Dorsal Preservation Rhinoplasty Using a Ferreira-Nakamura Spare Roof Technique B Highlighting the Low Septal Cartilage Strip.

Dorsal preservation rhinoplasty techniques can be surface or foundation techniques and respect the philosophy of preserving the osteocartilaginous nasal vault. A spare roof technique (SRT) aims to preserve the upper lateral cartilages through surface techniques. In tension noses with considerable caudal septum deviations, the septal can be repositioned after a low strip of septal cartilage is removed, and the SRT-B is used to reduce the osteocartilaginous hump. This inclusion of the low septal cartilage strip in the SRT-B rhinoplasty is termed as SRT-B3 and builds upon the previously reported philosophy advocated in SRT-A and SRT-B. Correction of moderate deviations of the nasal axis and/or the caudal septum can be addressed with this modification.

An Innovative Treatment Using Calcium Hydroxyapatite for Non-Surgical Facial Rejuvenation: The Vectorial-Lift Technique.

BACKGROUND: The facial aging process entails alterations in the volume, shape, and texture of all skin layers over time. Calcium hydroxyapatite (CaHA) is a well-established safe skin filler with unique properties to resolve some skin alterations by stimulating neocollagenesis. The vectoral-lift (V-lift) technique targets the global repositioning of facial structures by addressing distinct anatomical injection planes. It includes deep facial augmentation with Radiesse PlusTM to retain ligament restructuring and superficial subcutaneous enhancement with diluted Radiesse DuoTM. Herein, we present cases that illustrate the use of this approach. METHODS: This pilot study enrolled 36 participants (33 women and three men; ages 37-68 years) in a Brazilian clinical setting, and all patients underwent a single treatment. Photographs were taken at rest, in frontal and oblique views, before injection, and 90 days after treatment. RESULTS: Treatment resulted in elevation of the upper and middle face, notable improvements in the infraorbital hollow, and adjustment of the mean facial volume. CONCLUSIONS: The V-lift technique is a three-dimensional pan-facial treatment that relies on ligament support and face vectoring to obtain a lifting effect and facial contour restoration. It encompasses deep facial augmentation involving the use of Radiesse PlusTM for restructuring and retaining ligaments and Radiesse DuoTM for superficial subcutaneous enhancement. This approach targets a global repositioning of the facial structures by addressing distinct anatomical injection planes. It achieves a repositioning of the overall facial anatomy without requiring a substantial volumetric expansion. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Advanced Injection of Botulinum Toxin in the Nasal Muscles: A Novel Dynamic Change in Facial Expression.

BACKGROUND: Among the nasal muscles, the levator labii superior alaeque nasi (LLSAN) acts as a transitional muscle that conjugates with other nasal and perinasal muscles. Thus, when treating the nasal region with Botulinum toxin (BTX), it is important to understand local nasal muscular dynamics and how they can influence the muscular dynamics of the entire face. METHODS: This is a retrospective analysis of cases treated by an injection pattern encompassing the face, including nasal muscles. Photographs were taken at rest and during motion (frontal and oblique views), before and after treatment. RESULTS: A total of 227 patients have been treated in the last 18 months with the following results: eyebrow tail lifting, softness of crow's feet, improvement of the drooping of the tip of the nose, and shortening of the lip philtrum when smiling. We present cases illustrating the use of this approach. CONCLUSIONS: Treating the facial muscles globally (including the frontal, corrugators, procerus, orbicularis oculi, platysma, DAO, and nasal muscles) can improve the smile and facial expressions. This is believed to occur because the elevated portion of the upper lip muscle becomes stronger as the nasal part of the LLSAN is paralyzed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Experimental Estimation of Lamb Wave Dispersion Curves for Adhesively Bonded Aluminum Plates, Using Two Adjacent Signals.

In this study, dispersion curve estimation of a bonded aluminum plate is carried out by proposing a specific signal processing procedure. In this proposed method, the angle beam ultrasonic transducer measurement system in a pitch-catch configuration is used to acquire Lamb wave signals from two adjacent positions. The obtained signals are processed then by using signal processing techniques, including bandpass filters, fast Fourier transform (FFT), and bandpass Gaussian filters. Various transmitted signals with different central frequencies are used to estimate four modes of the utilized bonded specimen for frequencies less than 1 MHz. The dispersion curve results in terms of phase velocity and wavenumbers are compared with theoretical dispersion curves and 2-D FFT. This comparison is carried out by using three different metrics, which shows the maximum mean relative error of 3.46% with low variance.

Noncanonical roles of p53 in cancer stemness and their implications in sarcomas.

