Acute Coronary Syndrome During the Era of COVID-19: Perspective and Implications Using Google Trends.

Background: Acute coronary syndrome (ACS) hospital admissions decreased during the start of the COVID-19 outbreak. Information is limited on how Google searches were related to patients' behaviour during this time. Methods: We examined de-identified data from 2019 through 2020 regarding the following monthly items: (i) admissions for ACS from the Veterans Affairs Healthcare System; (ii) out-of-hospital cardiac arrest (OHCA) from the National Emergency Medical Services Information System (NEMSIS) public dataset; and (iii) Google searches for "chest pain," "coronavirus," "chest pressure," and "hospital safe" from Google Trends. We analyzed the trends for ACS admissions, OHCA, and Google searches. Results: During the early months of the first COVID-19 outbreak, the following occurred: (i) Veterans Affairs data showed a significant reduction in ACS admissions at a national and regional (Florida) level; (ii) the NEMSIS database showed a marked increase in OHCA at a national level; and (iii) Google Trends showed a significant increase in the before-mentioned Google searches at a national and regional level. Conclusions: ACS hospital admissions decreased during the beginning of the pandemic, likely owing to delayed healthcare utilization secondary to patients fear of acquiring a COVID-19 infection. Concordantly, the volume of Google searches for hospital safety and ACS symptoms increased, along with OHCA events, during the same time. Our results suggest that Google Trends may be a useful tool to predict patients' behaviour and increase preparedness for future events, but statistical strategies to establish association are needed.

Contexte: Les admissions à l'hôpital pour un syndrome coronarien aigu (SCA) ont diminué au début de la pandémie de COVID-19. Or, il existe peu de données sur les recherches effectuées par les patients dans Google pendant cette période. Méthodologie: Nous avons examiné des données mensuelles dépersonnalisées de 2019 à 2020 sur les éléments suivants : i) admissions pour un SCA dans le système de santé de Veterans Affairs aux États-Unis; ii) arrêts cardiaques extrahospitaliers (ACEH) de l'ensemble de données publiques du National Emergency Medical Services Information System (NEMSIS); et iii) les recherches dans Google selon Google Trends pour « chest pain ¼ (douleur thoracique), « coronavirus ¼, « chest pressure ¼ (oppression thoracique) et « hospital safe ¼ (sécurité dans les hôpitaux). Nous avons également analysé les tendances relatives aux admissions pour un SCA, aux ACEH et aux recherches dans Google. Résultats: Pour les premiers mois de la première vague de COVID-19, les observations sont les suivantes : i) les données de Veterans Affairs ont montré une réduction significative des admissions pour un SCA à l'échelle nationale et régionale (Floride); ii) la base de données du NEMSIS a montré une augmentation marquée des ACEH à l'échelle nationale; et iii) les tendances observées au moyen de Google Trends indiquent une augmentation significative à l'échelle nationale et régionale des recherches dans Google à l'aide des termes mentionnés précédemment. Conclusions: Les admissions à l'hôpital pour un SCA ont diminué au début de la pandémie, probablement en raison de la crainte des patients de contracter la COVID-19, qui les a amenés à repousser le recours à des soins de santé. Pendant la même période, le volume des recherches dans Google à propos de la sécurité dans les hôpitaux et les symptômes de SCA a augmenté, tout comme le nombre d'ACEH. Nos résultats semblent indiquer que Google Trends pourrait être un outil pratique pour prédire les comportements des patients et mieux se préparer aux événements futurs, mais il convient d'élaborer des stratégies statistiques permettant de mieux caractériser ces liens.

NLRP3 and AIM2 inflammasomes expression is modified by LPS and titanium ions increasing the release of active IL-1ß in alveolar bone-derived MSCs.

