Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

Activation of Angiopoietin-Tie2 Signaling Protects the Kidney from Ischemic Injury by Modulation of Endothelial-Specific Pathways.

SIGNIFICANCE STATEMENT: Ischemia-reperfusion AKI (IR-AKI) is common and causes significant morbidity. Effective treatments are lacking. However, preclinical studies suggest that inhibition of angiopoietin-Tie2 vascular signaling promotes injury, whereas activation of Tie2 is protective. We show that kidney ischemia leads to increased levels of the endothelial-specific phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP; PTPRB), which inactivates Tie2. Activation of Tie2 through VE-PTP deletion, or delivery of a novel angiopoietin mimetic (Hepta-ANG1), abrogated IR-AKI in mice. Single-cell RNAseq analysis showed Tie2 activation promotes increased Entpd1 expression, downregulation of FOXO1 target genes in the kidney vasculature, and emergence of a new subpopulation of glomerular endothelial cells. Our data provide a molecular basis and identify a candidate therapeutic to improve endothelial integrity and kidney function after IR-AKI. BACKGROUND: Ischemia-reperfusion AKI (IR-AKI) is estimated to affect 2%-7% of all hospitalized patients. The significant morbidity and mortality associated with AKI indicates urgent need for effective treatments. Previous studies have shown activation of the vascular angiopoietin-Tie2 tyrosine kinase signaling pathway abrogates ischemia-reperfusion injury (IRI). We extended previous studies to (1) determine the molecular mechanism(s) underlying kidney injury and protection related to decreased or increased activation of Tie2, respectively, and (2) to test the hypothesis that deletion of the Tie2 inhibitory phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP) or injection of a new angiopoietin mimetic protects the kidney from IRI by common molecular mechanism(s). METHODS: Bilateral IR-AKI was performed in VE-PTP wild-type or knockout mice and in C57BL/6J mice treated with Hepta-ANG1 or vehicle. Histologic, immunostaining, and single-cell RNA sequencing analyses were performed. RESULTS: The phosphatase VE-PTP, which negatively regulates the angiopoietin-Tie2 pathway, was upregulated in kidney endothelial cells after IRI, and genetic deletion of VE-PTP in mice protected the kidney from IR-AKI. Injection of Hepta-ANG1 potently activated Tie2 and protected the mouse kidney from IRI. Single-cell RNAseq analysis of kidneys from Hepta-ANG1-treated and vehicle-treated mice identified endothelial-specific gene signatures and emergence of a new glomerular endothelial subpopulation associated with improved kidney function. Overlap was found between endothelial-specific genes upregulated by Hepta-ANG1 treatment and those downregulated in HUVECs with constitutive FOXO1 activation, including Entpd1 / ENTPD1 that modulates purinergic receptor signaling. CONCLUSIONS: Our data support a key role of the endothelium in the development of IR-AKI, introduce Hepta-ANG1 as a putative new therapeutic biologic, and report a model to explain how IRI reduces Tie2 signaling and how Tie2 activation protects the kidney. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_05_23_JSN_Ang_EP23_052323.mp3.

Gut microbiota and physical exercise in obesity and diabetes - A systematic review.

BACKGROUND AND AIM: The gut microbiota (GM) plays an essential role in maintaining health, and imbalance in its composition is associated with the physiopathogenesis of metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Diet and antibiotics are known modulators of GM, but the influence of physical exercise in modulating the diversity and abundance of hindgut bacteria is still poorly understood. The aim of this systematic review was to investigate the scientific evidence about the effect of physical exercise on GM modulation in subjects with obesity and T2DM. METHODS AND RESULTS: A search in PubMed, Web of Science, Scopus, Cochrane and Embase databases using keywords related to gut microbiota, physical exercise and metabolic diseases was performed. Eight clinical studies met the inclusion criteria, six in subjects with obesity and two in individuals with T2DM. In three studies carried out in individuals with obesity, exercise was able to positively modulate the diversity of GM and the abundance of some species of bacteria, mostly by increasing the Bifidobacteriaceae family, and the Bacteroides and Akkermansia genera, and by decreasing the Proteobacteria phylum. The studies in subjects with T2DM found that physical exercise may reduce metabolic endotoxemia markers. CONCLUSIONS: Physical exercise may be a beneficial modulation strategy of GM composition in metabolic diseases, specifically aerobic exercises carried out for at least 6 weeks with moderate or high intensity. Nevertheless, well-designed clinical trials are needed to clarify the role of physical exercise on GM in subjects with obesity and T2DM.

