Inhibition of cancer stem cells promoted by Pimozide.

Over the past years, studies have described that users of antipsychotics are less likely to develop cancer than the population in general due to cytotoxic properties of this class of drugs on cancer cells. For this reason, Pimozide has been widely studied as a potential anticancer treatment, and satisfactory results in melanoma, central nervous system tumours, osteosarcoma, neuroblastoma, myeloproliferative neoplasms, breast, lung, prostate, ovarian, colorectal, pancreatic, and hepatocellular carcinoma have been showed. Moreover, advantages as clinical use approved by the Food and Drug Administration (FDA), high clinical safety, low side effects, and reasonable price have stimulated the treatment with Pimozide instead of other agents. The action mechanism remains unclear, but three vias associated to cancer stem cell (CSC) hypothesis show that Pimozide: (a) blocks CSC features, as epithelial-to-mesenchymal transition (EMT), through inhibition of Wnt-ß/catenin signalling; (b) acts as an inhibitor of signal transducer and activator of transcription (STAT-3 and 5), pathway which is activated and up-regulated in CSCs; (c) inhibits ubiquitine specific protease (USP1) and WD repeat-containing protein 48 (WDR48), that are proteins responsible to inhibit the differentiation and to maintain the cell in an undifferentiated state. Based on this perspective, the aim of this manuscript is to review the antineoplastic role of Pimozide during tumorigenesis and its potential to revert the process of undifferentiation and proliferation of CSC through different vias.

Primary intraosseous carcinoma of the maxilla arising from an odontogenic keratocyst: a case report and review of the literature.

A 47-year-old man was referred for treatment of a painful lesion of 5 months' duration located on the left side of the maxilla. A small perforation in the buccal cortex was observed during the intraoral examination. Cone beam computed tomography (CBCT) showed an extensive, well-delimited radiolucent lesion extending from the alveolar ridge to the nasal cavity. An incisional biopsy was performed, and a cystic lesion consistent with an odontogenic keratocyst (OKC) was observed microscopically. The initial treatment option was decompression to be followed by enucleation. However, 3 months after decompression of the lesion, the patient returned because there was a significant increase in the size of the perforation. A destructive lytic lesion that involved the left side of the maxilla and crossed the midline was evident in the CBCT. The examination of a second incisional biopsy specimen showed epithelial neoplasia comprising islands and projections toward the surface. There was abundant keratin deposition, resulting in the formation of pearls and plugs. A diagnosis of primary intraosseous carcinoma arising from an OKC was confirmed, and the patient underwent a maxillectomy. After 1 year of follow-up, there were no signs of recurrence.

Pattern of grade C molar-incisor pattern periodontitis in families.

BACKGROUND: The aim of this study was to determine the clinical and inflammatory response patterns for individual siblings diagnosed with grade C molar-incisor pattern periodontitis (C-MIP) and between the related siblings within families. METHODS: Sixty-nine siblings within 28 families with moderate-to-severe C-MIP were included. Clinical parameters were evaluated for symmetry regarding the affected type of teeth, side and/or arch, and bone loss pattern. The protein concentrations from in vitro whole blood cultures for 14 different lipopolysaccharide-stimulated inflammatory markers were correlated with the extent and severity of disease, within an individual sibling and among siblings within a family. RESULTS: A similar disease pattern was observed among all siblings and within families. The most common teeth affected were first molars and incisors or first molars only within the permanent dentition and only molars within the primary dentition (p < 0.001). Symmetry involving molars was higher than in incisors in siblings, regardless of arch or side affected (p = 0.020). Arc-shape/vertical bone defects were the most common (p = 0.006) and higher symmetry was found for these defects in the permanent dentition (p = 0.005). Positive correlations were found between age, clinical attachment loss, and percent affected sites with several inflammatory markers. The inflammatory responses for several inflammatory markers were correlated within and among families (p < 0.050). Specifically, the intraclass correlation coefficient within families was highest (>0.5) for interleukin (IL)-8, IL-6, and IL-10. CONCLUSIONS: Families with C-MIP presented similar patterns of disease. The level of an inflammatory response to bacteria seemed to play a role in the extent and severity of this disease, exemplified by the high degree of correlation in these families.

