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Purpose: To evaluate the influence of initial implant protrusion within the subantral space on hard tissue gain for implants placed simultaneously with transcrestal sinus floor elevation (TSFE) with a biomaterial. Materials and Methods: A total of 50 implants were placed after TSFE in 44 patients using either a human demineralized bone matrix or a deproteinized bone mineral matrix. Intraoral radiographs were obtained before and immediately after surgery. CBCT scans were obtained at the last follow-up (mean: 6.6 years). Results: The initial bone crest height was 4.6 ± 1.4 mm, and the initial protrusion of the implants above the sinus floor was 3.5 ± 1.4 mm. At the follow-up assessments, the hard tissue mean gain was 2.5 ± 1.5 mm, resulting in a mean residual protrusion of 1.1 ± 1.3 mm. Only 10 implants did not protrude above the apical level of hard tissue. Positive correlations were found between hard tissue gain and initial protrusion (r = 0.55; 95% CI: 0.32 to 0.72; P = .0001), between the initial and final protrusions (r = 0.38; 95% CI: 0.10 to 0.60; P = .007), and between the follow-up period and final protrusion (r = 0.35; 95% CI: 0.07 to 0.58; P = .012). Conclusions: The higher the initial protrusion was, the higher were the hard tissue gain and the final protrusion of the implant above the apical level of the hard tissue. [ABSTRACT FROM AUTHOR]

Background: The mandible of the rabbit is considered a reliable model to be used to study bone regeneration in defects. The aim of the present study was to evaluate the formation of new bone around implants installed in defects of either 5 or 10 mm in the mandible of rabbits. Materials and methods: In 12 rabbits, 3 mm deep circumferential defect, either 5 or 10 mm in diameter, were prepared bilaterally and an implant was placed in the center. A collagen membrane was placed to close the entrance. After 10 weeks, biopsies were taken, histological slides were prepared, and different regions of the defects were analyzed. Results: Similar amounts of new bone were found in both defects. However, most of the 5 mm defects were filled with new bone. New bone was observed closing the entrance of the defect and laid onto the implant surface. Only in a few cases the healing was incomplete. Despite a similar percentage of new bone found within the 10 mm defects, the healing was incomplete in most of the cases, presenting a low rate of bone formation onto the implant surface within the defect. Only one case presented the closure of the entrance. Conclusions: The dimensions of the defect strongly influenced the healing so that a circumferential marginal defect of 10 mm around an implant in the mandible body should be considered a critical-sized defect. The presence of the implant and of residues of teeth might have strongly influenced the healing. [ABSTRACT FROM AUTHOR]

Background: To avoid cortical compression, several implant systems have included in the protocol dedicated drills aimed at widening the cortical region of osteotomy. However, the manual execution of this operation does not guarantee the necessary precision. Hence, the present study aimed to determine the optimal size of the recipient site at the level of the alveolar crest in relation to the size of the coronal region of the implant to achieve the best healing result. Materials and methods: Blades of different diameters were incorporated into the coronal part of the implant to prepare the cortical region of the mandibular alveolar bone crest in different dimensions in relation to the collar of the implant. The differences in diameter of the blades in relation to the collar of the implant were as follows: one control group, -175 μm, and three test groups, 0 μm, + 50 μm, or + 200 μm. Results: The marginal bone loss (MBL) at the buccal aspect was 0.7 mm, 0.5 mm, 0.2 mm, and 0.7 mm in the − 175 μm, 0.0 μm, + 50 μm, + 200 μm groups, respectively. The differences were statistically significant between group + 50 μm and control group − 175 μm (p = 0.019), and between + 50 μm and + 200 μm (p < 0.01) groups. The level of osseointegration at the buccal aspect was more coronally located in the test groups than in the control group, whereas the bone-to-implant contact percentage was higher in the + 50 μm and + 200 μm groups. However, these differences were not statistically significant. Conclusions: The lowest bone crest resorption and highest levels of osseointegration were observed in the 0.0 μm and + 50 μm groups. The cortical region where the blades had performed their cutting action showed regular healing with perfect hard and soft tissues sealing in all the groups. Cortical blades gathered bone particles, particularly in the + 200 μm group, which were incorporated into the newly formed bone. The results from the present experiment provide support to the use of blades that produce a marginal gap of 50 μm after implant insertion. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the biological behavior of a novel implant design incorporating decompressive cervical blades. Hence, the aim of the present study was to evaluate the healing outcomes in cortical regions where decompressive protocols were implemented using implants equipped with blades and installed applying a bicortical anchorage. Materials and Methods: Blades with varying diameters were integrated into the coronal portion of the implant to prepare the cortical region of rabbit tibiae. The blade diameters differed from the implant collar by the following amounts: control group (0 µm), +50 µm, and +200 µm. Results: No marginal bone loss was detected. Instead, all implants exhibited new bone formation in the coronal region. Complete closure was observed in the CG-0 group, as well as in the TG-50 and TG-200 groups, despite the presence of marginal gaps without primary bone contact at installation. In the apical region, most implants breached the cortical layer. Nevertheless, new bone formation in this region completely closed the osteotomy, effectively isolating the internal environment of the tibia from the external. Conclusions: The use of a blade incorporated into the implant body enabled precise preparation of the cortical layer, allowing for controlled decompression in the targeted area. This technique resulted in optimal osseointegration with no loss of marginal bone, and complete restoration of marginal gaps ranging from 0 µm to 200 µm. [ABSTRACT FROM AUTHOR]

5‐HT1A receptor (5‐HT1A‐R) is a serotoninergic G‐protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5‐HT‐R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure‐activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5‐HT1A‐R selective/preferential ligands; (ii) identification of 5‐HT1A‐R biased agonists, differentiating pre‐ versus post‐synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well‐defined poly‐pharmacological profiles targeting 5‐HT1A‐R along with other serotonin receptors, serotonin transporter (SERT), D2‐like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5‐HT1A‐R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017–2023) have been discussed. The development of chemical and pharmacological 5‐HT1A‐R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5‐HT1A‐R and the therapeutic potential of ligands targeting this receptor have been considered. [ABSTRACT FROM AUTHOR]

Objective: Binge‐eating disorder is an eating disorder characterized by recurrent binge‐eating episodes, during which individuals consume excessive amounts of highly palatable food (HPF) in a short time. This study investigates the intricate relationship between repeated binge‐eating episode and the transcriptional regulation of two key genes, adenosine A2A receptor (A2AAR) and dopamine D2 receptor (D2R), in selected brain regions of rats. Method: Binge‐like eating behavior on HPF was induced through the combination of food restrictions and frustration stress (15 min exposure to HPF without access to it) in female rats, compared to control rats subjected to only restriction or only stress or none of these two conditions. After chronic binge‐eating episodes, nucleic acids were extracted from different brain regions, and gene expression levels were assessed through real‐time quantitative PCR. The methylation pattern on genes' promoters was investigated using pyrosequencing. Results: The analysis revealed A2AAR upregulation in the amygdala and in the ventral tegmental area (VTA), and D2R downregulation in the nucleus accumbens in binge‐eating rats. Concurrently, site‐specific DNA methylation alterations at gene promoters were identified in the VTA for A2AAR and in the amygdala and caudate putamen for D2R. Discussion: The alterations on A2AAR and D2R genes regulation highlight the significance of epigenetic mechanisms in the etiology of binge‐eating behavior, and underscore the potential for targeted therapeutic interventions, to prevent the development of this maladaptive feeding behavior. These findings provide valuable insights for future research in the field of eating disorders. Public Significance: Using an animal model with face, construct, and predictive validity, in which cycles of food restriction and frustration stress evoke binge‐eating behavior, we highlight the significance of epigenetic mechanisms on adenosine A2A receptor (A2AAR) and dopamine D2 receptor (D2R) genes regulation. They could represent new potential targets for the pharmacological management of eating disorders characterized by this maladaptive feeding behavior. [ABSTRACT FROM AUTHOR]