Impairment of the prominent tumor suppressor p53, well known for its canonical role as the "guardian of the genome", is found in almost half of human cancers. More recently, p53 has been suggested to be a crucial regulator of stemness, orchestrating the differentiation of embryonal and adult stem cells, suppressing reprogramming into induced pluripotent stem cells, or inhibiting cancer stemness (i.e., cancer stem cells, CSCs), which underlies the development of therapy-resistant tumors. This review addresses these noncanonical roles of p53 and their implications in sarcoma initiation and progression. Indeed, dysregulation of p53 family proteins is a common event in sarcomas and is associated with poor survival. Additionally, emerging studies have demonstrated that loss of wild-type p53 activity hinders the terminal differentiation of mesenchymal stem cells and leads to the development of aggressive sarcomas. This review summarizes recent findings on the roles of aberrant p53 in sarcoma development and stemness and further describes therapeutic approaches to restore normal p53 activity as a promising anti-CSC strategy to treat refractory sarcomas.

Structural and Drug Targeting Insights on Mutant p53.

p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.

A Diarylpentanoid with Potential Activation of the p53 Pathway: Combination of in silico Screening Studies, Synthesis, and Biological Activity Evaluation.

In silico studies of a library of diarylpentanoids led us to the identification of potential new MDM2/X ligands. The diarylpentanoids with the best docking scores obeying the druglikeness and ADMET prediction properties were subsequently synthesized and evaluated for their antiproliferative activity on colon cancer HCT116 and fibroblasts HFF-1 cells. The effect on p53-MDM2/X interactions was evaluated through yeast-based assays for compounds showing potent antiproliferative activity in HCT116 cells and low toxicity in normal cells, resulting in the identification of a potential dual inhibitor. Moreover, its antiproliferative effect was significantly reduced in the absence of p53 and in MDA-MB-231 cells expressing a mutant p53 form. The antiproliferative effect of this compound was associated with induction of cell cycle arrest, apoptosis, PARP cleavage and increased p53 and its transcriptional targets, p21 and PUMA, in HCT116 cells. Docking poses and residues involved in the inhibition of p53-MDM2/X interactions were predicted by docking studies.

A selective p53 activator and anticancer agent to improve colorectal cancer therapy.

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.

Management of Patients Seeking Surgical Rhinoplasty with Previous Nasal Injections of Hyaluronic Acid.

BACKGROUND: Patients are looking for procedures which are minimally invasive and consequently incur minimal downtime. However, these procedures are not usually long lasting and have limited outcomes both esthetically and functionally. For these reasons, the number of patients seeking surgical rhinoplasty and who have previous nasally injected hyaluronic acid is increasing. METHODS: The aim of this article is to provide the surgeon with information for both the identification and surgical approach for those patients who seek nasal cosmetic surgery, and who have previously been treated with nasal injections of hyaluronic acid filler. RESULTS: We present cases that illustrate the use of this approach and suggest three possible patient management. CONCLUSIONS: There are three possible approaches: wait HA to be naturally reabsorbed; apply hyaluronidase before the surgery or proceed to rhinoplasty with no prior application of hyaluronidase. The physician must be aware of this progression and know how to manage each case to optimize the surgical outcome. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .

Outcome of Free Diced Cartilage Grafts in Rhinoplasty: A Systematic Review.

Diced cartilage grafts are used to increase and refine the nasal contour, providing easy molding and versatility when compared with block grafts. However, all grafts present the possibility of visibility, distortion, and absorption. The aim of this study is to evaluate, through a systematic review, the outcome of the use of the free diced graft cartilage in rhinoplasty. A systematic search of the literature was performed in the databases (PubMed, Lilacs, Scielo, Cochrane) with the terms "diced cartilage" and "rhinoplasty." Studies were selected according to the inclusion and exclusion criteria and data extracted and grouped for analysis. Six eligible studies were included. In total, 4,044 patients underwent rhinoplasty with free diced cartilage graft, with 61 (1.51%) of them requiring reoperation. The main reasons were overcorrection and irregularities of the nasal dorsum. The infection rate was reported in three studies, with 2 (0.06%) of 3,252 patients presenting infection at the graft site. Two cases of displacement were treated with external molding, without reoperation. The graft resorption was reported in four articles, which described 22 (0.67%) cases of partial resorption in 3,288 patients. Therefore, the available evidence suggests that resorption of the graft and unfavorable outcomes are rare.

p73: From the p53 shadow to a major pharmacological target in anticancer therapy.

p73, along with p53 and p63, belongs to the p53 family of transcription factors. Besides the p53-like tumor suppressive activities, p73 has unique roles, namely in neuronal development and differentiation. In addition, the TP73 gene is rarely mutated in tumors. This makes p73 a highly appealing therapeutic target, particularly towards cancers with a null or disrupted p53 pathway. Distinct isoforms are transcribed from the TP73 locus either with (TAp73) and without (ΔNp73) the N-terminal transactivation domain. Conversely to TA tumor suppressors, ΔN proteins exhibit oncogenic properties by inhibiting p53 and TA protein functions. As such, p73 isoforms compose a puzzled and challenging regulatory pathway. This state-of-the-art review affords an update overview on p73 structure, biological functions and pharmacological regulation. Importantly, it addresses the relevance of p73 isoforms in carcinogenesis, highlighting their potential as drug targets in anticancer therapy. A critical discussion of major pharmacological approaches to promote p73 tumor suppressive activities, with relevant survival outcomes for cancer patients, is also provided.

