Gelatinolytic activity in dentin upon adhesive treatment.

In this multi-parameter study, the effect of diverse factors related to adhesive application on the activation of host-derived gelatinases was investigated by gelatin zymography, in-situ zymography, fluorogenic DQ-gelatin assay and micro-tensile bond-strength (μTBS) testing. Gelatin zymography disclosed the presence of gelatinases in phosphoric acid-etched dentin powder, while two gold-standard adhesives generated no measurable MMP activation. In-situ zymography revealed that the interfacial gelatinolytic activity from specimens treated with the two adhesives appeared similar as that of the EDTA negative control, indicating no detectable gelatinases were activated upon adhesive treatment.

Poly(D,l-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids.

The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs.

Compartmentalized role of xCT in supporting pancreatic tumor growth, inflammation and mood disturbance in mice.

xCT (Slc7a11), the specific subunit of the cystine/glutamate antiporter system x, is present in the brain and on immune cells, where it is known to modulate behavior and inflammatory responses. In a variety of cancers -including pancreatic ductal adenocarcinoma (PDAC)-, xCT is upregulated by tumor cells to support their growth and spread. Therefore, we studied the impact of xCT deletion in pancreatic tumor cells (Panc02) and/or the host (xCT mice) on tumor burden, inflammation, cachexia and mood disturbances.

Fourteen-year Clinical Performance of a HEMA-free One-step Self-etch Adhesive in Non-carious Cervical Lesions.

Purpose: This randomized controlled trial aimed to evaluate the 14-year clinical performance of a HEMA-free 1-step self-etch adhesive (1SEa) compared with that of a 3-step etch-and-rinse adhesive (3E&Ra).

Materials And Methods: 267 non-carious cervical lesions in 52 patients were restored with the microhybrid composite Gradia Direct (GC), bonded in random order either with the HEMA-free 1SEa G-Bond (GB; GC) or the 3E&Ra Optibond FL (OFL; Kerr), which is considered the gold-standard E&Ra (control). The restorations were followed over 14 years for retention, marginal adaptation and discoloration, and caries occurrence.

Three-year Clinical Performance of a Universal Adhesive in Non-Carious Cervical Lesions.

Purpose: The aim of this randomized controlled clinical trial was to evaluate the 3-year clinical performance of a universal adhesive (Clearfil Universal Bond Quick (CUBQ); Kuraray Noritake) when restoring non-carious cervical lesions (NCCLs) using two different application modes (etch-and-rinse vs self-etch with prior selective enamel etching).

Materials And Methods: Fifty-one patients participated in this study. A total of 251 NCCLs (n = 251) were assigned to two groups: 1) CUBQ applied in etch-and-rinse mode (n = 122; CUBQ-ER) and 2) CUBQ applied in self-etch mode with prior selective etching of enamel with phosphoric acid (n = 129; CUPQ-SEE).

Oncolytic Herpes Simplex Virus Type 1 Induces Immunogenic Cell Death Resulting in Maturation of BDCA-1 Myeloid Dendritic Cells.

Recently, a paradigm shift has been established for oncolytic viruses (OVs) as it was shown that the immune system plays an important role in the specific killing of tumor cells by OVs. OVs have the intrinsic capacity to provide the right signals to trigger anti-tumor immune responses, on the one hand by delivering virus-derived innate signals and on the other hand by inducing immunogenic cell death (ICD), which is accompanied by the release of various damage-associated molecules from infected tumor cells. Here, we determined the ICD-inducing capacity of Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1 based OV, and benchmarked this to other previously described ICD (e.

Quercetin Mitigates Endothelial Activation in a Novel Intestinal-Endothelial-Monocyte/Macrophage Coculture Setup.

Atherosclerosis initiation is associated with a pro-inflammatory state of the endothelium. Quercetin is a flavonoid abundantly present in plant-based foods, with a possible impact on cardiovascular health. In this study, the effects of quercetin on lipopolysaccharide (LPS)-mediated endothelial inflammation and monocyte adhesion and migration, which are initial steps of the atherogenic process, are studied.

Lifespan extension with preservation of hippocampal function in aged system x-deficient male mice.

The cystine/glutamate antiporter system x has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT mice led to the hypothesis that system x deletion would negatively affect life- and healthspan. Still, till now the role of system x in physiological aging remains unexplored.

Mini-iFT Confirms Superior Adhesive Luting Performance using Light-curing Restorative Composites.

Purpose: To validate the rationale of using a conventional light-curing resin-based composite (RBC) to lute thick indirect restorations by measuring mini-interfacial fracture toughness (mini-iFT).

Materials And Methods: Freshly exposed dentin of extracted third molars (n = 64) was immediately sealed with a thin layer of an experimental RBC with a 50 wt% or 75 wt% (IDS) filler load. Two- or 6-mm-thick CAD/CAM composite blocks were luted onto IDS using either pre-heated light-cure or dual-cure luting RBC, with the latter having served as control.