Objective: Test the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge‐eating disorder (BED) and study its dose–response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin‐A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge‐eating phenotype in the rat model used. Method: Binge‐like eating of highly palatable food (HPF) in rats was induced through priming by intermittent, repeated periods of dieting and access to HPF, followed by an additional challenge with acute stress. Effects of nivasorexant were compared to the SO1RAs ACT‐335827 and IDOR‐1104‐2408. OXA expression in neurons and neuronal fibers as well as ΔFosB and OXA‐ΔFosB co‐expression was studied in relevant brain regions using immuno‐ or immunofluorescent histochemistry. Results: All SO1RAs dose‐dependently reduced binge‐like eating with effect sizes comparable to the positive control topiramate, at unbound drug concentrations selectively blocking brain OX1Rs. Nivasorexant's efficacy was maintained upon chronic dosing and under conditions involving more frequent stress exposure. Priming for binge‐like eating or nivasorexant treatment resulted in only minor changes in OXA or ΔFosB expression in few brain areas. Discussion: Selective OX1R blockade reduced binge‐like eating in rats. Neither ΔFosB nor OXA expression proved to be a useful classifier for their binge‐eating phenotype. The current results formed the basis for a clinical phase II trial in BED, in which nivasorexant was unfortunately not efficacious compared with placebo. Public Significance: Nivasorexant is a new investigational drug for the treatment of binge‐eating disorder (BED). It underwent clinical testing in a phase II proof of concept trial in humans but was not efficacious compared with placebo. The current manuscript investigated the drug's efficacy in reducing binge‐like eating behavior of a highly palatable sweet and fat diet in a rat model of BED, which initially laid the foundation for the clinical trial. [ABSTRACT FROM AUTHOR]

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The classic paradigm for the management of locally advanced rectal cancer (LARC) consists of (chemo)radiotherapy (C)RT), total mesorectal excision, and adjuvant chemotherapy (CHT). At present, due to the high rate of distant metastasis (up to 30%), the total neoadjuvant therapy (TNT) with the administration of systemic CHT in the neoadjuvant setting has gained acceptance as standard of care. Our aim is to critically review the current literature on LARC management and summarize the different approaches recently proposed to improve clinical outcomes. It represents a starting step to develop an effective strategy that ultimately could harmonize the standard of care in daily clinical practice. Studies reporting the impact of TNT approaches were deemed eligible. De-escalation strategies, including non-operative management (NOM) after TNT, as well as RT omission or systemic therapy alone, were also investigated. The year 2020 has seen promising new data from randomized phase III trials in the field of LARC management. Nowadays, TNT strategy has been accepted as the primary treatment for LARC. The role of de-escalation strategies is still unknown. The goal is to achieve better survival outcomes with improving quality of life. Only selected patients are likely to benefit from NOM or immunotherapy alone. [ABSTRACT FROM AUTHOR]

In our previous article, we observed and measured a spontaneous growth in the coronal direction of the keratinized tissues present around implants. This growth involved both free margins and interdental papillae, and we indicated our hypothesis on the probable cause of this still-unexplained phenomenon. The growth of oral soft tissues involves several other structures, such as the linea alba and tongue indentation. Our idea holds that growth of these tissues is generated by the negative intraoral pressure created in the oral phase of swallowing and the subsequent resting position, which through the resulting suction causes a shift of these soft structures in the gaps around the dental crowns. Other hypotheses have been suggested in the past to understand this phenomenon of soft tissue growth, which still lacks data supporting etiological evidence. The purpose of this article is to thoroughly analyze and verify our model by comparing the clinical observations with citations and examples from the literature, combined with notions of physiology, biology, and physics that help in clarifying these events. To better explain the mechanisms of oral soft tissue growth, photographs of clinical cases paradigmatic of the phenomenon are shown. [ABSTRACT FROM AUTHOR]

Essential oils represent a good alternative to chemical biocides as they have antiseptic, antibacterial and antifungal properties, inhibiting the formation and proliferation of biofilms which can occur on outdoor and indoor surfaces of ancient and modern artworks. In this review, we illustrate how their antimicrobial properties, known since antiquity in phytotherapy, have been studied and tested for conservation purposes since the 1970s. In vitro tests on a wide range of plant extracts and in situ applications of specific volatile compounds have shown selective antibacterial and antifungal properties after the individual action of pure components or as the synergic effects of pre-determined mixtures. The review emphasizes the broad spectrum of materials—organic and inorganic—that essential oils can be applied to as biocides and finally emphasizes how the demand for commercial solutions has rapidly grown in bioconservation. The review demonstrates how research on the subject has been powerfully boosted by the ecofriendly and harmless character of essential oil applications, which makes them one of the most sustainable options in heritage conservation nowadays. The review elucidates how research is developing novel solutions for the application of EO blends—like encapsulation and microemulsions—and their optimization in commercial products for heritage conservation. [ABSTRACT FROM AUTHOR]

Purpose: The term of placenta accreta spectrum (PAS) disorder includes all grades of abnormal placentation. It is crucial for pathologist provide standardized diagnostic assessment to evaluate the outcome of management strategies. Moreover, a correct and safe diagnosis is useful in the medico-legal field when it becomes difficult for the gynecologist to demonstrate the suitability and legitimacy of demolitive treatment. The purposes of our study were: (1) to assess histopathologic features according to the recent guidelines; (2) to determine if immunohistochemistry can be useful to identify extravillous trophoblast (EVT) and to measure the depth of infiltration into the myometrium to improve the diagnosis of PAS. Methods: The retrospective study was conducted on 30 cases of gravid hysterectomy with histopathologic diagnosis of PAS. To identify the depth of EVT, immunohistochemical stainings were performed using anti MNF116 (cytokeratins 5, 6, 8, 17, 19), actin-SM, HPL (Human Placental Lactogen), vimentin and GATA3 antibodies. Results: Our cases were graded based on the degree of invasion of the myometrium. Ten were grade 1 (33.3%), 12 grade 2 (40%) and 8 grade 3A (26.7%). EVT invasion was best seen and evident by double immunostainings with actin-SM and cytokeratins, actin-SM and HPL, actin-SM and GATA3. Conclusion: The role of pathologist is decisive to determine the different grades of PAS. A better understanding of the depth of myometrial invasion can be achieved by the use of immunohistochemistry affording an important tool to obtain reproducible grading of PAS. This purpose is crucial in the setting of postoperative quality reviews and particularly in the forensic medicine field. [ABSTRACT FROM AUTHOR]

Background: Healing of critical-size defects is a well-known problem that has been challenged in several studies. The aim of the experiment was to evaluate bone formation and osseointegration of implants installed in critical defects of the mandibular body simultaneously grafted with Bio-Oss® or Cerabone®. Material and methods: Defects, 10 mm wide and 3 mm deep, were prepared at both lateral aspects of the mandible in 12 rabbits. One implant was installed in the center of the defect, and bovine xenografts produced either at low (Bio-Oss®; Low-T) or high (Cerabone®; High-T) temperatures were used to fill the defects. A collagen membrane was placed to cover the sites. Healing was evaluated 10 weeks after surgery. Results: In both groups, most sites showed optimal healing with closure of the coronal entrance of the defects. However, residual defects occupied by soft tissues and biomaterial particles were observed, even though generally limited to some regions of the defect. Osseointegration of the implant surface in the region of the defect was poor in both groups. Conclusions: Circumferential marginal critical-size defects around implants filled with bovine xenografts presented regions with a complete healing in both groups. However, the healing was not complete at all regions in most defects; therefore, a complete optimal healing of critical-size marginal defects cannot be predicted. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to apply the break-even point concept to express the dynamics of bone formation and resorption around implants. Methods: Published data on new bone and parent bone densities around implants from one human and three dog studies were selected and used for analysis. The break-even point (BEP) of the bone density (BD) was assessed. The BEP is the point at which, in a graph, the lines representing the formation of new bone and resorption of old bone intersect. BEP is expressed in time (x; days) of occurrence and percentage of bone (y; %) at which the break-even point occurs and illustrates the grade of bone modeling. The sooner the occurrence, the faster the bone formation in relation to the resorption of the old bone. Results: In the marrow and cortical compartments, BEP of bone density occurred after 7.9 days (BD% 24.5%) and >30 days, respectively. Different surfaces presented similar BEP, ranging between 9.7 and 11.2 days (BD% 19.1–22.5%). BEP at implants installed in the human maxilla occurred after 29–30.4 days (BD% 28.3–29.6%). Conclusion: The present study showed that the parameters used to express the break-even point can provide information on the influence of the model used, surface characteristics, and bone quality on bone modeling/remodeling around implants. [ABSTRACT FROM AUTHOR]

