The use of digital technologies in peri-implant soft tissue augmentation - A narrative review on planning, measurements, monitoring and aesthetics.

OBJECTIVE: To identify the different uses and modalities of digital technologies to diagnose, plan and monitor peri-implant soft tissue conditions and aesthetics. METHODS: A comprehensive narrative review of pertinent literature was conducted, critically appraising key digital technologies that may assist peri-implant soft tissue augmentation and assessment. An electronic search on four databases including studies published prior to 1st July 2023 was performed and supplemented by a manual search. RESULTS: Predominantly, tools such as cone beam computed tomography (CBCT), intraoral scanning (iOS), intraoral ultrasonography and digital spectrophotometry were commonly to assess and monitor peri-implant soft tissues. The main clinical and research applications included: (i) initial assessment of mucosal thickness, supra-crestal tissue height and keratinized mucosa width, (ii) evaluation of peri-implant soft tissue health and inflammation, (iii) monitoring profilometric changes and midfacial mucosal margin stability over time and (iv) aesthetic evaluation through colour assessment. While evidence for some digital tools may be limited, the integration of digital technologies into peri-implant soft tissue management holds great promise. These technologies offer improved precision, comfort and speed in assessment, benefiting both patients and clinicians. CONCLUSION: As digital technologies progress, their full potential in peri-implant soft tissue augmentation and their value will become more evident with ongoing research. Embracing these innovations and their potential benefits is recommended to ensure that during progress in implant dentistry, patient care is not hindered.

Early implant placement versus ridge preservation and delayed implant placement: Analysis of profilometric, clinician- and patient-reported outcomes from a two-centre RCT.

OBJECTIVES: To compare early implant placement (EP) to alveolar ridge preservation and delayed implant placement (ARP/DP) in terms of contour changes, along with clinician- and patient-reported outcome measures (PROMs) until the delivery of the implant-supported restoration. MATERIALS AND METHODS: Patients with a failing single tooth in the maxilla or mandible were recruited in two centres. After tooth extraction, patients were randomly assigned (1:1) to either EP or ARP/DP. At abutment connection and crown delivery, the buccal contour changes at 3 mm below the mucosal margin (primary outcome) along with clinician- (ease of treatment) and patient-reported outcomes were assessed using numeric rating scales and OHIP-14. RESULTS: A total of 46 patients were analysed. The mean buccal contour at abutment connection decreased by -1.2 ± 0.6 mm in group EP and -1.6 ± 0.8 mm in group ARP/DP (estimated mean difference; 0.45 [95%CI, -0.02; 0.94]; p = .061) with no significant differences between the groups. ARP/DP was consistently easier than EP across all stages of the surgery (estimated mean difference; 2.0 [95%CI, 1.3; 2.7] p < .001): during flap elevation (EP: 4.8 vs. ARP/DP: 1.6), implant placement (EP: 5.7 vs. ARP/DP: 2.2) and wound closure (EP: 3.4 vs. ARP/DP: 1.6). Both interventions improved quality of life but patients who underwent ARP/DP were significantly more satisfied at the time of crown delivery (ARP/DP: 9.6 vs. EP: 9.1, p = .02). CONCLUSIONS: EP and ARP/DP show no significant differences in buccal contour changes, aesthetics and patient-reported outcomes. However, ARP/DP is an easier procedure at all stages of the surgery compared to EP and could therefore be the preferred therapy for less experienced clinicians.

Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis.