Cognitive impairment and edentulism among older adults: an observational study using claims data.

BACKGROUND: The scientific link between mastication strength and cognitive function has not yet been strongly corroborated in population studies. Utilizing large-scale claims, we aim to investigate the association between edentulism and cognitive impairment in older American adults. METHODS: Using de-identified claims from a commercial insurer from 2015-2019, we conducted a retrospective cohort study using multilevel regression models to evaluate the association between denture status and clinically diagnosed cognitive impairment. Secondary analysis included symptomatic cognitive impairment in the outcome. RESULTS: Adjusting for individual-level risk factors, denture status was significantly associated with clinical cognitive impairment with odds ratios of 1.13 (95%CI: 1.02-1.25) and 1.26, (95%CI: 1.09-1.45) for complete dentures on one or both jaws, respectively. Including symptomatic cognitive impairment in the analysis did not substantially change our fundamental findings. CONCLUSION: Prevention and treatment of oral diseases should be considered a key component in preserving the overall wellness of older adults.

Botryosphaeran Attenuates Tumor Development and the Cancer Cachexia Syndrome in Walker-256 Tumor-Bearing Obese Rats and Improves the Metabolic and Hematological Profiles of These Rats.

Studies demonstrate that obesity can increase tumor development. Botryosphaeran, a fungal (1→3)(1→6)-ß-D-glucan, presents antimutagenic, antiproliferative and pro-apoptotic activities. This study evaluated the effects of botryosphaeran on tumor development and metabolic and hematological parameters in tumor-bearing obese and non-obese rats. Obesity was induced by a high-fat and high-sugar diet, while control rats received standard diet and water without sugar for 10 weeks. On 8th-week, Walker-256 tumor cells were inoculated in the rats, and treatment with botryosphaeran (12 mg/Kg b.w.) started. Groups:control tumor-CT, control tumor botryosphaeran-CTB, obese tumor-OT and obese tumor botryosphaeran-OTB. On 10th-week, tumor development, cachexia, metabolic and hematological parameters were analyzed. Tumor development and cachexia were significantly higher in the OT group compared to the CT group, and botryosphaeran attenuated these parameters. OT rats presented accumulation of adipose tissue, reduced muscle mass, glucose intolerance, insulin resistance, hyperglycemia, anemia, leukocytosis, and thrombocytopenia. Botryosphaeran corrected insulin resistance and hyperglycemia, modulated cholesterol levels, and increased leukocyte and lymphocytes in obese rats, which can be attributable to an inflammatory response against the Walker-256 tumor, contributing to a lower tumor development. Our data demonstrated that botryosphaeran was effective in attenuating tumor growth and in improving the metabolic and hematological profiles of the tumor-bearing rats, demonstrating its potential role in the cancer's management.

Efficacy of bisphosphonates in detection of early enamel caries using NIR fluorescence imaging and inhibition of caries progression.

NIR fluorescence imaging using bisphosphonate-Indocyanine green has been indicated for early interproximal caries detection. This study assessed diagnostic accuracy of caries detection by NIR fluorescence imaging with OsteoSense 750® (OS750) in vitro and ex vivo, and to analyze the therapeutic efficacy of a bisphosphonate (Etidronate) in inhibiting enamel caries progression in vitro. Methods: Four experiments were conducted using extracted human teeth; 1) to calculate the infiltration rate of OS750 into interproximal white spot lesions using fluorescence microscope, 2) to assess diagnostic accuracy of interproximal natural white spot lesions using desktop NIR fluorescence imaging device in vitro setting, 3) to assess diagnostic accuracy of artificially created deeper enamel carious lesion (0.5 mm~1.0 mm) using NIR fluorescence image through the head-mount display in ex vivo setting, 4) to compare the progression on the enamel caries lesions treated by Etidronate, NaF and distilled-water. Diagnostic accuracy was analyzed using sensitivity, specificity and receiver operating curves (ROC). The caries progression was calculated with micro-CT and was statistically analyzed using a two-way ANOVA and the Tukey HDS post-hoc test. Results: 1) The infiltration rate of OS750 was 101.83% ± 8.66 (Min: 90.10%, Max: 133.94%). 2) The average of sensitivity and specificity in vitro setting experiments were 86.7% ± 4.4% and 70% ± 11%, respectively. The average of area under the ROC curves (AUC) was 0.883 ± 0.059 indicating excellent performance. 3) The mean sensitivity and specificity in ex vivo setting was 82.97% ± 15% and 76.78% ± 13.27% respectively. 4) The carious lesion volume treated by Etidronate was significantly smaller at post treatment-1 (p<0.05) and treatment-2 (p<0.01) than the control. There was no significant difference in lesion volume in the Etidronate and NaF group at the time point of post treatment-1. Conclusion: This study suggests that bisphosphonates contribute to both early diagnosis of enamel caries and inhibition of caries progression.