Purpose: Limited data is reported regarding the bone mineralization around dental implants in the first months from insertion. The study analyzed the peri-implant bone around loaded and unloaded implants retrieved from human mandible after 4 months from placement. Method: The composition and mineralization of human bone were analyzed through an innovative protocol technique using Environmental-Scanning-Electron-Microscopy connected with Energy-Dispersive-X-Ray-Spectroscopy (ESEM/EDX). Two regions of interest (ROIs, approximately 750×500 μm) for each bone implant sample were analyzed at the cortical (Cortical ROI) and apical (Apical ROI) implant threads. Calcium, phosphorus, and nitrogen (atomic%) were determined using EDX, and the specific ratios (Ca/N, P/N, and Ca/P) were calculated as mineralization indices. Results: Eighteen implant biopsies from ten patients were analyzed (unloaded implants, n=10; loaded implants, n=8). For each ROI, four bone areas (defined bones 1–4) were detected. These areas were characterized by different mineralization degree, varied Ca, P and N content, and different ratios, and by specific grayscale intensity detectable by ESEM images. Bony tissue in contact with loaded implants at the cortical ROI showed a higher percentage of low mineralized bone (bone 1) and a lower percentage of remodeling bone (bone 2) when compared to unloaded implants. The percentage of highly mineralized bone (bone 3) was similar in all groups. Conclusion: Cortical and apical ROIs resulted in a puzzle of different bone "islands" characterized by various rates of mineralization. Only the loaded implants showed a high rate of mineralization in the cortical ROI. [ABSTRACT FROM AUTHOR]

Background: A new access technique was developed to reduce postoperative adverse events after the extraction of impacted maxillary wisdom teeth. Hence, this study aimed to assess the occurrence of adverse events after the extraction of maxillary impacted wisdom teeth using a traditional access (TA) or a new technique (NT). Methods: Two different surgical incision designs were used for bilateral wisdom tooth extractions in 30 patients. The traditional incision was performed distal to the second molar in the center of the tuberosity, followed by a buccal releasing incision. After the tooth extraction, the wound was secured by sutures. The new technique consists of an oblique incision from the distal palatal aspect of the tuberosity towards the buccal aspect of the second molar. After the tooth extraction, cyanoacrylate glue was used on the wound. Results: Lower pain was reported by patients at the site treated with the new technique (p < 0.01). Edema, postsurgical bleeding, and hematoma were similar in both groups. The surgical time was shorter for the new technique (p < 0.01). Conclusions: The new technique applied for the extraction of impacted maxillary wisdom teeth reduced postsurgical pain and the duration of surgery. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the influence on peri-implant soft and hard tissues of one-piece implants with a convergent hyperbolic profile collar placed at different depths with respect to the bone crest. Materials and Methods: Six dogs were included in the experiment. Three months after mandibular tooth extractions, two one-piece implants carrying a 2.8-mm--high convergent hyperbolic profile collar were placed in the alveolar crest with the coronal margin of the rough surface either 0.8 mm (test-1) or 1.8 mm (test-2) deeper with respect to the bone crest (Ct0). Two similar implants were instead placed flush to Ct0 as controls (control-1 and control-2, respectively). Healing screws were connected, and nonsubmerged healing was allowed. After 4 months, block sections were harvested, and histologic slides were prepared in a buccolingual plane. Results: In the histologic analyses, both the buccal crest and coronal level of osseointegration were located more coronally at the test compared to the control implants concerning the implant. However, the buccal bone crest with respect to Ct0 presented a loss of 0.8 ± 0.4 mm at the test-1 and 0.5 ± 0.4 mm at the control-1 implants (P = .028), and a loss of 2.0 ± 1.0 mm and 0.7 ± 0.4 mm at the test-2 and control-2 implants (P = .028), respectively. At the control implants, the collars were exposed above the peri-implant mucosa, while those of the test implants were not. However, the coronal level of the peri-implant mucosa with respect to Ct0 was located more apically at the test compared to the control implants. Conclusion: The placement of implants with a hyperbolic convergent profile collar in the subcrestal position resulted in higher buccal bone resorption and more soft tissue recession compared to the crestal implants with respect to the level of the bone crest at placement. [ABSTRACT FROM AUTHOR]

Purpose: To monitor the early bone reaction in a canine model to a conventional sandblasted and dual acid-etched implant surface (ABT), a nanostructured hydrophilic surface (Nano), a dry salt--bioactivated ultra-hydrophilic surface (Hydro), and a bioactivated nanosurface obtained from the addition of dry salts to the Nano surface (Nano-Active). Materials and Methods: ABT, Nano, Hydro, and Nano-Active implants were placed in 12 dogs. A randomized split-mouth design was adopted. One implant of each type was placed in the mandible 3 months after tooth extraction in healed sites at the first molar region bilaterally. In the same session, the third and fourth premolars were extracted bilaterally and one implant of each type was immediately placed into the extraction socket. The dogs were euthanized at 14 and 28 days following surgery, and the peri-implant bone reaction was assessed histologically using Stevenel's blue and alizarin red in nondecalcified sections. Results: The postoperative healing was uneventful. The 14-day histologic analysis reported nonsignificant results in terms of difference between the groups, while significant results were found 28 days after surgery. In fact, a significantly higher rate of new bone around the implant was reported in the Nano-Active compared to the Nano groups (51.0% ± 10.2% vs 36.0% ± 10.2%) and Hydro compared to the Nano groups (47.3% ± 10.7% vs 36.0% ± 10.2%). Conclusion: The results obtained indicate that new bone formed after 4 weeks demonstrated a tendency for dry salt--treated bioactivated surfaces to improve bone deposition in the interface in the early stages of healing; however, due to the limited number of dogs, the results failed to show a statistical significance. A study with a significantly larger group of animals should be performed in order to challenge the assumption that ultra-hydrophilic--surface implants might show higher bone-implant contact in immediate postextraction replacement. [ABSTRACT FROM AUTHOR]

Background: The KEYNOTE-048 trial showed that pembrolizumab-based first-line treatment for R/M HNSCC led to improved OS in the PD-L1 CPS ≥ 1 population when compared to the EXTREME regimen. However, the R/M HNSCC real-world population is generally frailer, often presenting with multiple comorbidities, worse performance status and older age than the population included in phase III clinical trials. Methods: This is a retrospective, single-centre analysis of patients with R/M HNSCC treated with pembrolizumab-based first-line treatment. Results: From February 2021 to March 2023, 92 patients were treated with pembrolizumab-based first-line treatment. Patients treated with pembrolizumab-based chemoimmunotherapy had better ECOG PS and younger age than those treated with pembrolizumab monotherapy. Median PFS and OS were 4 months and 8 months, respectively. PFS was similar among patients treated with pembrolizumab-based chemoimmunotherapy and pembrolizumab monotherapy, while patients treated with pembrolizumab monotherapy had worse OS (log-rank p =.001, HR 2.7). PFS and OS were improved in patients with PD-L1 CPS > = 20 (PFS: log-rank p =.005, HR 0.50; OS: log-rank p =.04, HR 0.57). Patients with higher ECOG PS scores had worse PFS and OS (PFS, log-rank p =.004; OS, log-rank p = 6e-04). In multivariable analysis, ECOG PS2 was associated with worse PFS and OS. Conclusions: PFS in our real-world cohort was similar to the KEYNOTE-048 reference while OS was numerically inferior. A deeper understanding of clinical variables that might affect survival outcomes of patients with R/M HNSCC beyond ECOG PS and PD-L1 CPS is urgently needed. [ABSTRACT FROM AUTHOR]