Transcription factor EBF1 (early B-cell factor 1) regulates early B-cell differentiation by poising or activating lineage-specific genes and repressing genes associated with alternative cell fates. To identify proteins that regulate the diverse functions of EBF1, we used SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry of proteins associated with endogenous EBF1 in pro-B cells. This analysis identified most components of the multifunctional CCR4-NOT complex, which regulates transcription and mRNA degradation. CNOT3 interacts with EBF1, and we identified histidine 240 in EBF1 as a critical residue for this interaction. Complementation of Ebf1-/- progenitors with EBF1H240A revealed a partial block of pro-B-cell differentiation and altered expression of specific EBF1 target genes that show either reduced transcription or increased mRNA stability. Most deregulated EBF1 target genes show normal occupancy by EBF1H240A, but we also detected genes with altered occupancy, suggesting that the CCR4-NOT complex affects multiple activities of EBF1. Mice with conditional Cnot3 inactivation recapitulate the block of early B-cell differentiation, which we found to be associated with an impaired autoregulation of Ebf1 and reduced expression of pre-B-cell receptor components. Thus, the interaction of the CCR4-NOT complex with EBF1 diversifies the function of EBF1 in a context-dependent manner and may coordinate transcriptional and post-transcriptional gene regulation.

New adhesive rehabilitation technique with indexed occlusal tabletops made by 3D printing technology.

OBJECTIVE: In oral rehabilitation, a full mouth minimal invasive treatment can represent a major challenge for the patient and the dentist. The purpose of this article is to present a new technique to restore eroded teeth and recover the vertical dimension with a simple and predictable technique. CLINICAL CONSIDERATIONS: Occlusal tabletop restorations are a suitable conservative option to restore anatomy and vertical dimension augmentation but highly sensitive. The cementation of those restorations without stable landmarks, the cement excess removal, the insertion path, or the time needed are some of the difficulties can be faced. Now a days with the new CAD-CAM techniques is possible to develop a new occlusal tabletop manufacturing alternative utilizing 3D-printed technology by unifying the restorations with a customized connector that allows us to print several onlays at same time, as a single object, also being cemented at once. CONCLUSIONS: This protocol reduces the technique sensitivity of a vertical dimension oral rehabilitation process, reduce the chair time, enhancing the patient-comfort and delivers a unique way to restore dental lost anatomy as a definitive or temporary way with printing materials. CLINICAL SIGNIFICANCE: With the advent of new CAD-CAM 3D printing materials, which are increasingly versatile and gaining favor among clinicians, it is now possible to address complex clinical situations with greater predictability. This technology enables the development of treatment solutions that are both effective and efficient, consequently reducing clinical time for the patient.

The Hypotensive and Vasodilatory Effects Observed in Rats Exposed to Chiranthodendron pentadactylon Larreat Flowers Can Be Attributed to Cyanidin 3-O-Glucoside.

Chiranthodendron pentadactylon Larreat is a tree native to southeastern Mexico and Guatemala. Its flower is used in Mexican folk medicine to treat a variety of diseases, including conditions of blood pressure. However, scientific information on its usefulness in this pathology is lacking. The present study evaluates the effect of a methanolic extract (ME) from the flower and its active constituents on heart rate (HR) and mean arterial pressure (MAP) in anesthetized rats (MAPHR). The study also analyzed the effects on rat-isolated aortic rings (RIAR) and the rat mesenteric arterial bed (MABR). Active fractions were chromatographed, which led to the isolation of cyanidin 3-O-glucoside (C3G) identified through HPLC. The Chiranthodendron pentadactylon flowers produced hypotensive and vasorelaxant effects associated with C3G. The vasorelaxant effect is a mechanism underlying the synthesis and release of nitric oxide (NO). Neither cholinergic receptors nor prostaglandins are involved. ME and C3G cause cardiovascular depression in anesthetized rats via cholinergic and prostanoid mechanisms. Our research expands the scientific understanding of the flowers on the rat cardiovascular system. This amplifies the appreciation of the flower's ethnomedicine employed to control blood pressure. However, researchers need to conduct toxicity studies to determine the safety of this plant.

Discovering Potential Compounds for Venous Disease Treatment through Virtual Screening and Network Pharmacology Approach.