The challenging diagnosis of low-grade myofibroblastic sarcoma: A case report and literature update.

Low-Grade Myofibroblastic sarcoma (LGMS) is categorized as an extremely rare malignant neoplasia of myofibroblasts, which has only recently become more widely studied. Our patient was referred for evaluation of a nodule involving the palate. The histopathological analysis showed a mesenchymal tumor formed for stellate-shaped cells. Negativity for Laminin, Desmin, Collagen IV, CK pool, CD34, S100, and ALK1, discarded epithelial, endothelial, neural, and inflammatory origin. On the other hand, the positivity for Calponin and SMA demonstrated myofibroblastic and smooth muscle differentiation. The diagnosis of LGMS was endorsed and the patient was submitted for medical treatment. To date, only 18 cases describing patients diagnosed with intrabuccal LGMS have been reported in the scientific literature. Here, we introduce a rare report and for the first time, also provide an update of the literature and a clear review regarding the immunohistochemical panel to diagnose this entity, once the histopathological diagnosis is still challenging.

Oral involvement of sinonasal undifferentiated carcinoma: A case report and immunohistochemical study of a challenging case.

INTRODUCTION: Sinonasal undifferentiated carcinoma (SNUC) is a rare tumor highly aggressive most frequently arise in the maxillary sinus and nasal cavity. Oral involvement is extremely rare. CASE REPORT: A 62-years-old male presents a large infiltrative mass involving the hard palate and left alveolar ridge. Computed tomography showed bone destruction and invasion of paranasal sinuses and orbits. Histology revealed a malignant neoplasm consisting of small round cells with minimal cytoplasm and hyperchromatic nuclei without any connection with the oral mucosal epithelium. Immunohistochemical analysis showed epithelial origin (CK-7+, CK-20+, AE1/AE3+, EMA+) and lacked strong evidence of squamous and neuroendocrine differentiation (p63-, 34ßE12-, NSE-/+, chromogranin-, synaptophysin-). TTF-1 negative ruled out the metastatic origin. A diagnosis of SNUC subtype positive for SMARCB1 (INI1) was reached. The patient was submitted to concurrent radiotherapy and chemotherapy without signs of recurrence after 2 years. CONCLUSION: SNUC involving the oral cavity is a rare malignancy that may mimic symptoms of dental infection or sinusitis. A careful correlation of clinical, microscopic, and immunohistochemical characteristics is mandatory for early diagnosis.

Expression of Cancer Stem Cell Biomarkers in Human Head and Neck Carcinomas: a Systematic Review.

Malignant neoplasms may be composed of several cell groups, including cancer stem cells (CSC). These cells have been related with the capacity of metastasis, relapse and resistance to multiple drugs during chemotherapy. This study aims to identify CSC biomarkers and their expression pattern in human head and neck carcinomas. This study was conducted following the PRISMA checklist. The search for articles was carried out in five databases (PubMed, Scopus, Web of Science, Lilacs and Scielo). The articles found were selected in two phases: 1) reading the titles and / or abstract and 2) reading the full text. At the end, the selected articles were evaluated by QUADAS-2. Most studies evaluated oral neoplastic tissues and, as a control, samples of normal local mucosa. All studies performed immunohistochemistry as a method of immunolocalization and some also applied immunofluorescence. The most commonly used biomarker was CD44. However, other such as Sox2, Oct4, Nestin, Nanog, BMI1, ALDH1, CD133 and CD166 were also found. Several biomarkers were (ALDH1, Sox2, Oct4, ABCB5, AGR2 and TAZ) correlated with clinical characteristics of the tumor, such as staging, tumor size and lymph node metastasis. These data reinforce the CSC theory and favor the use of these biomarkers as possible determinants of prognosis.