Establishment of perpendicular protrusion of type I collagen on TiO2 nanotube surface as a priming site of peri-implant connective fibers.

Natural teeth are supported by connective tissue collagen fibers that insert perpendicularly in the tooth cementum. Perpendicular insertion plays an important role in the maintenance of the junction between the oral epithelium and the periodontal connective tissue. Most titanium dental implant surfaces have no micro or macro structure to support perpendicularly oriented collagen attachment. Without this tight biologic seal to resist bacterial invasion and epithelial downgrowth, progressive bone loss in peri-implantitis is seen around dental implants. The purpose of this study was to establish the perpendicularly oriented collagen attachment to titanium oxide nanotube (TNT), and to assess its binding stability. TNT was prepared on the titanium-surface by anodization. Scanning electron microscopy (SEM) showed a regularly aligned TNT with an average 67 nm-diameter when anodized at 30 V for 3 h. Subsequently, collagen type I (CoI) was electrophoretically fused to anodic TNT in native polyacrylamide gel system where negatively charged CoI-C term was perpendicularly navigated to TNT. SEM and atomic force microscopy (AFM) were used to analyze CoI on the TiO2 and TNT surface. Several tens of nanometers of CoI protrusion were recorded by AFM. These protrusions may be long enough to be priming sites for cell-secreted CoI. CoI laid parallel to the titanium surface when fused by a chemical linker. Binding resistance of CoI against drastic ultrasonication was measured by Fourier-transform infrared spectroscopy attenuated total reflection (FTIR-ATR). The electrophoretically fused CoI in the titanium nanotube (TNT-CoIEPF) showed the significantly greatest binding resistance than the other groups (P < 0.01, a 1-way ANOVA and Tukey HSD post hoc test). Furthermore, TNT-CoIEPF surface rejected epithelial cell stretching and epithelial sheet formation. Chemically linked horizontal CoI on titanium oxide (TiO2) facilitated epithelial cell stretching and sheet formation.

Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3Kδ.

Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small-molecule inhibitor of PI3Kδ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive, and selective PI3Kδ inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, seletalisib inhibited N-formyl peptide-stimulated but not phorbol myristate acetate-stimulated superoxide release from human neutrophils, consistent with a PI3Kδ-specific activity. No indications of cytotoxicity were observed in peripheral blood mononuclear cells (PBMCs) or other cell types treated with seletalisib. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib showed dose-dependent inhibition in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Collectively, these data characterize seletalisib as a selective PI3Kδ inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated proinflammatory cytokine secretion.

A prospective clinical trial to assess the optical efficacy of pink neck implants and pink abutments on soft tissue esthetics.