The advent of deep learning algorithms for protein folding opened a new era in the ability of predicting and optimizing the function of proteins once the sequence is known. The task is more intricate when cofactors like metal ions or small ligands are essential to functioning. In this case, the combined use of traditional simulation methods based on interatomic force fields and deep learning predictions is mandatory. We use the example of [FeFe] hydrogenases, enzymes of unicellular algae promising for biotechnology applications to illustrate this situation. [FeFe] hydrogenase is an iron–sulfur protein that catalyzes the chemical reduction of protons dissolved in liquid water into molecular hydrogen as a gas. Hydrogen production efficiency and cell sensitivity to dioxygen are important parameters to optimize the industrial applications of biological hydrogen production. Both parameters are related to the organization of iron–sulfur clusters within protein domains. In this work, we propose possible three-dimensional structures of Chlorella vulgaris 211/11P [FeFe] hydrogenase, the sequence of which was extracted from the recently published genome of the given strain. Initial structural models are built using: (i) the deep learning algorithm AlphaFold; (ii) the homology modeling server SwissModel; (iii) a manual construction based on the best known bacterial crystal structure. Missing iron–sulfur clusters are included and microsecond-long molecular dynamics of initial structures embedded into the water solution environment were performed. Multiple-walkers metadynamics was also used to enhance the sampling of structures encompassing both functional and non-functional organizations of iron–sulfur clusters. The resulting structural model provided by deep learning is consistent with functional [FeFe] hydrogenase characterized by peculiar interactions between cofactors and the protein matrix. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) treatment has recently been revolutionized by the introduction of newer targeted agents, that helped tailoring therapies around the single patient. Along with increased survival rates, a careful evaluation of diet, lifestyle habits, physical activity, emotional and psychological experiences linked to the treatment journey, is now mandatory. However, a true proposal for an omnicomprehensive and "integrative" approach is still lacking in literature. Methods: A scientific board of internationally recognized specialists throughout different disciplines designed a shared proposal of holistic approach for BC patients. Results: A narrative review, containing information on BC treatment, endocrinological and diet aspects, physical activity, rehabilitation, integrative medicine, and digital narrative medicine, was developed. Conclusions: In the context of a patient-centered care, BC treatment cannot be separated from a patient's long-term follow-up and care, and an organized interdisciplinary collaboration is the future in this disease's cure, to make sure that our patients will live longer and better. Trial Registration: NCT05893368: New Model for Integrating Person-based Care (PbC) in the Treatment of Advanced HER2-negative Breast Cancer (PERGIQUAL). Registration date: 29th May 2023. [ABSTRACT FROM AUTHOR]

The oral microbiome represents an essential component of the oral ecosystem whose symbiotic relationship contributes to health maintenance. The biofilm represents a state of living of microorganisms surrounding themselves with a complex and tridimensional organized polymeric support and defense matrix. The substrates where the oral biofilm adhere can suffer from damages due to the microbial community metabolisms. Therefore, microbial biofilm represents the main etiological factor of the two pathologies of dental interest with the highest incidence, such as carious pathology and periodontal pathology. The study, analysis, and understanding of the characteristics of the biofilm, starting from the macroscopic structure up to the microscopic architecture, appear essential. This review examined the morphological methods used through the years to identify species, adhesion mechanisms that contribute to biofilm formation and stability, and how the action of microbicidal molecules is effective against pathological biofilm. Microscopy is the primary technique for the morphological characterization of biofilm. Light microscopy, which includes the stereomicroscope and confocal laser microscopy (CLSM), allows the visualization of microbial communities in their natural state, providing valuable information on the spatial arrangement of different microorganisms within the biofilm and revealing microbial diversity in the biofilm matrix. The stereomicroscope provides a three-dimensional view of the sample, allowing detailed observation of the structure, thickness, morphology, and distribution of the various species in the biofilm while CLSM provides information on its three-dimensional architecture, microbial composition, and dynamic development. Electron microscopy, scanning (SEM) or transmission (TEM), allows the high-resolution investigation of the architecture of the biofilm, analyzing the bacterial population, the extracellular polymeric matrix (EPS), and the mechanisms of the physical and chemical forces that contribute to the adhesion of the biofilm to the substrates, on a nanometric scale. More advanced microscopic methodologies, such as scanning transmission electron microscopy (STEM), high-resolution transmission electron microscopy (HR-TEM), and correlative microscopy, have enabled the evaluation of antibacterial treatments, due to the potential to reveal the efficacy of different molecules in breaking down the biofilm. In conclusion, evidence based on scientific literature shows that established microscopic methods represent the most common tools used to characterize biofilm and its morphology in oral microbiology. Further protocols and studies on the application of advanced microscopic techniques are needed to obtain precise details on the microbiological and pathological aspects of oral biofilm. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137+ Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1+)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137+ Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers. Methods: The levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137+ Tcell subsets also combined with CD3+, CD8+, PD1+, and Ki67+ markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS. The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients). Results: In both groups of patients, high levels of circulating CD137+ and CD137+PD1+ T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1+)-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137+ Tcells or PMN(Lox1+)-MDSC/CD137+ Tcells was higher in non-responding patients and was associated with poor survival. CD137+ Tcells and Tregs resulted as two positive independent prognostic factors. Conclusion: High levels of CD137+, CD137+PD1+ Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137+ Tcells and Tregs also as Treg/CD137+ T cells ratio it is possible to identify naive patients with longer survival. [ABSTRACT FROM AUTHOR]

Background Trastuzumab deruxtecan (T-DXd) demonstrated unprecedented efficacy in patients with pretreated HER2+ metastatic breast cancer (mBC). However, few data are available about its efficacy in routine clinical practice. In this multicenter retrospective study, we examined effectiveness and safety of T-DXd in a real-world population. Methods Clinico-pathological information about patients with HER2+ mBC who received T-DXd were collected from 12 Italian hospitals. HER2 status was determined locally. Patients who received at least one administration of T-DXd, as any therapy line for advanced disease were included in the analysis. The primary endpoint was real-word PFS (rwPFS). Results One hundred and forty-three patients were included. Median age was 66 (range: 37-90), and 4 men were included. Hormone receptor (HR) status was positive in 108 (75%) patients and negative in 35(25%). T-DXd was administered as first, second, third, or subsequent lines in 4 (3%), 16 (11%), 42 (29%), and 81 (57%) patients, respectively. Among 123 patients with measurable disease, the ORR was 68%, and the DCR was 93% (9 CRs, 74 PRs, and 30 SD). Nine (7%) patients had a primary resistance to T-DXd. With a median follow-up of 12 months, the median rwPFS was 16 months. RwPFS was 84%, 59%, and 39% at 6, 12, and 18 months, respectively. A favorable trend in rwPFS was reported in patients receiving T-DXd as I/II line versus further lines (17 vs. 15 months; P  = .098). Any-grade toxicity was registered in 84 patients (59%). Most common adverse events (AEs) reported were nausea (33%), neutropenia (21%), and asthenia (21%). Liver toxicity and diarrhea were uncommon (5% and 1%). Severe toxicities was registered in 18% of patients, and the most frequent were neutropenia, nausea/vomiting, and ILD observed in 15, 2, and 3 patients. AEs led to dose reduction in 37 patients (26%). Dose reduction and AEs do not affect patients' response and survival outcomes. Conclusions Efficacy and safety of T-DXd were confirmed in an unselected real-world population of HER2+ mBC. These results are consistent with the results of known findings, and no new safety concerns were reported. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a highly complex structure through which biochemical and mechanical signals are transmitted. In processes of cell migration, the ECM also acts as a scaffold, providing structural support to cells as well as points of potential attachment. Although the ECM is a well-studied structure, its role inmany biological processes remains difficult to investigate comprehensively due to its complexity and structural variation within an organism. In tandem with experiments, mathematical models are helpful in refining and testing hypotheses, generating predictions, and exploring conditions outside the scope of experiments. Such models can be combined and calibrated with in vivo and in vitro data to identify critical cell-ECM interactions that drive developmental and homeostatic processes, or the progression of diseases. In this review, we focus on mathematical and computational models of the ECM in processes such as cell migration including cancer metastasis, and in tissue structure and morphogenesis. By highlighting the predictive power of these models, we aim to help bridge the gap between experimental and computational approaches to studying the ECM and to provide guidance on selecting an appropriate model framework to complement corresponding experimental studies. [ABSTRACT FROM AUTHOR]