Oral manifestations and injuries related to covid- 19: an experience report on the role of hospital dentistry / Manifestações orais e lesões relacionadas à covid-19: um relatório de experiência sobre o papel da odontologia hospitalar / Manifestaciones orales y lesiones relacionadas con covid- 19: un informe de experiencia sobre el papel de la odontología hospitalaria

SARS-COV-2 is transmitted among human beings by saliva droplets that come in direct contact with the oral cavity, nose, and eyes. Since the mouth is one of the anatomical sites primarily contaminated, oral manifestations have also been reported beyond the serious consequences inherent to progressive respiratory failure. This study aimed to identify oral manifestations possibly related to the infection by COVID-19 in hospitalized patients. A prospective study was carried out with patients diagnosed with COVID-19 in the period between March and June 2021, admitted to the Moderate COVID-19 Care Unit of the Hans Dieter Schmidt Regional Hospital, by applying a form and performing a clinical exam of the oral cavity. Out of all patients (n=45), 33.3% reported both olfactory (anosmia) and taste dysfunction (dysgeusia), with an average duration of 5.9 ±3.0 days. Regarding other oral manifestations evaluated, two patients reported dry and burning mouth and one patient reported a change in taste associated with plaque-like changes in the tongue. No patients presented ulcers or other lesions in the oral cavity. Olfactory and taste dysfunction were symptoms recognized of the novel coronavirus disease (COVID-19). However, the association with other oral manifestations is still controversy. Unfortunately, dentistry professionals are still not part of most teams in the hospital environment, mostly because of the lack of prioritization of dental care. Working with a multidisciplinary team may avoid possible systemic complications due to poor dental care.

Sars-COV-2 é transmitida entre os seres humanos por gotículas de saliva que entram em contato direto com a cavidade oral, nariz e olhos. Uma vez que a boca é um dos sítios anatômicos principalmente contaminados, as manifestações orais também foram relatadas para além das graves consequências inerentes à insuficiência respiratória progressiva. Este estudo teve como objetivo identificar manifestações orais possivelmente relacionadas à infecção por Covid-19 em pacientes hospitalizados. Foi realizado um estudo prospetivo com pacientes diagnosticados com Covid-19 no período entre março e junho de 2021, internados na Unidade de Atendimento Moderado contra a Covid-19 do Hospital Regional Hans Dieter Schmidt, aplicando um formulário e realizando um exame clínico da cavidade oral. De todos os pacientes (n=45), 33,3% relataram disfunção olfativa (anosmia) e gustativa (disgeusia), com duração média de 5,9 ±3,0 dias. Em relação a outras manifestações orais avaliadas, dois pacientes relataram boca seca e ardente e um paciente relatou alteração no paladar associada a alterações semelhantes a placas na língua. Nenhum paciente apresentou úlceras ou outras lesões na cavidade oral. Disfunção olfativa e gustativa foram sintomas reconhecidos do novo coronavírus (Covid-19). No entanto, a associação com outras manifestações orais ainda é controversa. Infelizmente, os profissionais de odontologia ainda não fazem parte da maioria das equipes do ambiente hospitalar, principalmente por causa da falta de priorização dos cuidados odontológicos. Trabalhar com uma equipe multidisciplinar pode evitar possíveis complicações sistêmicas devido a cuidados odontológicos deficientes.