Hyaluronic Acid Filler in the Treatment for Drooping Tip: Anatomical Concepts and Clinical Results.

The plunging nasal tip is a challenging condition because, although it is predominantly a dynamic deformity which occurs during smiling, it also indicates a structural problem. When a person smiles, the paired depressor septi nasi muscles pull the tip caudally at the same time as the levator labii superioris alaeque nasi muscles pull the alar base and lateral lip cephalically. This movement causes straightening of the alar rim. Even though surgical rhinoplasty is the gold standard to restore nasal appearance, the procedure may fail to treat the dynamic cause of the drooping tip. This article outlines the anatomical concepts that lead to a drooping tip and presents a technique that can treat both the dynamic and structural causes of the drooping tip using hyaluronic acid filler. Cases are also presented that illustrate these concepts. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

BRCA1/P53: Two strengths in cancer chemoprevention.

Increasing emphasis has been given to prevention as a feasible approach to reduce the cancer burden. However, for its clinical success, further advances are required to identify effective chemopreventive agents. This review affords a critical and up-to-date discussion of issues related to cancer prevention, including an in-depth knowledge on BRCA1 and p53 tumor suppressor proteins as key molecular players. Indeed, it compiles the most recent advances on the topic, highlighting the unique potential of BRCA1 and p53 germline mutations as molecular biomarkers for risk assessment and targets for chemoprevention. Relevant evidences are herein provided supporting the effectiveness of distinct pharmacological agents in cancer prevention, by targeting BRCA1 and p53. Moreover, the rationale for using germline mutant BRCA1- or p53-related cancer syndromes as model systems to investigate effective chemopreventive agents is also addressed. Altogether, this work provides an innovative conception about the dependence on p53 and BRCA1 co-inactivation in tumor formation and development, emphasizing the relationship between these two proteins as an encouraging direction for future personalized pharmacological interventions in cancer prevention.

SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner.

The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination.

SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations.

BACKGROUND: Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. METHODS AND RESULTS: By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. CONCLUSIONS: SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. GENERAL SIGNIFICANCE: This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.

SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma.

Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

Effects of diode laser setting for laryngeal surgery in a rabbit model.

PURPOSE: To study the damaging effect of different diode laser settings on vocal folds 7 days after injury in a rabbit model. METHODS: Twenty-one male New Zealand white rabbits were randomized into three groups with seven animals per group. A 980-nm diode laser was used to create a single spot injury in each vocal fold. Different modulation frequencies (10 Hz versus 1000 Hz) in pulsed mode, different powers (3 W versus 5 W), and distinct wave modes of radiation (pulsed versus continuous) were compared. RESULTS: The extent of the inflammatory infiltrate and ablation crater were greater when using 5-W optical power compared with 3 W. The extent and depth of the inflammatory infiltrate, and the width and depth of the ablation crater were greater with continuous wave mode compared with pulsed mode. The density of collagen fibers only increased when using the laser in continuous wave mode. CONCLUSION: The use of the 980-nm diode laser with an output power of 5 W produced an increased extent of thermal injury compared to an output power of 3 W and, more importantly, using continuous rather than pulsed wave mode significantly increased the extent and depth of thermal injury in rabbit vocal folds.

New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma.

TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.

p53 and glucose metabolism: an orchestra to be directed in cancer therapy.

Metabolic reprogramming is a hallmark of cancer with a strong impact on tumor cell survival, proliferation, dissemination, and resistance to therapy. As such, it has represented a promising therapeutic target for cancer. Although cancer cells may exhibit a wide range of metabolic profiles, the enhancement of aerobic glycolysis to generate lactate and ATP (Warburg effect) is a cancer-associated trait, which is under regulation of both oncogenes and tumor suppressor genes. Particularly, the tumor suppressor protein p53 was shown to revert the Warburg effect, and to negatively influence the oncogenic metabolic adaption of cancer cells. This review provides a systematization of the p53 influence on glycolysis and oxidative phosphorylation (OXPHOS), giving attention to the interplay of p53 with key signaling pathways, including c-Myc, HIF-1, LKB1/AMPK, and PI3K/Akt, as well as to mutant p53 gain-of-function. It also contributes to a better understanding of distinct metabolic profiles in heterogeneous tumor cell populations, and of its impact on cancer therapeutic resistance. Additionally, a reflection on current strategies adopted in clinical trials to overcome therapeutic resistance is presented, highlighting the main limitations and future therapeutic perspectives based on metabolic reprogramming. In particular, this review emphasizes the p53 activation as a promising therapeutic strategy to reprogram tumor glucose metabolism, conducting to cell death. Moreover, potential synergisms between p53-activating agents and metabolic inhibitors are discussed, fostering the improvement of cancer therapy.