In a recent non-destructive analytical campaign at Museo Civico, Castello Ursino, in Catania, Italy, several paintings in the permanent collection were investigated by MA-XRF scanning, with a special focus on Matthias Stomer's production. On one depiction of the Mocking of Christ (ca. 1640) donated to the municipality of Catania by G.B. Finocchiaro in 1826, the analysis documented the use of Naples yellow. Sb with Pb was detected in yellow areas of the Mocking of Christ, but not in his work Tobias healing his father. This finding possibly suggested an early use of lead antimonate yellow in South Italy, although it is generally accepted that this pigment was introduced in painting in the eighteenth century. Further details on his technique and later conservation treatments are provided, as well as literary comparisons with the artistic production during the same period, in Sicily and elsewhere. A systematic study of Stomer's works, for example examining paintings produced while he was in Naples or Rome, might determine whether this material choice depended on local availability. Overall, it would shed light on his technique, as well as on the history of Naples yellow in southern Italy and beyond, before this pigment became so popular in the eighteenth century. [ABSTRACT FROM AUTHOR]

Simple Summary: The evaluation of additional body composition measures, such as visceral adipose tissue area, subcutaneous adipose tissue area, and sarcopenic obesity, could be useful to improve our understanding of the prognostic role of body composition parameters in women with breast cancer. The aim of our review was to summarize current evidence about sarcopenia in non-metastatic as well as metastatic breast cancer (MBC) and to identify any correlation between sarcopenia and patient outcomes. We observed a correlation between sarcopenia and significantly higher rates of treatment-related toxicities in both settings (metastatic and non-metastatic) compared with patients without sarcopenia. It was found that sarcopenic patients were more likely to deal with severe toxicities compared to patients classified as non-sarcopenic. This finding suggests that sarcopenia recently emerged as a new condition that, independently from malnutrition, may adversely affect patient outcomes and may be used as a reference for chemotherapy dose selection to better balance individual pharmacokinetic differences. (1) Background: We estimated the prevalence and clinical outcomes of sarcopenia among breast cancer patients. (2) Methods: A systematic literature search was carried out for the period between July 2023 and October 2023. Studies with breast cancer patients evaluated for sarcopenia in relation to overall survival (OS), progression-free survival (PFS), relapse of disease (DFS), pathological complete response (pCR), or toxicity to chemotherapy were included. (3) Results: Out of 359 screened studies, 16 were eligible for meta-analysis, including 6130 patients, of whom 5284 with non-MBC. Sarcopenia was evaluated with the computed tomography (CT) scan skeletal muscle index and, in two studies, with the dual-energy x-ray absorptiometry (DEXA) appendicular lean mass index. Using different classifications and cut-off points, overall, there were 2007 sarcopenic patients (33%), of whom 1901 (95%) presented with non-MBC. Sarcopenia was associated with a 33% and 29% higher risk of mortality and progression/relapse of disease, respectively. Sarcopenic patients were more likely to develop grade 3–4 toxicity (OR 3.58, 95% CI 2.11–6.06, p < 0.0001). In the neoadjuvant setting, a higher rate of pCR was observed among sarcopenic patients (49%) (OR 2.74, 95% CI 0.92–8.22). (4) Conclusions: Our meta-analysis confirms the correlation between sarcopenia and negative outcomes, especially in terms of higher toxicity. [ABSTRACT FROM AUTHOR]

We aim at investigating the association between subclinical autoimmunity and immune-related adverse events (irAEs) in a cohort of patients treated by immune checkpoint inhibitors for solid metastatic cancer. In the context of an oncology/rheumatology outpatient clinic, we evaluated patients treated with anti-PD-1 or anti-PD-L1. Before treatment, each patient underwent a physical evaluation and a blood sample to identify the presence of a set of autoantibodies. Indeed, all the patients were followed during treatment to identify irAEs and to assess the association with autoantibodies. Fifty-one patients (M/F 16/35; median age 70 years, IQR 16.5) were evaluated; 34.8% of patients showed ANA positivity, 6.5% ENA positivity (anti-SSA), 4.3% Ratest positivity, and 2.1% (one patient) ACPA positivity. During a median period of 21 months (IQR 38.75), 39.2% of patients developed irAEs. Musculo-skeletal manifestations, in particular arthritis, were the most frequent. We found a significant association between the positivity for ANA and the development of irAES (p = 0.03, RR 2.01, 95% CI 1.03–3.92). Furthermore, the progression-free survival was significantly longer in patients developing irAEs compared to those who are not experiencing these events (p = 0.007). This study underlines the potential role of ANA positivity as a predictive biomarker for the development of irAEs. [ABSTRACT FROM AUTHOR]

Objectives: The primary aim was to study upper incisor severe apical root resorption (RR) related to ectopic canine eruption and its association with timing of diagnosis and type of intervention conducted. The secondary aim was to correlate resorption with other dental anomalies. Materials and Methods: Digital journals and radiographic material of all ectopic maxillary canines registered in 2012 in the regional public paediatric dental clinics in the Council of Aarhus were inspected retrospectively. Data related to 10 variables were retrieved. Post‐treatment radiographs were used for evaluation of incisor RR. Results: A total of 260 ectopic maxillary canines were diagnosed in 2012. The majority were found in the 9‐13‐year‐old age group (0.8% prevalence within the total population). In all, 244 canines were assessed for eligibility and 181 had adequate final radiographs for evaluation of RR. Among ectopic maxillary canines, 9.4% caused severe incisor RR to neighbouring teeth. Timely palpation for canine eruption significantly reduced the odds for upper incisor resorption by 80%. Multiple regression showed that when the permanent canine cannot be palpated and the deciduous has been extracted, delaying the first X‐rays was associated with a 38% odds ratio increase for RR for each year of delay after the age of 10 years. No significant associations were found between incisor RR and intervention conducted or other dental anomalies. Conclusion: Palpation of erupting maxillary canines is crucial for timely diagnosis of ectopic eruption and initiation of treatment to avoid RR. If the canine cannot be palpated at 10 years of age, radiographic examination is highly recommendable. [ABSTRACT FROM AUTHOR]

Introduction: Vaginal cancer is a rare gynecologic malignancy. While in a localized disease, concurrent chemoradiation grants local control and better overall survival, in a metastatic setting, the management options are very limited. Furthermore, recurrent cervical, vulvar, and vaginal carcinomas notoriously develop resistance to treatment, and consequently, their prognosis is still poor. Case Presentation: We herein present the case of a woman with a nodal relapse of vaginal carcinoma, effectively treated with third-line immunotherapy. We will also provide a review of the literature on the new therapeutic strategies for advanced vaginal carcinoma, with a focus on pembrolizumab immunotherapy. Conclusion: Pembrolizumab might represent a promising option for the management of vaginal and vulvar cancer, but data to support its use in this setting are still lacking. This case highlights the need for further investigation and trial designs for this rare disease. [ABSTRACT FROM AUTHOR]