Periodontitis and peri-implantitis are inflammatory diseases of infectious etiology that lead to the destruction of the supporting tissues located around teeth or implants. Although both pathologies share several characteristics, it is also known that they show important differences which could be due to the release of particles and metal ions from the implant surface. The activation of the inflammasome pathway is one of the main triggers of the inflammatory process. The inflammatory process in patients who suffer periodontitis or peri-implantitis has been mainly studied on cells of the immune system; however, it is also important to consider other cell types with high relevance in the regulation of the inflammatory response. In that context, mesenchymal stromal cells (MSCs) play an essential role in the regulation of inflammation due to their ability to modulate the immune response. This study shows that the induction of NLRP3 and absent in melanoma 2 (AIM2) inflammasome pathways mediated by bacterial components increases the secretion of active IL-1ß and the pyroptotic process on human alveolar bone-derived mesenchymal stromal cells (hABSCs). Interestingly, when bacterial components are combined with titanium ions, NLRP3 expression is further increased while AIM2 expression is reduced. Furthermore, decrease of NLRP3 or AIM2 expression in hABSCs partially reverses the negative effect observed on the progression of the inflammatory process as well as on cell survival. In summary, our data suggest that the progression of the inflammatory process in peri-implantitis could be more acute due to the combined action of organic and inorganic components.

LINC00662 Promotes Aggressive Traits by Modulating OCT4 Expression through miR-335-5p in Gallbladder Cancer Cells.

Long non-coding RNAs (lncRNAs) are nucleotide sequences that participate in different biological processes and are associated with different pathologies, including cancer. Long intergenic non-protein-coding RNA 662 (LINC00662) has been reported to be involved in different cancers, including colorectal, prostate, and breast cancer. However, its role in gallbladder cancer has not yet been described. In this article, we hypothesize that LINC00662 has an important role in the acquisition of aggressiveness traits such as a stem-like phenotype, invasion, and chemoresistance in gallbladder cancer. Here, we show that LINC00662 is associated with larger tumor size and lymph node metastasis in patients with gallbladder cancer. Furthermore, we show that the overexpression of LINC00662 promotes an increase in CD133+/CD44+ cell populations and the expression of stemness-associated genes. LINC00662 promotes greater invasive capacity and the expression of genes associated with epithelial-mesenchymal transition. In addition, the expression of LINC00662 promotes resistance to cisplatin and 5-fluorouracil, associated with increased expression of chemoresistance-related ATP-binding cassette (ABC) transporters in gallbladder cancer (GBC) cell lines. Finally, we show that the mechanism by which LINC00662 exerts its function is through a decrease in microRNA 335-5p (miR-335-5p) and an increase in octamer-binding transcription factor 4 (OCT4) in GBC cells. Thus, our data allow us to propose LINC00662 as a biomarker of poor prognosis and a potential therapeutic target for patients with GBC.

Pancreatic neuroendocrine tumors: Are tumors smaller than 2 cm truly indolent?

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are relatively rare but rank as the second most common pancreatic neoplasm. They can be functional, causing early metabolic disturbances due to hormone secretion, or non-functional and diagnosed later based on tumor size-related symptoms. Recent diagnoses of PNETs under 2 cm in size have sparked debates about their management; some practitioners advocate for surgical removal and others suggest observation due to the tumors' lower potential for malignancy. However, it is unclear whether managing these small tumors expectantly is truly safe. AIM: To evaluate poor prognostic factors in PNETs based on tumor size (> 2 cm or < 2 cm) in surgically treated patients. METHODS: This cohort study included 64 patients with PNETs who underwent surgical resection between 2006 and 2019 at a high-complexity reference hospital in Medellín, Colombia. To assess patient survival, quarterly follow-ups were conducted during the first year after surgery, followed by semi-annual consultations at the hospital's hepatobiliary surgery department. Qualitative variables were described using absolute and relative frequencies, and quantitative variables were expressed using measures of central tendency and their corresponding measures of dispersion. RESULTS: The presence of lymph node involvement, neural involvement, and lymphovascular invasion were all associated with an increased risk of mortality, with hazard ratios of 5.68 (95%CI: 1.26-25.61, P = 0.024), 6.44 (95%CI: 1.43-28.93, P = 0.015), and 24.87 (95%CI: 2.98-207.19, P = 0.003), respectively. Neural involvement and lymphovascular invasion were present in tumors smaller than 2 cm in diameter and those larger than 2 cm in diameter. The recurrence rates between the two tumor groups were furthermore similar: 18.2% for tumors smaller than 2 cm and 21.4% for tumors larger than 2 cm. Patient survival was additionally comparable between the two tumor groups. CONCLUSION: Tumor size does not dictate prognosis; lymph node and lymphovascular involvement affect mortality, which highlights that histopathological factors-rather than tumor size-may play a role in management.