Peripheral venous hypertension has emerged as a prominent characteristic of venous disease (VD). This disease causes lower limb edema due to impaired blood transport in the veins. The phlebotonic drugs in use showed moderate evidence for reducing edema slightly in the lower legs and little or no difference in the quality of life. To enhance the probability of favorable experimental results, a virtual screening procedure was employed to identify molecules with potential therapeutic activity in VD. Compounds obtained from multiple databases, namely AC Discovery, NuBBE, BIOFACQUIM, and InflamNat, were compared with reference compounds. The examination of structural similarity, targets, and signaling pathways in venous diseases allows for the identification of compounds with potential usefulness in VD. The computational tools employed were rcdk and chemminer from R-Studio and Cytoscape. An extended fingerprint analysis allowed us to obtain 1846 from 41,655 compounds compiled. Only 229 compounds showed pharmacological targets in the PubChem server, of which 84 molecules interacted with the VD network. Because of their descriptors and multi-target capacity, only 18 molecules of 84 were identified as potential candidates for experimental evaluation. We opted to evaluate the berberine compound because of its affordability, and extensive literature support. The experiment showed the proposed activity in an acute venous hypertension model.

Strength of implant-supported lithium disilicate and polymer-infiltrated ceramic network restorations after thermomechanical aging.

AIM: To evaluate the fracture load and type of failure of two different monolithic restorative materials bonded to standardized titanium bases and fabricated by two different procedures regarding the bonding interface. MATERIALS AND METHODS: All screw-retained implant crown specimens (n = 40), subjected to fatigue by thermomechanical loading, differed in the restorative material (lithium disilicate [LDS] or polymer-infiltrated ceramic network [PICN], referred to as 'hybrid ceramic' [HYC]) and the interface type between the restorative material and the titanium base abutment (prefabricated ex-factory or produced during a CAM-milling procedure). This resulted in the following groups (n = 10/group): 1) LDS-M: lithium disilicate crown with a CAM-milled interface; 2) LDS-P: lithium disilicate crown with a prefabricated interface; 3) HYC-M: PICN crown with a CAM-milled interface; and 4) HYC-P: PICN crown with a prefabricated interface. Aged specimens underwent static fracture load testing. The load (N) at which the initial crack occurred was denoted as Finitial, and the maximal load (N) at which the restorations fractured as Fmax. All specimens were examined under a stereomicroscope to determine the failure mode. RESULTS: The median Finitial values were 180 N for LDS-M, 343 N for LDS-P, 340 N for HYC-M, and 190 N for HYC-P. The median Fmax values were 1822 N for LDS-M, 2039 N for LDS-P, 1454 N for HYC-M, and 1581 N for HYC-P. The intergroup differences were significant for Finitial (KW: P = 0.0042) and for Fmax (KW: P = 0.0010). The failure types also showed differences between the restorative groups. CONCLUSIONS: The choice of restorative material had a stronger influence on the fracture load than the abutment interface workflow. Lithium disilicate showed the highest load for initial crack appearance (Finitial) and for complete fracture of the restoration (Fmax).

Management and prevention of soft tissue complications in implant dentistry.

The management and prevention of soft tissue complications is of key importance in modern implant dentistry and influences biologic and esthetic outcomes. The assessment of the soft tissue conditions from a quantitative and qualitative perspective should, therefore, be part of the overall treatment plan. Such an assessment dictates a potential indication as well as an ideal time point for additional soft tissue management. A proper risk assessment and management of the soft tissues at the planned implant site are of key importance prior to any implant-related surgery. Cases with peri-implant soft tissue complications generally involve: (a) a lack of attached and keratinized mucosa; (b) insufficient volume; (c) development of mucosal dehiscences; or (d) a combination of (a), (b), and (c). In case of soft tissue deficiencies, these should be addressed as early as possible to increase the predictability of the surgical interventions. This article reviews the main causes for peri-implant soft tissue complications and presents different therapeutic options for the management of various clinical scenarios.