OBJECTIVE: The purpose of this prospective, randomized, controlled, multicenter clinical study was to analyze the optical effects of an anodized pink colored implant shoulder/abutment system in the peri-implant mucosa of immediately placed dental implants. MATERIALS AND METHOD: Forty subjects with a restoratively hopeless tooth in the maxillary esthetic zone, were recruited and randomized to receive either a pink-neck implant, or a conventional gray implant. All patients received an immediate implant and immediate provisional and two identical CAD/CAM titanium abutments with different surface colors: pink and gray, and one zirconia all-ceramic crown. The color of the peri-implant mucosa was measured using a dental spectrophotometer and analyzed using CIELAB color system. RESULTS: The overall color difference between the peri-implant mucosa with a pink abutment and a gray abutment was ΔE = 4.22. Patients with gray implants presented a color change of ΔE = 3.86-4.17 with this abutment change, while patients with pink implants had a color change of ΔE = 3.84-4.69. The peri-implant mucosa with a pink abutment was significantly more red when compared with a gray abutment (P ≤ .01). CONCLUSIONS: When a pink abutment was used, there is a significant color change of the peri-implant mucosa that is above the detectable color threshold. CLINICAL SIGNIFICANCE: Esthetic outcomes are important for the success of implant treatment of maxillary anterior implants. The phenomenon of the gray color of a dental implant and abutment shining through the peri-implant mucosa has been documented in the literature. The objective of this study was to assess the optical effect of an anodized pink-neck implant and a pink abutment on the color of peri-implant mucosa. This study demonstrates that using pink-neck implant and a pink abutment would contribute positively to the overall esthetic outcome for an anterior implant.

The Effect of a Toothbrush Handle Design in Combating Microbial Contamination.

OBJECTIVES: This study aims to assess the difference in microbial contamination of a toothbrush with a smooth handle versus a toothbrush with a grooved handle design. METHODS: Twenty-six volunteers were randomized into two groups. The first group used a smooth handle toothbrush for two months, followed by a grooved handle toothbrush for two months. The second group had the order reversed. Following the two-month use, the toothbrushes were submitted for microbial analysis. Effect size, as well as Wilcoxon signed-rank test were used to calculate the differences between total colony count, bacterial DNA, and endotoxin levels from the two toothbrush handle types. RESULTS: There was no significant difference in colony count between the smooth (mean 580 CFU/mL, SD 1,684 CFU/mL) and grooved (mean 19,059 CFU/mL, SD 80,972 CFU/mL) handles (p = 0.12). Total DNA count was significantly less (p = 0.01) on the smooth handle (mean 68,038 RFU/mL, SD 81,659) compared to the grooved handle (mean 209,312 RFU/mL, SD 257,169 RFU/mL). Endotoxin levels were significantly less (p = 0.01) on the smooth handle (mean 0.16 EU/mL, SD 0.30 EU/mL) compared to the grooved handle (mean 0.43 EU/mL, SD 0.49 EU/mL). CONCLUSIONS: The smooth handle toothbrush had significantly less bacterial contamination compared to the grooved handle toothbrush, as measured by total DNA count and endotoxin levels.

The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation.

Human immunoglobulin G isotype 4 (IgG4) antibodies (Abs) are potential candidates for immunotherapy when reduced effector functions are desirable. IgG4 Abs are dynamic molecules able to undergo a process known as Fab arm exchange (FAE). This results in functionally monovalent, bispecific antibodies (bsAbs) with unknown specificity and hence, potentially, reduced therapeutic efficacy. IgG4 FAE is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 Abs. To date, the mechanism of FAE is not entirely understood and studies measuring FAE in ex vivo matrices have been hampered by the presence and abundance of endogenous IgG4 wild-type (WT) Abs. Using representative humanized WT IgG4 monoclonal Abs, namely, anti-IL-6 and anti-TNF, and a core-hinge stabilized serine 228 to proline (S228P) anti-IL-6 IgG4 mutant, it is demonstrated for the first time how anti-IgG4 affinity chromatography can be used to prepare physiologically relevant matrices for assessing and quantifying FAE. A novel method for quantifying FAE using a single MSD immunoassay is also reported and confirms previous findings that, dependent on the redox conditions, the S228P mutation can prevent IgG4 FAE to undetectable levels both in vitro and in vivo. Together, the findings and novel methodologies will allow researchers to monitor and quantify FAE of their own IgG4 molecules in physiologically relevant matrices.

Clinical documentation of dental care in an era of electronic health record use.