Risks posed by invasive species to the provision of ecosystem services in Europe.

Invasive species significantly impact biodiversity and ecosystem services, yet understanding these effects at large spatial scales remains a challenge. Our study addresses this gap by assessing the current and potential future risks posed by 94 invasive species to seven key ecosystem services in Europe. We demonstrate widespread potential impacts, particularly on outdoor recreation, habitat maintenance, crop provisioning, and soil and nitrogen retention. Exposure to invasive species was higher in areas with lower provision of ecosystem services, particularly for regulating and cultural services. Exposure was also high in areas where ecosystem contributions to crop provision and nitrogen retention were at their highest. Notably, regions vital for ecosystem services currently have low invasion suitability, but face an average 77% increase in potential invasion area. Here we show that, while high-value ecosystem service areas at the highest risk represent a small fraction of Europe (0-13%), they are disproportionally important for service conservation. Our study underscores the importance of monitoring and protecting these hotspots to align management strategies with international biodiversity targets, considering both invasion vulnerability and ecosystem service sustainability.

Current Emerging Concepts on the Pathogenesis of Peri-implant Diseases: A Narrative Review.

OBJECTIVES: The aim of this narrative review is to describe the emerging evidence concerning etiological factors and pathophysiological mechanisms involved in peri-implant inflammatory diseases. MATERIAL AND METHODS: An electronic search for articles published until November 2022 was conducted in MEDLINE by three independent reviewers to identify manuscripts reporting data on etiological factors and pathophysiological mechanisms associated with peri-implant diseases. RESULTS: Current evidence suggests that peri-implant mucositis and peri-implantitis are inflammatory conditions linked to a microbial challenge. However, in recent years, there has been increasing evidence indicating that certain peri-implant inflammatory conditions may not be primarily related to biofilm-mediated infectious processes but rather to other biological mechanisms, such as a foreign body response. CONCLUSION: The current evidence, not only in the dental literature, opens new avenues for a more complex interpretation of the etiopathogenetic factors involved in peri-implant diseases. A better understanding of various factors related to the host response, including dysbiosis mechanisms associated with changes in microbiota composition, is necessary for a more precise physiopathological characterization of these diseases.

Detection and comparison of neutrophil extracellular traps in tissue samples of peri-implantitis, periodontitis, and healthy patients: A pilot study.

OBJECTIVE: The aim of this study was to detect and compare the tissular expression of neutrophil extracellular traps (NETs) in peri-implant and periodontal samples of patients with peri-implantitis, periodontitis, and controls. MATERIALS AND METHODS: An observational study was performed on patients with peri-implantitis, periodontitis, and controls. Peri-implant and/or periodontal clinical examinations were performed on each participant. Tissue samples were collected during tooth/implant extraction for clinical reasons. Electron microscopy analysis, Picro-Sirius red staining, immunohistochemical (CD15), and immunofluorescence (citrullinated H3 and myeloperoxidase) techniques were performed to detect NET-related structures and the degree of connective tissue destruction, between the study groups. RESULTS: Sixty-four patients were included in the study: 28 peri-implantitis, 26 periodontitis, and 10 controls, with a total of 51 implants, 26 periodontal teeth, and 10 control teeth. Neutrophil release of nuclear content was observed in transmission electron microscopy. Immunohistochemical analysis showed a greater CD15 expression in both peri-implantitis and periodontitis compared to controls (p < 0.001), and peri-implantitis presented lower levels of connective tissue and collagen compared to both periodontitis (p = 0.044; p < 0.001) and controls (p < 0.001). Immunofluorescence showed greater citH3 expression in peri-implantitis than the one found in both periodontitis (p = 0.003) and controls (p = 0.048). CONCLUSIONS: A greater presence and involvement of neutrophils, as well as a greater connective tissue destruction were observed in cases of peri-implantitis. A higher expression of NET-related markers was found in mucosal samples of peri-implantitis compared to periodontitis and controls.

Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

CDK4/6i-treated HR+/HER2- breast cancer tumors show higher ESR1 mutation prevalence and more altered genomic landscape.

As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical for precision oncology. Using real-world data (RWD) with tumor genomic profiling from 5910 patients with metastatic HR+/HER2- BC, we investigated the evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 is more often altered in tumors exposed to at least 1 year of adjuvant endocrine therapy, contrasting with TP53 alterations. We observed a similar trend after first-line treatments in the advanced setting, but strikingly exposure to aromatase inhibitors (AI) combined with CDK4/6i led to significantly higher ESR1 alteration prevalence compared to AI alone, independent of treatment duration. Further, CDK4/6i exposure was associated with higher occurrence of concomitant alterations in multiple oncogenic pathways. Differences based on CDK4/6i exposure were confirmed in samples collected after 2L and validated in samples from the acelERA BC clinical trial. In conclusion, our work uncovers opportunities for further treatment personalization and stresses the need for effective combination treatments to address the altered tumor genomic landscape following AI+CDK4/6i exposure. Further, we demonstrated the potential of RWD for refining patient treatment strategy and guiding clinical trial design.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

Effect of Abutment Height on Marginal Bone Loss Around Dental Implants: A Systematic Review.

PURPOSE: To analyze the influence of abutment height (AH) on marginal bone loss (MBL). MATERIALS AND METHODS: A literature search was performed for human studies (RCTs, prospective and retrospective cohorts) reporting on AH and MBL. The data obtained-including clinical outcomes, treatment covariates, and patient characteristics-were analyzed. Meta-regression was performed on the effect size of the differences between the shorter and larger AHs on the MBL of each study. The estimation was done using the restricted maximum likelihood method. RESULTS: The initial screening and full-text analysis resulted in 7,936 and 46 articles, respectively. Finally, 14 articles were included in the systematic review, reporting a total of 1,606 implants. An overall high-to-moderate risk of bias was determined among the included investigations. Meta-regression analysis revealed that AH had a significant effect on MBL (b = -1.630, P < .003), demonstrating that longer abutments were correlated with less MBL. No effects were observed for the study type (P = .607), the number of stages (P = .510), or the elapsed time (P = .491). CONCLUSIONS: The height of the abutment has a significant impact on MBL. As such, increased AH is related to less MBL. Nevertheless, the role of confounding variables remains to be studied and determined.

Correlation between Inflammasomes and Microbiota in Peri-Implantitis.

The activation of inflammasomes is thought to induce the inflammatory process around dental implants. No information is available on the correlation between microbiota and inflammasomes in clinical samples from patients suffering peri-implantitis. For this cross-sectional study, 30 biofilm samples were obtained from 19 patients undergoing surgical treatment for peri-implantitis because of the presence of bleeding on probing, probing depth higher than 6 mm, and radiographic bone loss higher than 3 mm. Then, soft tissue samples from around the implant were also collected. The relative abundance of bacteria and alpha-diversity indexes were calculated after analyzing the 16S rRNA gene using next-generation sequencing. The soft-tissue samples were processed for evaluation of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß. The relative abundance (mean (SD)) of specific species indicated that the most abundant species were Porphyromonas gingivalis (10.95 (14.17)%), Fusobacterium vincentii (10.93 (13.18)%), Porphyromonas endodontalis (5.89 (7.23)%), Prevotella oris (3.88 (4.94)%), Treponema denticola (2.91 (3.19)%), and Tannerella forsythia (2.84 (4.15)%). Several correlations were found between the species and the immunohistochemical detection of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß, both in the epithelium and the lamina propria. A network analysis found an important cluster of variables formed by NLRP3 in the lamina propria and AIM2, caspase-1, and IL-1ß in the lamina propria and the epithelium with Prevotella dentalis, Prevotella tannerae, Tannerella forsythia, or Selenomonas timonae. Thus, it could be concluded that inflammasomes NLRP3 and AIM2 and their downstream effectors caspase-1 and interleukin-1ß can be significantly associated with specific bacteria.

Auritidibacter ignavus in ear discharge of paediatric patients: Two cases reports and literature review.