Pol5 is an essential ribosome biogenesis factor required for 60S ribosomal subunit maturation in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, more than 250 trans-acting factors are involved in the maturation of 40S and 60S ribosomal subunits. The expression of most of these factors is transcriptionally coregulated to ensure correct ribosome production under a wide variety of environmental and intracellular conditions. Here, we identified the essential nucleolar Pol5 protein as a novel trans-acting factor required for the synthesis of 60S ribosomal subunits. Pol5 weakly and/or transiently associates with early to medium pre-60S ribosomal particles. Depletion of and temperature-sensitive mutations in Pol5 result in a deficiency of 60S ribosomal subunits and accumulation of half-mer polysomes. Both processing of 27SB pre-rRNA to mature 25S rRNA and release of pre-60S ribosomal particles from the nucle(ol)us to the cytoplasm are impaired in the Pol5-depleted strain. Moreover, we identified the genes encoding ribosomal proteins uL23 and eL27A as multicopy suppressors of the slow growth of a temperature-sensitive pol5 mutant. These results suggest that Pol5 could function in ensuring the correct folding of 25S rRNA domain III; thus, favoring the correct assembly of these two ribosomal proteins at their respective binding sites into medium pre-60S ribosomal particles. Pol5 is homologous to the human tumor suppressor Myb-binding protein 1A (MYBBP1A). However, expression of MYBBP1A failed to complement the lethal phenotype of a pol5 null mutant strain though interfered with 60S ribosomal subunit biogenesis.

Soft tissue contour and radiographic evaluation of ridge preservation in early implant placement: A randomized controlled clinical trial.

OBJECTIVES: To compare two ridge preservation techniques and spontaneous healing in terms of hard and soft tissue changes 2 months after tooth extraction. MATERIAL AND METHODS: The study was designed as a randomized controlled trial and included 75 patients. After single tooth extraction in the maxillary incisor/premolar area, patients were randomly allocated to one of the following groups: (a) ridge preservation with a xenogeneic bone substitute covered with a collagen matrix (CM-group), (b) ridge preservation with a xenogeneic bone substitute covered with a free palatal graft (PG-group) or (c) spontaneous healing (control). Eight weeks after tooth extraction, implants were placed and clinical, profilometric and radiographic evaluations were performed. In addition, the need for further guided bone regeneration (GBR) at implant placement was assessed. The differences between the treatment groups were compared with the One-way ANOVA or Kruskal-Wallis test with the corresponding post hoc analysis. The proportions of the categorical parameters were compared with the Fisher´s exact test. RESULTS: Seventy-five patients underwent early implant placement 8 weeks after tooth extraction and were evaluated. CM-group (-0.9 SD 0.6 mm) and PG-group (-1.0 SD 0.8 mm) showed less horizontal bone resorption compared to the control group (-3.2 SD 2.1 mm) (p < .001). Moreover, the necessity of GBR at implant placement was significantly less in CM-group (32%) and PG-group (24%) when compared to control group (72%) (p = .001). Patients in CM-group experienced less pain than PG-group, one week after tooth extraction (p = .042). No significant differences were found regarding graft evaluation, post-operative complications, and soft tissue contour. CONCLUSIONS: Ridge preservation using a xenogeneic bone substitute covered with a collagen matrix or a palatal graft, results in less bone resorption and fewer GBR procedures at early implant placement compared to spontaneous healing.

Biosensors Platform Based on Chitosan/AuNPs/Phthalocyanine Composite Films for the Electrochemical Detection of Catechol. The Role of the Surface Structure.