BACKGROUND: Although complete and accurate clinical records do not guarantee the provision of excellent dental care, they do provide an opportunity to evaluate the quality of care provided. However, a lack of universally accepted documentation standards, incomplete record-keeping practices, and unfriendly electronic health care record (EHR) user interfaces are factors that have allowed for persistent poor dental patient record keeping. METHODS: Using 2 different methods-a validated survey, and a 2-round Delphi process-involving 2 appropriately different sets of participants, we explored what a dental clinical record should contain and the frequency of update of each clinical entry. RESULTS: For both the closed-ended survey questions and the open-ended Delphi process questions, respondents had a significant degree of agreement on the "clinical entry" components of an adequate clinical record. There was, however, variance on how frequently each of those clinical entries should be updated. SUMMARY: Dental providers agree that complete and accurate record keeping is essential and that items such as histories, examination findings, diagnosis, radiographs, treatment plans, consents, and clinic notes should be documented. There, however, does not seem to be universal agreement how frequently such items should be recorded. CLINICAL IMPLICATIONS: As the dental profession moves towards prevalent use of electronic health care records, the issue of standardization and interoperability becomes ever more pressing. Settling issues of standardization, including record documentation, must begin with guideline-creating dental professional bodies, who need to clearly define and disseminate what these standards should be and everyday dentists who will ultimately ensure that these standards are met and kept.

Identification of putative bone anabolic peptides targeting adherent plasma membrane.

Bone matrix provides unknown essential cues for osteoblast lineage cells to develop, grow, repair and remodel bones via adherent plasma membrane. Because of its tight sealing with bone matrix in vivo and culture surface in vitro as well, the adherent plasma membrane has been unveiled target of investigation to date. Herein, we report a new approach to explore the adherence plasma membrane of osteoblasts with biofunctional peptide candidates in a bacterial peptide library. To accomplish this, human osteoblast like hFOB 1.19 cells were cultured on porous filter with 8 µm pore through which bacterial peptides were allowed to meet the membrane for affinity selection. The affinity-selected peptides were coated on culture plate to further evaluate their influence on osteoblastic cell adhesion, as well as expressions of osteoblast differentiation markers, alkaline phosphatase and osteocalcin. Finally, the serial screenings identified two prominent active peptides that enhanced the differentiation markers nearly to the same level as a control peptide of bone morphogenetic protein-2. Osteogenic activity is expected for the peptides when immobilized on bone implant surface.

Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities.

Latrophilin 1 (LPH1), a neuronal receptor of α-latrotoxin, is implicated in neurotransmitter release and control of presynaptic Ca(2+). As an "adhesion G-protein-coupled receptor," LPH1 can convert cell surface interactions into intracellular signaling. To examine the physiological functions of LPH1, we used LPH1's extracellular domain to purify its endogenous ligand. A single protein of ∼275 kDa was isolated from rat brain and termed Lasso. Peptide sequencing and molecular cloning have shown that Lasso is a splice variant of teneurin-2, a brain-specific orphan cell surface receptor with a function in neuronal pathfinding and synaptogenesis. We show that LPH1 and Lasso interact strongly and specifically. They are always copurified from rat brain extracts. Coculturing cells expressing LPH1 with cells expressing Lasso leads to their mutual attraction and formation of multiple junctions to which both proteins are recruited. Cells expressing LPH1 form chimerical synapses with hippocampal neurons in cocultures; LPH1 and postsynaptic neuronal protein PSD-95 accumulate on opposite sides of these structures. Immunoblotting and immunoelectron microscopy of purified synapses and immunostaining of cultured hippocampal neurons show that LPH1 and Lasso are enriched in synapses; in both systems, LPH1 is presynaptic, whereas Lasso is postsynaptic. A C-terminal fragment of Lasso interacts with LPH1 and induces Ca(2+) signals in presynaptic boutons of hippocampal neurons and in neuroblastoma cells expressing LPH1. Thus, LPH1 and Lasso can form transsynaptic complexes capable of inducing presynaptic Ca(2+) signals, which might affect synaptic functions.

Assessing the accuracy of computer color matching with a new dental porcelain shade system.