INTRODUCTION: The development and research of new technologies for identifying microorganisms, has allowed the identification of hitherto unknown bacteria. Auritidibacter ignavus is a newly described Gram-positive rod possibly associated with otitis, although its role as an etiologic agent in otitis is currently controversial. METHODS: We report two cases of recurrent otitis in paediatric patients in which A. ignavus was isolated and review the previous cases reported in the literature. RESULTS: All the isolates were identified as A. ignavus by proteomic and genomic methods. Both patients recovered from their symptoms. CONCLUSION: A. ignavus was recovered from ear discharges of paedriatic patients with chronic ear problems. All the cases previously reported in the literature were adults. More evidence is needed for the association between A. ignavus and otitis, since data regarding this species are still scarce.

Transcriptomic profiles and diagnostic biomarkers in the Mediterranean seagrasses Posidonia oceanica and Cymodocea nodosa reveal mechanistic insights of adaptative strategies upon desalination brine stress.

Seawater desalination by reverse osmosis is growing exponentially due to water scarcity. Byproducts of this process (e.g. brines), are generally discharged directly into the coastal ecosystem, causing detrimental effects, on benthic organisms. Understanding the cellular stress response of these organisms (biomarkers), could be crucial for establishing appropriate salinity thresholds for discharged brines. Early stress biomarkers can serve as valuable tools for monitoring the health status of brine-impacted organisms, enabling the prediction of long-term irreversible damage caused by the desalination industry. In this study, we conducted laboratory-controlled experiments to assess cellular and molecular biomarkers against brine exposure in two salinity-sensitive Mediterranean seagrasses: Posidonia oceanica and Cymodocea nodosa. Treatments involved exposure to 39, 41, and 43 psu, for 6 h and 7 days. Results indicated that photosynthetic performance remained unaffected across all treatments. However, under 43 psu, P. oceanica and C. nodosa exhibited lipid oxidative damage, which occurred earlier in P. oceanica. Additionally, P. oceanica displayed an antioxidant response at higher salinities by accumulating phenolic compounds within 6 h and ascorbate within 7 d; whereas for C. nodosa the predominant antioxidant mechanisms were phenolic compounds accumulation and total radical scavenging activity, which was evident after 7 d of brines exposure. Finally, transcriptomic analyses in P. oceanica exposed to 43 psu for 7 days revealed a poor up-regulation of genes associated with brassinosteroid response and abiotic stress response, while a high down-regulation of genes related to primary metabolism was detected. In C. nodosa, up-regulated genes were involved in DNA repair, cell cycle regulation, and reproduction, while down-regulated genes were mainly associated with photosynthesis and ribosome assembly. Overall, these findings suggest that 43 psu is a critical salinity-damage threshold for both seagrasses; and despite the moderate overexpression of several transcripts that could confer salt tolerance, genes involved in essential biological processes were severely downregulated.

IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas.

INTRODUCTION: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. MATERIALS AND METHODS: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. RESULTS: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. CONCLUSIONS: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).

Periostin in the relation between periodontal disease and atherosclerotic coronary artery disease: A pilot randomized clinical study.

OBJECTIVE: The aim of this study was to analyze the effects of periodontal treatment on markers of atherosclerotic coronary artery disease and circulating levels of periostin. BACKGROUND: Periostin is necessary for periodontal stability, but it is highly present in atherosclerotic plaques. Treatment of periodontal disease, with low levels of local periostin, is thought to reduce systemic levels of periostin. Thus, this may contribute to cardiovascular health. METHODS: A pilot randomized controlled clinical trial was designed to include patients with severe periodontal disease and history of atherosclerotic coronary artery disease. Samples of gingival crevicular fluid (GCF) and serum were collected before and after periodontal treatment by periodontal surgery or non-surgical therapy. The levels of several markers of inflammation and cardiovascular damage were evaluated including CRP, IFN-γ, IL-1ß, IL-10, MIP-1α, periostin, and TNF-α in GCF and CRP, Fibrinogen, IFN-γ, IL-1ß, IL-6, IL-10, L-Selectin, MIP-1α, Periostin, TNF-α, and vWF in serum. RESULTS: A total of 22 patients with an average of 56 years old were recruited for participating in this study. Twenty of them were male. Most of them (82%) had suffered an acute myocardial event and underwent surgery for placing 1, 2, or 3 stents in the coronary arteries more than 6 months ago but less than 1 year. The treatment of periodontal disease resulted in an overall improvement of all periodontal parameters. Regarding the evaluation of GCF and serum, a significant increase of periostin in the GCF was observed after periodontal surgery. In contrast, although other markers in GCF and serum improved, no significant correlations were found. CONCLUSION: Treatment of periodontal disease through periodontal surgery induces a local and transient increase in the levels of periostin in the gingival crevicular fluid. The effects on systemic markers of inflammation and cardiovascular function have not been confirmed.