SARS-COV-2 se transmite entre los seres humanos por las gotitas de saliva que entran en contacto directo con la cavidad oral, la nariz y los ojos. Dado que la boca es uno de los sitios anatómicos principalmente contaminados, también se han informado manifestaciones orales más allá de las consecuencias graves inherentes a la insuficiencia respiratoria progresiva. El objetivo de este estudio fue identificar las manifestaciones bucales posiblemente relacionadas con la infección por COVID-19 en pacientes hospitalizados. Se realizó un estudio prospectivo con pacientes diagnosticados de COVID-19 en el periodo comprendido entre marzo y junio de 2021, ingresados en la Unidad de Cuidados Moderados de COVID-19 del Hospital Regional Hans Dieter Schmidt, mediante la aplicación de un formulario y la realización de un examen clínico de la cavidad oral. De todos los pacientes (n=45), el 33,3% notificó tanto disfunción olfativa (anosmia) como gustativa (disgeusia), con una duración media de 5,9 ±3,0 días. En cuanto a las demás manifestaciones orales evaluadas, dos pacientes notificaron sequedad y ardor de boca y un paciente notificó un cambio en el gusto asociado a cambios en la lengua en forma de placa. Ningún paciente presentó úlceras u otras lesiones en la cavidad oral. La disfunción olfativa y gustativa fueron síntomas reconocidos de la nueva enfermedad por coronavirus (COVID-19). Sin embargo, la asociación con otras manifestaciones orales es aún controvertida. Desafortunadamente, los profesionales de la odontología todavía no son parte de la mayoría de los equipos en el entorno hospitalario, principalmente debido a la falta de priorización de la atención odontológica. Trabajar con un equipo multidisciplinario puede evitar posibles complicaciones sistémicas debido a la mala atención dental.

The Role of the Complex USP1/WDR48 in Differentiation and Proliferation Processes in Cancer Stem Cells.

BACKGROUND: Recently, some studies identified the Basic-Helix-Loop-Helix (bHLH) transcription factor as a significant regulator for the evolution of neoplasms. The binding between bHLH proteins and DNA is restricted by heterodimerization with Inhibitors of DNA binding (ID). IDs prevent cellular differentiation, promote growth and sustain tumor development. The wide presence of stem cells in cancers suggests that genes ID are essential to cancer stem cells (CSC) progress. The enzyme Ubiquitin-specific protease 1 (USP1) is reported to deubiquitinate and stabilize IDs. Considering the action of the proteins ID, USP1 contributes to prevent differentiation mediated by bHLH and, consequently, keep CSC original characteristics. USP1 has its activity potentiated when bound to protein WD repeat-containing protein (WDR48). OBJECTIVE: To identify the influence of the complex USP1/WDR48 during the CSC tumorigenesis process, and whether this complex is a possible therapeutic target. METHODS: A literature search regarding the role of the complex USP1/WDR48 in inhibiting differentiation and increasing proliferation of CSC was performed, and possible selective molecule inhibitors of these deubiquitinase proteins were investigated. RESULTS: There is evidence that USP1/WDR48 complex promotes stem cell conservation and regulation of DNA damage repair. For this reason, inhibitors as Pimozide, GW7647, C527, SJB2-043, ML323 have been studied to inhibit USPs in cases of treatment intervention. CONCLUSION: It is consolidated in the literature the role of USP1/WDR48 during tumorigenesis. However, these studies are not enough to completely clarify the process; but certainly, the researchers are converging towards a promising direction to provide a new treatment option for cancer.

Proliferative verrucous leukoplakia: diagnosis, management and current advances.

INTRODUCTION: Proliferative verrucous leukoplakia is a multifocal and progressive lesion of the oral mucosa, with unknown etiology, and commonly resistant to all therapy attempts with frequent recurrences. It is characterized by a high rate of oral squamous cell carcinoma and verrucou carcinoma transformations. OBJECTIVE: To analyze the studies about Proliferative verrucous leukoplakia and develop a concise update. METHODS: A Pubmed search identifying studies (laboratory research, case series and reviews of literature) that examined patients with Proliferative verrucous leukoplakia was realized. RESULTS: There are not enough studies about Proliferative verrucous leukoplakia in the literature. The few found studies not present a consensus about its etiology and diagnosis criteria. Although several treatment strategies have been proposed, most of them still show a high recurrence rate. CONCLUSION: More research about Proliferative verrucous leukoplakia is necessary to understand and treat this disease.

Niacin metabolite excretion in alcoholic pellagra and AIDS patients with and without diarrhea.