STATEMENT OF PROBLEM: In a previous study, a novel computer color matching system for dental ceramic restoration was developed, and 21 new shades were established. Theoretically, a natural tooth color can be accurately reproduced by combining 2 or 3 ceramic mixtures from the database of 21 new shades. PURPOSE: The purpose of this study was to test the use of these shades in conjunction with the computer color matching system to determine their ability to accurately reproduce the body color of 29 shade tabs from a shade guide (VITAPAN 3D-Master). MATERIAL AND METHODS: Disks of 21 reference shades were prepared with porcelain (Cerabien CZR) and polished to 1.0 mm thickness. A spectrophotometer was used to measure the reflectance values from 380 to 780 nm for each disk; the scattering coefficient and absorption coefficient were determined. By using the reflectance values and the scattering and absorption coefficients, the computer color matching program generated porcelain prescriptions incorporating proportions from the 21 reference shades to reproduce the shade tabs. Disks were fabricated from the prescriptions, polished to 1.0 mm thickness, then placed over a zirconia core plate and measured with the spectrophotometer. The color differences (ΔE*) between the shade tabs and the corresponding ceramic disks were calculated. Statistical analysis was performed with the 1-sample t test. RESULTS: The ΔE* values between computer color matching specimens and the target shade tabs varied from 0.5 to 1.9, with an average ΔE* of 1.3, which was significantly less than the clinically detectable ΔE* threshold of 1.6 (P<.001). CONCLUSIONS: The computer color matching system with the established 21 new shades is accurate and effective for reproducing tooth shades.

Microscopic in-situ analysis of the mucosal healing around implants treated by protease activated receptor 4-agonist peptide or perpendicularly protruded type I collagen in rats.

Enhanced mucosal sealing around titanium implants can reduce complications such as peri-implantitis. The present study aims to investigate the mucosal healing at the early stage around the protease activated receptor 4-agonist peptide (PAR4-AP)- or perpendicularly protruded type I collagen (pCol)-treated titanium implants. A total of 72 implants were placed in 36 rats in the study. Following extractions, two tissue-level implants among the following three different surfaces, PAR4-AP-coated (PAR4 group, n = 24), pCol-treated (pCol group, n = 24) and non-treated (control group, n = 24) ones, were placed in the maxillae of each rat based on a split-mouth design. The specimens retrieved at 8 h (n = 8 per group), 3 days (n = 8 per group), and 2 weeks (n = 8 per group), were immunostained and tissue-cleared, and the signals of laminin-5 and collagen fibers were observed under multiphoton microscopy. Statistical analyses were performed using linear mixed model with post hoc tests to compare differences between the groups. While there was no intergroup difference at 8 h, the laminin-5 at 3 days was more abundant near the PAR4-group-surface, and its area was significantly larger in the PAR4 group (0.0204 ± 0.0194 mm2 ) than the control (0.0019 ± 0.0025 mm2 , p = .001) and pCol (0.0023 ± 0.0022 mm2 , p < .001) groups. The pCol group showed a significantly larger area of collagen fibers (0.0230 ± 0.0148 mm2 ) compared to the control (0.0035 ± 0.0051 mm2 , p = .002) and PAR4 (0.0031 ± 0.0057 mm2 , p < .001) groups at 3 days. At 3 days and 2 weeks, the collagen fiber orientation of the pCol group showed a more perpendicular manner compared to the control and PAR4 groups. The signal of basal lamina and collagen fibers were stronger around the PAR4-AP- and pCol-treated titanium surfaces, respectively during the early healing stage. This could have implications for improved mucosal sealing around dental implants, potentially reducing complications such as peri-implantitis.

Multimodal management of giant solid hemangioblastomas in two patients with preoperative embolization.

Background: Hemangioblastomas are benign vascular neoplasms, World Health Organization grade I, with the most frequent location in the cerebellum. Complete microsurgical resection can be a challenge due to excessive bleeding, which is why preoperative embolization takes importance. Case Description: Two clinical cases are presented, a 25-year-old woman and a 75-year-old man, who presented with intracranial hypertension symptoms due to obstructive hydrocephalus; a ventriculoperitoneal shunt was placed in both cases; in addition, they presented with cerebellar signs. Both underwent embolization with ethylene vinyl alcohol copolymer, with blood flow reduction. After that, they underwent microsurgical resection within the 1st-week post embolization, obtaining, in both cases, gross total resection without hemodynamic complications, with clinical improvement and good surgical outcome. It is worth mentioning that surgical management is the gold standard that allows a suitable surgical approach, like in our patients, for which a lateral suboccipital craniotomy was performed. Conclusion: Solid hemangioblastomas are less frequent than their cystic counterparts. The treatment is the surgical resection, which is a challenge and always has to be considered as an arteriovenous malformation in the surgical planning, including preoperative embolization to reduce perioperative morbidity and mortality and get good outcomes.