Biosensor platforms consisting of layer by layer films combining materials with different functionalities have been developed and used to obtain improved catechol biosensors. Tyrosinase (Tyr) or laccase (Lac) were deposited onto LbL films formed by layers of a cationic linker (chitosan, CHI) alternating with layers of anionic electrocatalytic materials (sulfonated copper phthalocyanine, CuPcS or gold nanoparticles, AuNP). Films with different layer structures were successfully formed. Characterization of surface roughness and porosity was carried out using AFM. Electrochemical responses towards catechol showed that the LbL composites efficiently improved the electron transfer path between Tyr or Lac and the electrode surface, producing an increase in the intensity over the response in the absence of the LbL platform. LbL structures with higher roughness and pore size facilitated the diffusion of catechol, resulting in lower LODs. The [(CHI)-(AuNP)-(CHI)-(CuPcS)]2-Tyr showed an LOD of 8.55∙10-4 µM, which was one order of magnitude lower than the 9.55·10-3 µM obtained with [(CHI)-(CuPcS)-(CHI)-(AuNP)]2-Tyr, and two orders of magnitude lower than the obtained with other nanostructured platforms. It can be concluded that the combination of adequate materials with complementary activity and the control of the structure of the platform is an excellent strategy to obtain biosensors with improved performances.

Biomechanical aspects: Summary and consensus statements of group 4. The 5th EAO Consensus Conference 2018.

OBJECTIVES: The aim of the present publication was to report on the EAO Workshop group-4 discussions and consensus statements on the five reviews previously prepared. These reviews provided the scientific evidence on the effect of crown-to-implant ratio, on reconstructions with cantilevers in fully and partially edentulous patients, on biological and technical complications of tilted in comparison with straight implants, and on the effects of osseointegrated implants functioning in a residual dentition. MATERIAL AND METHODS: The group discussed, evaluated, corrected where deemed appropriate, and made recommendations to the authors regarding the following five reviews submitted: (a) Is there an effect of crown-to-implant ratio on implant treatment outcomes?; (b) Implant-supported cantilevered fixed dental rehabilitations in fully edentulous patients; (c) and in partially edentulous patients; (d) Biological and technical complications of tilted implants in comparison with straight implants supporting fixed dental prostheses; (e) What are the adverse effects of osseointegrated implants functioning among natural teeth of a residual dentition? Based on the five manuscripts and the discussion among the group as well as the plenum members, the major findings were summarized, consensus statements were formulated, clinical recommendations were proposed, and areas of future research were identified. RESULTS: Crown-to-implant ratios ranging from 0.9 to 2.2 did not influence the occurrence of biological or technical complications also in single-tooth restorations. Reconstructions with cantilevers for the rehabilitation of fully and partially edentulous jaws showed high implant and reconstruction survival rates. In contrast, the rate of complications-in particular associated with veneering material-was high during the observation period of 5-10 years. The data reported were primarily derived from studies with high risk of bias. The data for single-implant reconstructions were small. There was no evidence that distally tilted implants were associated with higher failure rates and increased amounts of marginal bone loss. The data supporting these findings, however, were at high risk of bias and frequently incompletely reported. Frequent positional changes occurred between the natural teeth and the implant-supported restorations. These changes were more pronounced in younger individuals, and even though they were reduced with age, they still occurred in adult patients. Even though these changes were frequent, potential implications for the patient are unclear. CONCLUSIONS: The use of single-tooth restorations with crown-to-implant ratio in between 0.9 and 2.2 may be considered a viable treatment option. Multiunit reconstructions with cantilevers are a viable treatment option in fully and partially edentulous patients. Clinicians and patients should be aware, however, that complications are frequent and primarily related to resin material used for veneering. There is some evidence that tilting an implant does affect stability of the implant and the surrounding bone. Treatment options to tilted implants should carefully be considered, as the effect on soft tissues and on prosthesis behavior is poorly reported for tilted implants. Positional changes in the dentition in relation to implant-supported restorations occur frequently. The patient should be informed about the possible need for a treatment related to these changes in the long term.

Treatment of multiple recession defects with vestibular incision subperiosteal tunnel access (VISTA): A retrospective pilot study utilizing digital analysis.