With an ever-increasing number of reports denouncing systematic mistreatments against Uyghurs and other Muslim ethnic minorities detained in Xinjiang 're-education' camps, the time is ripe for the international community to explore possible judicial and quasi-judicial avenues to hold China to account. Excluding from the present analysis unilateral sanctions, as well as possible investigations and proceedings before international criminal tribunals, this article focuses on the role of inter-State human rights communications in securing justice. Given China's enduring reluctance to engage in dispute settlement mechanisms – particularly by formulating reservations to compromissory clauses enshrined in human rights treaties –, the quest for accountability poses significant challenges. By broadening the inquiry to alternative avenues, such as the inter-State quasi-judicial communication procedure under both the ICERD and the ILO's Constitution, as well as addressing the feasibility of requesting an ICJ's advisory opinion as an inter-State case in disguise, it is still possible to envisage narrow pathways that might be worth pursuing. [ABSTRACT FROM AUTHOR]

Background: Xenogenous bone has been proposed as an alternative to overcome the disadvantages of autogenous grafting. The aim of the present study was to study bone dynamics at inlay and onlay xenografts used for bone augmentation applying a ring technique. Methods: The bone at the lateral surface of the mandibular angle of 12 adult male New Zealand White rabbits was exposed bilaterally. The cortical layer received multiple perforations on one side of the mandible, and a xenograft block of collagenated cancellous equine bone, 7 mm in diameter and 3 mm in width, was fixed on the prepared surface using an implant (onlay group). On the opposite side, a defect 7 mm in diameter and 3 mm in depth was prepared, and the xenograft block was adapted to the defect and fixed with an implant (inlay group). Results: After ten weeks of healing, in the onlay grafts, new bone was mainly formed on the trabeculae surface, reaching in some specimens the most coronal regions of the block. In the inlay grafts, new bone was found arranged on the trabecular surfaces but also occupying the spaces among the trabeculae. The entrance of the defect was often found close to the top of the block by newly formed bone. A higher percentage of new bone was found in the inlay (19.0 ± 9.3%) compared to the onlay (10.4 ± 7.4%) groups (p = 0.031). The mean gain in osseointegration at the implant in relation to the base of the original 3 mm deep defect was 0.95 ± 1.05% in the onlay group and 0.78 ± 0.71% in the inlay group (p = 0.603). Conclusion: The inlay grafts exhibited a higher new bone percentage than the onlay block grafts possibly due to the defect conformation that presented more sources for bone growth. The trabecular conformation and the composition of the grafts made possible the expression of the osteoconductive properties of the material used. This resulted, in several specimens, in the growth of bone on the graft trabeculae toward the most superior regions in both groups and in the closure of the coronal entrance of the defects in the inlay group. The clinical relevance of this experiment is that the ring technique applied as an inlay method could be suitable for bone augmentation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression and localization of Vasorin (Vasn) in human female reproductive system. Methods: The presence of Vasorin was evaluated by RT-PCR and immunoblotting analyses in patient-derived endometrial, myometrial and granulosa cells (GCs) primary cultures. Immunostaining analyses were performed to detect Vasn localization in primary cultures and in ovarian and uterine tissues. Results: Vasn mRNA was detected in patient-derived endometrial, myometrial and GCs primary cultures without significant differences at the transcript level. Otherwise, immunoblotting analysis showed that Vasn protein levels were significantly higher in GCs than proliferative endometrial stromal cells (ESCs) and myometrial cells. Immunohistochemistry performed in ovarian tissues revealed that Vasn was expressed in the GCs of ovarian follicles at different stages of development with a higher immunostaining signal in mature ovarian follicles such as the antral follicle or on the surface of cumulus oophorus cells than in early-stage follicles. The immunostaining of uterine tissues showed that Vasn was expressed in the proliferative stroma endometrium while it was significantly less expressed in the secretory endometrium. Conversely, no protein immunoreactivity was revealed in health myometrial tissue. Conclusions: Our results revealed the presence of Vasn in the ovary and the endometrium. The pattern of Vasn expression and distribution suggests that this protein may have a role in the regulation of processes such as folliculogenesis, oocyte maturation, and endometrial proliferation. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic breast cancer patients are the most prevalent oncology population with advanced disease facing COVID-19 pandemic. Immune responses after mRNA-based vaccination during treatment with CDK4/6 inhibitors or HER2-directed agents remain unclear. We conducted a prospective analysis to elucidate changes in antibody titers and lymphocyte counts following full course of mRNA-BNT162b2 (tozinameran) vaccination in recipients undergoing these targeted therapies. Methods: Patients who had received a booster dosing and had been treated for at least 6 months were eligible. Antibody titers against SARS-CoV-2 spike protein were measured at four subsequent time points. Immunophenotyping of circulating lymphocytes was performed before the third dose of tozinameran and four weeks later to quantify the absolute counts of CD3+CD4+ T-helper cells, CD3+CD8+ T-cytotoxic cells, CD19+ B cells, and CD56+CD16+ NK cells. We also assessed the incidence of breakthrough infections and investigated whether immune changes affect time-to-treatment failure (TTF) after booster vaccination. Results: The current analysis included 69 patients, of whom 38 (55%) and 31 (45%) were being treated with CDK4/6 inhibitors and HER2-targeted therapies, respectively. All participants received a third dose of tozinameran between September 23 and October 7, 2021. Multivariate analysis revealed that CDK4/6 inhibition predicted a significantly impaired humoral response after the booster dose. This detrimental effect was also evident for T-helper cell counts before the third immunization, but it disappeared in the subsequent evaluation. After a median follow-up of 22.3 months, we observed 19 (26%) cases of COVID-19 outbreaks, all experiencing favorable clinical outcomes. Univariate analysis showed a significant association between the onset of SARS-CoV-2 infections and the use of CDK4/6 inhibitors, as well as with an impaired antibody and T- helper cell response. Only the last two covariates remained independent predictors after multivariate testing. Dynamic variations in antibody titers and T-helper cell counts did not affect TTF in multivariate regression analysis. Conclusions: Our results confirm that the immune response to tozinameran is impaired by CDK4/6 inhibitors, increasing the odds of breakthrough infections despite the third vaccine dose. Current evidence recommends maintaining efforts to provide booster immunizations to the most vulnerable cancer patients, including those with advanced breast cancer undergoing CDK4/6 inhibition. [ABSTRACT FROM AUTHOR]