Unraveling the Effects of a Talimogene Laherparepvec (T-VEC)-Induced Tumor Oncolysate on Myeloid Dendritic Cells.

T-VEC, a HSV-1 derived oncolytic virus, is approved for the treatment of advanced melanoma. The mechanisms that underly the systemic anti-tumor effect that is seen following intratumoral injection have not yet been studied but are likely to be mediated by myeloid dendritic cells (myDC) that initiate an adaptive immune response. In this study we could demonstrate that T-VEC is non-toxic for human myDC.

Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma.

Tolinapant (ASTX660) is a potent, nonpeptidomimetic antagonist of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) and X-linked IAP, which is currently being evaluated in a phase 2 study in T-cell lymphoma (TCL) patients. Tolinapant has demonstrated evidence of single-agent clinical activity in relapsed/refractory peripheral TCL and cutaneous TCL. To investigate the mechanism of action underlying the single-agent activity observed in the clinic, we have used a comprehensive translational approach integrating in vitro and in vivo models of TCL confirmed by data from human tumor biopsies.

Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer.

Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)-based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance.

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 () through structure-guided optimization of our previously published isoindolinone lead ().

ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design.

On the cutting edge of glioblastoma surgery: where neurosurgeons agree and disagree on surgical decisions.

Objective: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams.

Robust Deep Learning-based Segmentation of Glioblastoma on Routine Clinical MRI Scans Using Sparsified Training.

Purpose: To improve the robustness of deep learning-based glioblastoma segmentation in a clinical setting with sparsified datasets.

Materials And Methods: In this retrospective study, preoperative T1-weighted, T2-weighted, T2-weighted fluid-attenuated inversion recovery, and postcontrast T1-weighted MRI from 117 patients (median age, 64 years; interquartile range [IQR], 55-73 years; 76 men) included within the Multimodal Brain Tumor Image Segmentation (BraTS) dataset plus a clinical dataset (2012-2013) with similar imaging modalities of 634 patients (median age, 59 years; IQR, 49-69 years; 382 men) with glioblastoma from six hospitals were used. Expert tumor delineations on the postcontrast images were available, but for various clinical datasets, one or more sequences were missing.

Accurate MR Image Registration to Anatomical Reference Space for Diffuse Glioma.

To summarize the distribution of glioma location within a patient population, registration of individual MR images to anatomical reference space is required. In this study, we quantified the accuracy of MR image registration to anatomical reference space with linear and non-linear transformations using estimated tumor targets of glioblastoma and lower-grade glioma, and anatomical landmarks at pre- and post-operative time-points using six commonly used registration packages (FSL, SPM5, DARTEL, ANTs, Elastix, and NiftyReg). Routine clinical pre- and post-operative, post-contrast T1-weighted images of 20 patients with glioblastoma and 20 with lower-grade glioma were collected.

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation.

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation.

Quantifying eloquent locations for glioblastoma surgery using resection probability maps.

Objective: Decisions in glioblastoma surgery are often guided by presumed eloquence of the tumor location. The authors introduce the "expected residual tumor volume" (eRV) and the "expected resectability index" (eRI) based on previous decisions aggregated in resection probability maps. The diagnostic accuracy of eRV and eRI to predict biopsy decisions, resectability, functional outcome, and survival was determined.

The effect of water spray on the release of composite nano-dust.

Objective: To evaluate the collection efficiency of water spray on the release of airborne composite particles during grinding of composite materials.

Materials And Methods: Composite sticks (L:35 mm × W:5.4 mm × H:1.

Dual-Mechanism ERK1/2 Inhibitors Exploit a Distinct Binding Mode to Block Phosphorylation and Nuclear Accumulation of ERK1/2.

The RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date, ERKi display two distinct mechanisms of action (MoA): catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevents the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2.

Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy.

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung.

Non-linear registration improves statistical power to detect hippocampal atrophy in aging and dementia.

Objective: To compare the performance of different methods for determining hippocampal atrophy rates using longitudinal MRI scans in aging and Alzheimer's disease (AD).

Background: Quantifying hippocampal atrophy caused by neurodegenerative diseases is important to follow the course of the disease. In dementia, the efficacy of new therapies can be partially assessed by measuring their effect on hippocampal atrophy.

Quantitative Third Harmonic Generation Microscopy for Assessment of Glioma in Human Brain Tissue.

Distinguishing tumors from normal brain cells is important but challenging in glioma surgery due to the lack of clear interfaces between the two. The ability of label-free third harmonic generation (THG) microscopy in combination with automated image analysis to quantitatively detect glioma infiltration in fresh, unprocessed tissue in real time is assessed. The THG images reveal increased cellularity in grades II-IV glioma samples from 23 patients, as confirmed by subsequent hematoxylin and eosin histology.