OBJECTIVE: Malnourished patients with the acquired immunodeficiency syndrome (AIDS) can develop pellagra-like manifestations such as dermatitis, diarrhea, and dementia; therefore, we tested the hypothesis that patients with AIDS and diarrhea would have niacin depletion. This study compared 24-h urine excretion of N1-methyl-nicotinamide (N1MN) among patients with pellagra and patients with AIDS who did and did not have diarrhea. METHODS: Three groups were studied: G1 (patients with AIDS and diarrhea, n = 5); G2 (patients with AIDS and no diarrhea, n = 7), and G3 (patients with alcoholic pellagra and without the human immunodeficiency virus, n = 8). Diarrhea was defined as the production of at least three liquid stools per day over 3 to 5 d. Studies included mucosal intestinal biopsy, malabsorption tests, detection of parasites in stool, and serum albumin measurements. Semiquantitative food-frequency questionnaire, anthropometry, and daily urinary N1MN excretion were also determined. Groups were matched in relation to age, sex, presence of parasites in stool, and intestinal absorption results. RESULTS: G1 had normal intestinal examination by light microscopy and no parasites in stools. G2 group showed lower levels of serum albumin (2.6 +/- 0.3 g/dL) when compared with G1 (3.4 +/- 0.3 g/dL) and G3 (3.1 +/- 0.7 g/dL). Except for patients with pellagra, groups met their energy requirements. Patients in G3 (0.013, 0.01-0.081 mg/dL) and G1 (0.062, 0.001-0.33 mg/dL) excreted smaller amounts of N1MN in urine than did those in G2 (0.63, 0.02-2.9 mg/dL). CONCLUSIONS: Patients with AIDS and diarrhea excreted less N1MN in urine than did those without diarrhea. These patients may have an impaired niacin nutritional status, possibly associated with increased metabolic needs.

Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation.

AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmax (SS) mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmax(SS) than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmax(SS) mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmax(SS) mice susceptibility to PIA.

Proliferative verrucous leukoplakia: diagnosis, management and current advances / Leucoplasia verrucosa proliferativa: diagnóstico, conduta e avanços atuais

Abstract Introduction: Proliferative verrucous leukoplakia is a multifocal and progressive lesion of the oral mucosa, with unknown etiology, and commonly resistant to all therapy attempts with frequent recurrences. It is characterized by a high rate of oral squamous cell carcinoma and verrucou carcinoma transformations. Objective: To analyze the studies about Proliferative verrucous leukoplakia and develop a concise update. Methods: A Pubmed search identifying studies (laboratory research, case series and reviews of literature) that examined patients with Proliferative verrucous leukoplakia was realized. Results: There are not enough studies about Proliferative verrucous leukoplakia in the literature. The few found studies not present a consensus about its etiology and diagnosis criteria. Although several treatment strategies have been proposed, most of them still show a high recurrence rate. Conclusion: More research about Proliferative verrucous leukoplakia is necessary to understand and treat this disease.

Resumo Introdução: Leucoplasia verrucosa proliferativa (LVP) é uma lesão multifocal e progressiva da mucosa oral, com etiologia desconhecida e comumente resistente a todas as tentativas terapêuticas, com recorrências frequentes. É caracterizada por uma alta taxa de transformação em carcinoma de células escamosas e carcinoma verrucoso da cavidade oral. Objetivo: Analisar os estudos sobre LVP e elaborar uma atualização resumida. Método: Foi realizada uma pesquisa na base de dados Pubmed que identificou estudos (pesquisas laboratoriais, séries de casos e revisões de literatura) que avaliaram pacientes com LVP. Resultados e discussão: Não há estudos suficientes sobre LVP na literatura. Os poucos estudos encontrados não apresentam consenso quanto aos critérios de etiologia e diagnóstico. Embora várias estratégias de tratamento tenham sido propostas, a maioria ainda apresenta alta taxa de recorrência. Conclusão: Mais pesquisas sobre LVP são necessárias para entender e tratar essa doença.