Purpose: To examine the reaction of mucosa over time to a close contact with biomaterial after sinus elevation performed with deproteinized bovine bone mineral (DBBM) granules of two different sizes. Materials and Methods: Bilateral sinus mucosa elevation was performed in 18 New Zealand rabbits through access on the nasal dorsum. DBBM with granule dimensions of either 1 to 2 mm (large group) or 0.250 to 1.0 mm (small group) were used to randomly fill the subantral hollow spaces. Biopsy specimens of the experimental sites from six animals in each group were obtained 2, 4, and 8 weeks after the surgery. Results: The integrity of the sinus mucosa was clinically evaluated during surgery using a ×2.5 magnifying visual device. The sinus mucosa in contact with the biomaterial granules was found to be thinned compared with the pristine mucosa in all periods examined. Three hundred fifty-two thinned zones were found considering all 36 sinuses treated. Perforations of the sinus mucosa with extrusion of granules toward the sinus were observed, increasing in number over time. In the 8-week healing period, five perforations in three sinuses and eight perforations in four sinuses were found in the large and small groups, respectively. No differences were seen between the large and small groups. The differences between 2 and 8 weeks were statistically significant for the thinned mucosa width in both the large and the small groups and for the number of sinuses and perforations for the small group. Conclusion: Thinning zones and perforations of the sinus mucosa were seen increasing in number over time in regions in contact with graft granules in both the large and small groups. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact on healing of bioactivation with argon plasma of a xenogeneic graft with adequate fixation but poor adaptation to the native host bone. Materials and Methods: Xenogeneic grafts were either treated with argon plasma or left untreated and randomly secured with a titanium screw to both lateral aspects of the mandible angle of rabbits. A discrepancy was obtained between the xenograft and the mandible due to the convexity of the recipient site. Collagen membranes were placed on the grafts. Thirty animals were included and euthanized in groups of 10 after 2, 6, and 10 weeks, respectively. Histomorphometric evaluations were performed on ground sections. Newly formed bone was the primary outcome, while the distance between the peak of new bone inside the graft and the upper surface of the graft, the xenograft percentages, and the area of the xenograft were considered as secondary variables. The Wilcoxon test was applied for statistical analyses. Results: After 2 weeks of healing, gaps of ~0.5 mm were observed at the interface between the graft and the recipient sites, and new bone was mainly located in the interface and within the inferior regions of the grafts. New bone increased over time in all regions, including those in the upper zones of the graft, reaching proportions of 20.3% ± 6.5% and 19.3% ± 7.4% (P = .484) after 10 weeks in the plasma and control groups, respectively. The mean distance between the peak of new bone inside the graft and the upper surface of the graft decreased between 2 and 10 weeks of healing from 1.4 mm to 0.4 mm and from 1.7 mm to 0.3 mm at the plasma and control sites, respectively. Conclusion: The xenogeneic grafts of both groups were incorporated into the recipient sites by newly formed bone that presented a growth close to the upper surface of the graft. The bioactivation with argon plasma did not improve healing. [ABSTRACT FROM AUTHOR]

Background: The conformation of the recipient site for an inlay graft presents an increased contact with the parent bone compared to an onlay graft. This might favor bone growth within the inlay compared to onlay grafts. Hence, the objective of this study was to compare the bone incorporation and remodeling processes of xenogeneic en bloc grafts placed using two bone grafting techniques, i.e., onlay vs. inlay. Methods: In this prospective, randomized, split-mouth study (test and control sides in the same animal), two bone grafting techniques were comparatively evaluated. The lateral aspect of the rabbit mandible was used as the recipient site, bilaterally. On one side of the mandible, the cortical bone was perforated with drills to allow a better bone formation from the bone wound and the marrow spaces. A xenogeneic bone block was fixed in the center of the prepared region, representing the onlay site. On the other side of the mandible, a 7 mm wide and 3 mm deep circumferential defect was prepared using trephines and drills. A xenogeneic bone block was fixed in the center of the defect, representing the inlay site. Two healing periods were applied in the study: 2 and 10 weeks, each represented by 10 rabbits (n = 10 for each period). Results: After 2 weeks of healing, the mean percentage of new bone was 10.4% and 23.3% at the onlay and inlay grafts, respectively (p = 0.022). After 10 weeks of healing, new bone increased to 13.2% at the onlay sites and 25.4% at the inlay sites (p = 0.080). In the 10-week period, the inlay grafts presented a homogeneous growth of new bone in all regions, while in the onlay grafts, low percentages of new bone were observed in the external regions. Conclusion: The percentage of new bone increased faster and was higher in the inlay grafts than in the onlay grafts. This outcome might be related to the self-contained conformation of the recipient site in the inlay group, which offered more sources for new bone formation compared to the one-wall conformation of the recipient sites in the onlay group. The osteoconductive properties of the biomaterial allowed the newly formed bone to reach the most peripheral regions in both groups. The osteoconductive properties of the biomaterial, together with the protection offered by the collagen membrane, allowed marginal closure of the defects by newly formed bone in the inlay group. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug–drug interactions (DDIs) risk is quite common, potentially significant, and often underestimated. In this context, an advanced DDI detection software (Drug-PIN, V. 2/23) was used to assess the DDIs in a retrospective cohort of 177 patients with metastatic BRAF-mutated cutaneous melanoma treated with BRAF and MEK inhibitors. Furthermore, we evaluated the impact of DDIs on the toxicity profile. Here, we report that the median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Moreover, DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Both Drug-PIN score (p = 0.0291) and traffic light (p = 0.00821) were significant predictors of cardiotoxicity onset. Our results suggest evaluating DDIs in the clinical practice of melanoma patients treated with BRAF/MEK inhibitors to reduce potentially avoidable toxicities and improve treatment tolerability and patients' quality of life. Background: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug–drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. Methods: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. Results: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). Conclusions: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors. [ABSTRACT FROM AUTHOR]

Background: Metastasis is the main cause of breast cancer (BC) mortality. Increasing evidence points to a role of syndecan-1 (CD138) expression as a prognostic marker involved in BC tissue and leptomeningeal metastasis. Aim of this study was to investigate and compare syndecan-1 tissue expression and localization in primary and secondary BC, focusing on brain metastases. Methods: Syndecan-1 expression was determined by immunohistochemistry. Focal vs diffuse (< or > 50% of cancer cells, respectively) pattern of expression, cellular localization (cytoplasm vs membrane) and intensity of immunostaining on neoplastic cells were evaluated. Moreover, the extent and pattern of expression of syndecan-1 were compared between primary tumors and paired metastases and correlated with the tumor intrinsic subtype. Results: A total of 23 cases, 10 with paired primary and metastatic tumor and 13 brain metastases, were evaluated. Syndecan-1 was expressed in both primary and metastatic BC. A diffuse cytoplasmic expression was observed in most primary BCs; by contrast, all metastatic lesions showed a membrane pattern of expression, suggesting a shift in cellular localization of syndecan-1 during the metastatic process. Concerning the extent of expression, we observed in metastatic lesions, a trend of association between intrinsic subtypes and extent of positivity. In particular, both BC characterized by overexpression of HER2 and triple-negative tumors were correlated with a diffuse pattern of expression with a moderate to strong intensity. Conclusion: A diffuse cytoplasmic expression was observed in most primary BCs; by contrast, all metastatic lesions showed a membrane pattern of expression, suggesting a shift in cellular localization of syndecan-1 during the metastatic process. [ABSTRACT FROM AUTHOR]

Orexin‐A and orexin‐B, also named hypocretin‐1 and hypocretin‐2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein‐coupled receptors, namely orexin receptor type 1 (OX1‐R) and type 2 (OX2‐R), which share 64% amino acid identity. Given the wide expression of OX‐Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep‐wake cycle regulation (mainly mediated by OX2‐R), emotion, panic‐like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1‐R), both subtypes represent targets of interest for many structure–activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual‐orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1‐R and OX2‐R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype‐selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1‐R/OX2‐R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX‐R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly‐pharmacology applications and multitarget ligands have also been considered. [ABSTRACT FROM AUTHOR]

Aim: To describe the histological events that occur after maxillary sinus floor elevation when the elevated and undetached sinus mucosa are in close proximity or in contact with each other. Materials and methods: From 76 rabbits, 152 elevated maxillary sinuses were analyzed histologically. Sites without adhesions were classified as "No proximity," whereas the adhesion stages were divided into "Proximity," "Fusion," and "Synechia stages." The width of the pseudostratified columnar epithelium and the distance between the two layers of the elevated and undetached sinus mucosae were measured at various standardized positions. Results: Thirty‐one sites presenting with adhesions were found. Twelve sites were in the proximity stage," presenting cilia of the two epithelial layers that were shortened and interlinked within the mucous context. Hyperactivity of the goblet cells was also observed. In the other cases, the hyperplastic epithelium showed attempts to reach the contralateral mucosa. The 15 "fusion stage" sites presented regions with epithelial cells of the two mucosal layers that penetrated each other. Four sites presented "synechiae stages," represented by bridges of connective tissue connecting the two lamina propria. Conclusions: Close proximity or tight contact between the elevated and undetached mucosa adhering to the bone walls might occur after maxillary sinus floor elevation. This induced hyperplasia of the epithelial cells and adhesion of the two layers until synechiae formation. [ABSTRACT FROM AUTHOR]

Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence. Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response. By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients. In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications. [ABSTRACT FROM AUTHOR]

Purpose: This 3-year study aimed to evaluate hard and soft tissue modification around a two-piece implant characterized by a transmucosal hyperbolic neck in healthy consecutive patients with a need for single-tooth replacement. Materials and Methods: Two-piece implants (n = 66) were placed with a flapless technique in 56 patients (27 men; 29 women; mean age 55 ± 9 years): 16 immediately after root extraction (immediate group), 20 after 8 to 12 weeks (early group), and 30 after 10 or more months (delayed group). The transmucosal hyperbolic neck was exposed 1 to 1.5 mm above gingival level. Customized abutments were positioned 3 months later with the implant-abutment connection located approximately 1 to 1.5 mm above soft tissue level. Provisional cemented resin crowns were designed with the finishing line at the hyperbolic neck and then positioned to avoid excessive compression of soft tissue, to guide gingival contours. Twenty days later, a definitive metal-ceramic crown was cemented. In all patients, the gingival biotype (thin or thick) was also evaluated. The primary outcomes were as follows: 36-month implant survival rate, peri-implant marginal bone level (MBL, in mm) changes observed in single-blind on radiographs at 1, 3, 6, 12, 24, and 36 months (T1, T3, T6, T12, T24, and T36), and pink esthetic score (PES) at T6, T12, and T36 to analyze soft tissue adaptation after loading and crown application. The secondary outcomes were as follows: plaque score and bleeding on probing (BOP). Linear regression models and multilevel mixed logistic regression were used to detect any statistical difference of MBL according to operative parameters. Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks was performed to assess statistical differences of PES at T6, T12, and T36. Results: The survival rate was 100%. The dropout rate was 1.79%. No infections, mucositis, or peri-implantitis were reported. Implants placed in thick-biotype tissues showed a statistically different lower bone loss at 36 months with respect to the thin biotype (P < .05). At 36 months, the early group showed lower bone loss compared with the delayed group (P < .05). Multilevel mixed logistic regression revealed that gingival biotype was the parameter that was most related to MBL variations (P = .025). The PES value (mean ± SD) at T6 was 10.76 ± 1.19 (median: 11; range: 8 to 13; IQR: 10 to 12). The values statistically increased at T12 and T36, where the mean values were 11.76 ± 1.10 (median: 12; range: 9 to 13; IQR: 11 to 12) and 11.83 ± 1.03 (median: 12; range: 9 to 14; IQR: 11 to 13). Conclusion: MBL and soft tissue clinical parameters measured around two-piece hyperbolic-neck implants were stable during the 3-year follow-up and free from complications. The exposure of the hyperbolic neck for 1.0 to 1.5 mm allowed a flapless one-stage surgery, which supported fast adaptation of the soft tissues, evidenced by high PES values and low percentages of BOP. The results from the study imply a new simple approach in the clinical management of gingival and bone tissue. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the influence on healing of the bony window elevated inward in the sinus cavity as a cortical bone graft. Materials and Methods: Eighteen rabbits were included in the experiment. At the test sites (bony window), the antrostomy was prepared and the remaining bony window was elevated together with the sinus mucosa. At the control sites, the bony window was gently detached before the sinus mucosa elevation and discarded. The space obtained was grafted with deproteinized bovine bone mineral (DBBM). A collagen membrane was positioned on the antrostomy at both sides. The rabbits were euthanized after 2, 4, and 8 weeks in groups of six each. Histologic analyses in different regions of the elevated space were carried out, and a Wilcoxon test was used to estimate differences. Microcomputed tomography (microCT) analyses were also performed. Results: After 2 weeks of healing, higher proportions of new bone were found in the test group compared with the control group due to the higher amount of bone formed in the region subjacent to the sinus mucosa. In this region, higher amounts of new bone were also found in the test group after 4 (P = .028) and 8 weeks of healing (P = .345). After 8 weeks of healing, the percentage of new bone was higher at the control sites compared with the test sites, with the proportions being 25.4% ± 3.2% and 21.3% ± 6.1%, respectively. In this period of evaluation, the bony window contributed with 20.1% ± 5.3% of vital bone in the test group. A fraction of 60.4% ± 10.8% of its surface was surrounded by new bone. In the microCT analysis, after 8 weeks of healing, fractions of 22.3% ± 1.6% and 22.2% ± 0.7% of bone were found in the test and control groups, respectively. Conclusion: The presence of the bony window positively influenced the healing in the elevated space, especially in the submucosa region. The bony window was vital and incorporated into newly formed bone. [ABSTRACT FROM AUTHOR]

Purpose: To compare the osseointegration at the portion of the implant within the elevated space after sinus elevation using different sizes of xenograft. Materials and Methods: Eighteen New Zealand rabbits were selected, antrostomies were prepared bilaterally through the nasal dorsum, and the sinus mucosa was elevated. Deproteinized bovine bone mineral with granules of either 1 to 2 mm (large sites) or 0.250 to 1.0 mm (small sites) were randomly used to fill the elevated space of the two sinuses. Subsequently, mini-implants were placed through the antrostomy, one in each sinus. The animals were euthanized 2, 4, and 8 weeks after surgery, six animals for each group. Microcomputed tomography (micro-CT) and histologic analyses were performed. Results: In the elevated space, at the histologic analysis after 2 weeks of healing, new bone formed on the implant surface was found in fractions of 18.8% ± 6.8% and 15.8% ± 9.6% in the large and small sites, respectively (P = .249). After 4 weeks, the respective fractions of new bone were 20.3% ± 3.5% and 23.3% ± 5.6% (P = .249). After 8 weeks, the proportions reached 33.9% ± 9.5% and 28.5% ± 10.3% (P = .173), respectively. At the micro-CT analysis, bone-to-implant contact percentage (BIC%) was 21.0% ± 2.3% and 21.2% ± 2.4% in the large and small sites, respectively (P = 1.000). The respective proportions of BIC% at the large and small sites were 20.5% ± 3.3% and 23.4% ± 5.4% after 4 weeks (P = .463), and 23.0% ± 2.7% and 25.8% ± 4.1% after 8 weeks (P = .249). Conclusion: The use of xenograft granules of different dimensions resulted in similar amounts of bone-to-implant contact at implants placed simultaneously with sinus floor augmentation. [ABSTRACT FROM AUTHOR]

To evaluate the osseointegration of mini-implants placed in grafted sinuses with lateral windows of two different dimensions. Materials and Methods: Sinus floor augmentation was performed in volunteers using a lateral window. The antrostomy was systematically prepared with a height of either 8 mm (large group) or 4 mm (small group). After 6 months of healing, mini-implants were placed in the grafted region. Biopsy specimens including the mini-implants were harvested 3 months after placement. Results: Twenty biopsy specimens, 10 from each group, were suitable for the histologic analysis. Similar amounts of new bone-to-implant contact were obtained in both the large (41.1% ± 19.5%) and the small (42.8% ± 13.2%) groups (P = .940). Small percentages of residues of xenograft were found in contact with the implant surface, with 0.6% ± 1.1% in the large group and 5.9% ± 9.5% in the small group (P = .098). The new bone density around the implants was 31.7% ± 8.2% and 34.0% ± 7.9% in the large and small groups, respectively (P = .623).Conclusion: The dimensions of the antrostomy did not influence the histologic healing of implants placed 6 months after sinus floor augmentation. [ABSTRACT FROM AUTHOR]