OBJECTIVE: To examine the correlation between initial site-specific characteristics of patients with multiple gingival recession defects and the outcome of root coverage therapy. MATERIALS AND METHODS: Pretherapy and post-therapy study models of 21 patients (154 teeth) with multiple gingival recession defects, treated with Vestibular Incision Subperiosteal Tunnel Access (VISTA), were optically scanned. Three-dimensional analysis of superimposed preoperative and postoperative images was performed. Linear and surface root coverage were calculated and correlated to various clinical and/or anatomical parameters. A multilevel statistical analysis was conducted, adjusting for the correlation among multiple observations. RESULTS: The mean percentages of linear root coverage were 96.2 ± 13.1% and 84.3 ± 14.4% for Miller Class I/II and Class III recessions, respectively. The mean percentages of root surface area coverage were 92.1 ± 12.0% and 78.6 ± 15.7% for Miller Class I/II and III defects, respectively. Root prominence, initial recession width and posterior tooth type were negatively correlated with linear and root surface area coverage. Initial recession depth was negatively correlated with root surface area coverage. Initial gingival margin thickness was positively associated with both linear and root surface area coverage. CONCLUSION: The results of the present study identified important positive and negative site-specific characteristics that may have utility in predicting the outcome of root coverage. CLINICAL SIGNIFICANCE: This study used sensitive 3-dimensional digital analysis tools to examine the correlation between initial site-specific characteristics of patients with multiple gingival recession defects and the outcome of periodontal root coverage therapy. Results demonstrated that initial root prominence, loss of interdental tissue (Miller Class III), molar tooth type, initial recession depth and width were negatively correlated with the outcome of periodontal root coverage achieved. Conversely, initial gingival margin thickness was associated with increased percentage of root coverage. These site-specific characteristics may serve as important risk indicators to predict the outcome of root coverage procedure.

Activated and Micronized Zeolite in the Modulation of Cellular Oxidative Stress in Mexican Smokers: A Randomized Clinical Trial.

BACKGROUND: Activated and micronized zeolites are used as detoxifying agents in humans. Detoxification is attributed to their ability to reduce lipid peroxidation by scavenging free radicals. OBJECTIVE: To evaluate activated and micronized zeolites as modulators of cellular oxidative stress in Mexican smokers without lung diseases. METHODS: Randomized clinical trial. Subjects were randomly divided into three groups: activated and micronized zeolites, n = 29; vitamin E, an accepted antioxidant, n = 29; and maltodextrin as control, n = 27. Each group received the corresponding supplementation, dissolved in water, once a day for 30 days as follows: activated and micronized zeolites, 5.4 g activated and micronized zeolite; vitamin E, 400 mg D-alpha tocopheryl acetate; and maltodextrin, 250 mg of maltodextrin. The thiobarbituric acid reactive substances assay was used to screen for lipid peroxidation. Catalase activity, plasma antioxidant capacity, and hydrogen peroxide levels were also measured. Results were analyzed by a one-way ANOVA and post hoc test of Bonferroni. RESULTS: Subjects administered activated and micronized zeolites had equivalent antioxidant activities as subjects administered vitamin E. CONCLUSIONS: Activated and micronized zeolites may be useful as a modulator of oxidative stress in smokers. However, inclusion of a comparison group of non-smokers would be useful in future studies to assess the degree to which zeolites reverse the oxidant stress.

The prefoldin complex regulates chromatin dynamics during transcription elongation.

Transcriptional elongation requires the concerted action of several factors that allow RNA polymerase II to advance through chromatin in a highly processive manner. In order to identify novel elongation factors, we performed systematic yeast genetic screening based on the GLAM (Gene Length-dependent Accumulation of mRNA) assay, which is used to detect defects in the expression of long transcription units. Apart from well-known transcription elongation factors, we identified mutants in the prefoldin complex subunits, which were among those that caused the most dramatic phenotype. We found that prefoldin, so far involved in the cytoplasmic co-translational assembly of protein complexes, is also present in the nucleus and that a subset of its subunits are recruited to chromatin in a transcription-dependent manner. Prefoldin influences RNA polymerase II the elongation rate in vivo and plays an especially important role in the transcription elongation of long genes and those whose promoter regions contain a canonical TATA box. Finally, we found a specific functional link between prefoldin and histone dynamics after nucleosome remodeling, which is consistent with the extensive network of genetic interactions between this factor and the machinery regulating chromatin function. This study establishes the involvement of prefoldin in transcription elongation, and supports a role for this complex in cotranscriptional histone eviction.

