. Older age, alienated relationships and not being supported by families or relatives, as well as had mental health problems, are factors that affected the patients' insomnia, which showed that these sleep issues need to be screened and managed among adults who have recovered from COVID-19. Keywords: COVID-19, insomnia, recovery, sleep disturbance, Vietnam
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