Advances towards the use of gastrointestinal tumor patient-derived organoids as a therapeutic decision-making tool.

In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establishment and verification of ex vivo preclinical models that closely represent tumor complexity and that can predict therapeutic response. Fortunately, the emergence of patient-derived organoid (PDOs) culture has enabled the ex vivo mimicking of the pathophysiology of human tumors with the reassembly of tissue-specific features. These features include histopathological variability, molecular expression profiles, genetic and cellular heterogeneity of parental tissue, and furthermore growing evidence suggests the ability to predict patient therapeutic response. Concentrating on the highly lethal and heterogeneous gastrointestinal (GI) tumors, herein we present the state-of-the-art and the current methodology of PDOs. We highlight the potential additions, improvements and testing required to allow the ex vivo of study the tumor microenvironment, as well as offering commentary on the predictive value of clinical response to treatments such as chemotherapy and immunotherapy.

Experimental investigation on the physical, microstructural, and mechanical properties of hemp limecrete.

This paper investigates the hemp limecrete mechanical and microstructural performance of a new sustainable and environmental friendly building material. Several studies have investigated the hemp limecrete focusing on the non-structural applications. The newly developed hemp limecrete consists of high mechanical and microstructural properties. The specimens were prepared with varying lengths and proportions of hemp fibers with lime and tested for compressive strength, flexural strength, thermal conductivity and microstructural analysis like SEM and EDS. The study found that the optimal fiber content for making mortars was between 2 and 4%. This conclusion was reached after analyzing the influence of fiber length and ratio on the properties of the mortars. The dry unit weight decreased when the fiber content was higher than 4%. In terms of strength, the study found that the flexural strength of the hemp limecrete improved with an increase in fiber ratio, but the compressive strength decreased. However, with 2% hemp fiber, compressive strengths of 3.48 MPa and above were obtained. The study also highlighted the good thermal insulation properties and dimensional stability of hemp limecrete. These findings have important implications for the use of hemp limecrete as a sustainable building material. The results suggest that hemp limecrete has the potential to be a viable alternative to conventional concrete in specific applications, particularly in areas where environmental sustainability is a priority.

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.

The Influence of History of Severe Periodontitis on Estimated Long-Term Marginal Bone Loss around Implants Restored with Fixed Segmented Full-Arch Rehabilitation.

The aim of this study was to analyze the long-term marginal bone level (MBL) of implants supporting fixed full-arch restoration in patients who had previously lost their dentition due to severe periodontitis. This retrospective study included 35 patients in whom 342 implants with internal tapered conical connections were placed. MBL was analyzed radiographically over time and a long-term estimation of MBL was calculated. A mixed linear model with abutment height, graft, diameter and location (maxilla/mandible) as factors and gender, age, implant length and prosthetic variables as covariates was used to evaluate the influence on MBL. MBL in these patients showed an estimator of predictions at 4108 days after loading of -0.307 mm, SE = 0.042. Only 0.15% of implants were radiographically affected with MBL of 3 mm or more. The mixed linear model results showed a main effect of the type of opposing dentition, gender, implant diameter, and abutment height. Particularly, an abutment height of 1 mm had associated larger MBL than the remaining heights. Thus, it can be concluded that dental implants restored with fixed segmented full-arch rehabilitation in patients with a history of severe periodontal disease do not suffer important marginal bone loss if some specific factors are considered, mainly the use of long transmucosal abutments (≥2 mm).