Integration of stress signals by homeodomain interacting protein kinases.

The family of homeodomain interacting protein kinases (HIPKs) consists of four related kinases, HIPK1 to HIPK4. These serine/threonine kinases are evolutionary conserved and derive from the yeast kinase Yak1. The largest group of HIPK phosphorylation substrates is represented by transcription factors and chromatin-associated regulators of gene expression, thus transferring HIPK-derived signals into changes of gene expression programs. The HIPKs mainly function as regulators of developmental processes and as integrators of a wide variety of stress signals. A number of conditions representing precarious situations, such as DNA damage, hypoxia, reactive oxygen intermediates and metabolic stress affect the function of HIPKs. The kinases function as integrators for these stress signals and feed them into many different downstream effector pathways that serve to cope with these precarious situations. HIPKs do not function as essential core components in the different stress signaling pathways, but rather serve as modulators of signal output and as connectors of different stress signaling pathways. Their central role as signaling hubs with the ability to shape many downstream effector pathways frequently implies them in proliferative diseases such as cancer or fibrosis.

Network Pharmacology Approaches Used to Identify Therapeutic Molecules for Chronic Venous Disease Based on Potential miRNA Biomarkers.

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to identify, by network analysis, the miRNAs involved in CVD as potential biomarkers, either by interacting with small molecules such as toxins and pollutants or by searching for new drugs. Our study shows an updated landscape of the signaling pathways involving miRNAs in CVD pathology. This latest research includes data found through experimental tests and uses predictions to propose both miRNAs and genes as potential biomarkers to develop diagnostic and therapeutic methods for the early detection of CVD in the clinical setting. In addition, our pharmacological network analysis has, for the first time, shown how to use these potential biomarkers to find small molecules that may regulate them. Between the small molecules in this research, toxins, pollutants, and drugs showed outstanding interactions with these miRNAs. One of them, hesperidin, a widely prescribed drug for treating CVD and modulating the gene expression associated with CVD, was used as a reference for searching for new molecules that may interact with miRNAs involved in CVD. Among the drugs that exhibit the same miRNA expression profile as hesperidin, potential candidates include desoximetasone, curcumin, flurandrenolide, trifluridine, fludrocortisone, diflorasone, gemcitabine, floxuridine, and reversine. Further investigation of these drugs is essential to improve the treatment of cardiovascular disease. Additionally, supporting the clinical use of miRNAs as biomarkers for diagnosing and predicting CVD is crucial.

Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell features.

PURPOSE: CAR therapy targeting BCMA is under investigation as treatment for multiple myeloma. However, given the lack of plateau in most studies, pursuing more effective alternatives is imperative. We present the preclinical and clinical validation of a new optimized anti-BCMA CAR (CARTemis-1). In addition, we explored how the manufacturing process could impact CAR-T cell product quality and fitness. METHODS: CARTemis-1 optimizations were evaluated at the preclinical level both, in vitro and in vivo. CARTemis-1 generation was validated under GMP conditions, studying the dynamics of the immunophenotype from leukapheresis to final product. Here, we studied the impact of the manufacturing process on CAR-T cells to define optimal cell culture protocol and expansion time to increase product fitness. RESULTS: Two different versions of CARTemis-1 with different spacers were compared. The longer version showed increased cytotoxicity. The incorporation of the safety-gene EGFRt into the CARTemis-1 structure can be used as a monitoring marker. CARTemis-1 showed no inhibition by soluble BCMA and presents potent antitumor effects both in vitro and in vivo. Expansion with IL-2 or IL-7/IL-15 was compared, revealing greater proliferation, less differentiation, and less exhaustion with IL-7/IL-15. Three consecutive batches of CARTemis-1 were produced under GMP guidelines meeting all the required specifications. CARTemis-1 cells manufactured under GMP conditions showed increased memory subpopulations, reduced exhaustion markers and selective antitumor efficacy against MM cell lines and primary myeloma cells. The optimal release time points for obtaining the best fit product were > 6 and < 10 days (days 8-10). CONCLUSIONS: CARTemis-1 has been rationally designed to increase antitumor efficacy, overcome sBCMA inhibition, and incorporate the expression of a safety-gene. The generation of CARTemis-1 was successfully validated under GMP standards. A phase I/II clinical trial for patients with multiple myeloma will be conducted (EuCT number 2022-503063-15-00).

Kinetics of Phenotype Modification Therapy with VISTA: A Retrospective Case Series Using 3D Digital Analysis

Phenotype modification therapy has emerged as one of the main treatment objectives of periodontal plastic surgery. However, long-term data on the stability of gingival thickness gains are not available. This study examined the kinetics of mucosal thickness gain as a measure of phenotype modification therapy following treatment of multiple gingival recession defects with vestibular incision subperiosteal tunnel access (VISTA). Six patients with 14 recession type (RT) II teeth were treated using VISTA and subepithelial connective tissue grafts (SCTG). Scanned images of study casts at pre- and postoperative periods (6 to 66 months) were digitally superimposed for quantitative evaluation of soft tissue dimensional changes. Mucosal thickness gains ranged from 1.0 ± 0.7 mm (1 mm apical to cement-enamel junction [CEJ]) to 1.4 ± 0.4 mm (5 mm apical to CEJ). The gingival thickness gains remained relatively stable, with thickness gains at 66 months of 0.5 ± 0.8, 0.9 ± 0.6, 1.1 ± 0.6, 1.0 ± 0.4, and 1.2 ± 0.6 mm at 1, 2, 3, 4 and 5 mm apical to the CEJ, respectively. Treatment of multiple gingival recession defects with VISTA and SCTG led to stable gingival thickness gains and shows promise as a strategy for phenotype modification therapy.

Selection of Mexican Medicinal Plants by Identification of Potential Phytochemicals with Anti-Aging, Anti-Inflammatory, and Anti-Oxidant Properties through Network Analysis and Chemoinformatic Screening.

Many natural products have been acquired from plants for their helpful properties. Medicinal plants are used for treating a variety of pathologies or symptoms. The axes of many pathological processes are inflammation, oxidative stress, and senescence. This work is focused on identifying Mexican medicinal plants with potential anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects through network analysis and chemoinformatic screening of their phytochemicals. We used computational methods to analyze drug-like phytochemicals in Mexican medicinal plants, multi-target compounds, and signaling pathways related to anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence mechanisms. A total of 1373 phytochemicals are found in 1025 Mexican medicinal plants, and 148 compounds showed no harmful functionalities. These compounds displayed comparable structures with reference molecules. Based on their capacity to interact with pharmacological targets, three clusters of Mexican medicinal plants have been established. Curatella americana, Ximenia americana, Malvastrum coromandelianum, and Manilkara zapota all have anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects. Plumeria rubra, Lonchocarpus yucatanensis, and Salvia polystachya contained phytochemicals with anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence reported activity. Lonchocarpus guatemalensis, Vallesia glabra, Erythrina oaxacana, and Erythrina sousae have drug-like phytochemicals with potential anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects. Between the drug-like phytochemicals, lonchocarpin, vallesine, and erysotrine exhibit potential anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects. For the first time, we conducted an initial virtual screening of selected Mexican medicinal plants, which was subsequently confirmed in vivo, evaluating the anti-inflammatory activity of Lonchocarpus guatemalensis Benth in mice.