RESUMO
Palatal mucosal changes secondary to smoking habit have been recognised since at least the 19th century. Smoker's palate, or nicotinic stomatitis is associated with habitual cigar or pipe smoking, regular consumption of thermally hot beverages and more recently has been identified in those who vape. It is considered of negligible malignant transformation risk, typically resolving on habit cessation. However a variant, palatal keratosis associated with reverse smoking (PKARs), is recognised as an established oral potentially malignant disorder. Reverse smoking involves smoking the lit end of the cigarette intraorally and the condition may result in increased incidence of palatal squamous cell carcinoma development. We highlight a case to create awareness of both this unusual smoking habit, and the palate as an overlooked site in oral cancer screening.
Assuntos
Ceratose Actínica , Doenças da Boca , Humanos , Ceratose Actínica/patologia , Nova Zelândia , Palato/patologia , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. In addition, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East respiratory syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral that has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19.
Assuntos
Tratamento Farmacológico da COVID-19 , Infecções por Coronavirus , Pró-Fármacos , Adenosina/análogos & derivados , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Humanos , Camundongos , Nucleosídeos , Pais , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , SARS-CoV-2RESUMO
Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Infecções por Coronavirus/tratamento farmacológico , Interferon beta/uso terapêutico , Lopinavir/uso terapêutico , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Ritonavir/uso terapêutico , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Animais , Antivirais/uso terapêutico , Carboxilesterase/genética , Infecções por Coronavirus/patologia , Combinação de Medicamentos , Desenvolvimento de Medicamentos , Feminino , Humanos , Lesão Pulmonar/patologia , Masculino , Camundongos , Camundongos Knockout , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
The genetically diverse Orthocoronavirinae (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC50 values. Of known CoVs, the members of the deltacoronavirus genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV.
Assuntos
Monofosfato de Adenosina/farmacologia , Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Betacoronavirus/efeitos dos fármacos , Linhagem Celular , Coronavirus/classificação , Coronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Filogenia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Suínos , Replicação Viral/efeitos dos fármacosRESUMO
The purpose of this study is to use cone-beam computerized tomography (CBCT) scans with oblique-transverse reconstruction modality to measure and compare the anterior loop length (AnLL) of the mental nerve between gender and age groups and to compare the difference between the right and left sides. Sixty-one female and 61 male CBCT scans were randomly selected for each age group: 21-40, 41-60, and 61-80 years. Both right- and left-side AnLLs were measured in each subject using i-CATVision software to measure AnLLs on the oblique transverse plane using multiplanar reconstruction. The anterior loop was identified in 85.2% of cases, with the mean AnLL of the 366 subjects (732 hemimandibles) being 1.46 ± 1.25 mm with no statistically significant difference between right and left sides or between different gender groups. However, the mean AnLL in the 21-40 year group (1.89 ± 1.35 mm) was larger than the AnLL in the 41-60 year group (1.35 ± 1.19 mm) and the 61-80 year group (1.13 ± 1.08 mm). In conclusion, when placing implants in close proximity to mental foramina, caution is recommended to avoid injury to the inferior alveolar nerve. No fixed distance anteriorly from the mental foramen should be considered safe. Using CBCT scans with the oblique-transverse method to accurately identify and measure the AnLL is of utmost importance in avoiding and protecting its integrity.
Assuntos
Tomografia Computadorizada de Feixe Cônico , Nervo Mandibular , Feminino , Humanos , Masculino , Mandíbula , SoftwareRESUMO
It is hypothesized that use of an angulation sensor could increase the alignment accuracy of multiple implant osteotomies without requiring the use of guided-surgical templates. Therefore, the purpose of this study was to determine if use of such a sensor mounted on a surgical handpiece could improve implant placement.
Assuntos
Implantação Dentária Endóssea/instrumentação , Mandíbula/cirurgia , Implantação Dentária Endóssea/normas , Humanos , Osteotomia/instrumentação , Cirurgia Assistida por Computador/instrumentaçãoRESUMO
Although interferon (IFN) has been often used as immunotherapy for bladder cancer, its efficacy is rather unsatisfactory, demanding further improvement. Combination therapy is one of viable options, and grape seed proanthocyanidin (GSP) could be such an agent to be used with IFN because it has been shown to have anticancer activity. We thus investigated whether combination of IFN and GSP might enhance the overall antiproliferative effect on bladder cancer cells in vitro. Human bladder cancer T24 cells were employed and treated with the varying concentrations of recombinant IFN-α(2b) (0-100,000 IU/ml), GSP (0-100 µg/ml), or their combinations. IFN-α(2b) alone led to a ~50% growth reduction at 20,000 (20K) IU/ml, which further declined to ~67% at ≥50K IU/ml. Similarly, GSP alone induced a ~35% and ~100% growth reduction at 25 and ≥50 µg/ml, respectively. When IFN-α(2b) and GSP were then combined, combination of 50K IU/ml IFN-α(2b) and 25 µg/ml GSP resulted in a drastic >95% growth reduction. Cell cycle analysis indicated that such an enhanced growth inhibition was accompanied by a G(1) cell cycle arrest. This was further confirmed by Western blot analysis revealing that expressions of G(1)-specific cell cycle regulators (CDK2, CDK4, cyclin E and p27/Kip1) were distinctly modulated with such IFN-α(2b)/GSP treatment. Therefore, these findings support the notion that combination of IFN-α(2b) and GSP is capable of additively enhancing antiproliferative effect on T24 cells with a G(1) cell cycle arrest, implying an adjuvant therapeutic modality for superficial bladder cancer.
RESUMO
⺠Bevacizumab may increase the risk of mucosal ulceration and subsequent bone necrosis. ⺠Patients receiving bevacizumab should be closely monitored for dental symptoms.
RESUMO
OBJECTIVE: To examine whether the combination of interferon (IFN)-alpha and maitake mushroom D-fraction (PDF), a bioactive mushroom extract, might potentiate the anticancer activity of IFN-alpha in bladder cancer T24 cells in vitro. MATERIALS AND METHODS: Effects of recombinant IFN-alpha(2b) (0-50 000 IU/mL), PDF (0-700 microg/mL), or their combinations were assessed on T24 cell growth at 72 h. Cell cycle analysis and assays for double-stranded DNA-dependent protein kinase (DNA-PK) were performed to explore possible antiproliferative mechanism of these agents. RESULTS: IFN-alpha(2b) was able to induce a significant ( approximately 50%) growth reduction at 20 000 IU/mL, which further declined to approximately 66% at 50 000 IU/mL. PDF had no effects up to 200 microg/mL, but there was an approximately 20% and approximately 53% growth reduction at 400 and 700 microg/mL, respectively. When the varying concentrations of IFN-alpha(2b) and PDF were combined, 10 000 IU/mL of IFN-alpha(2b) combined with 200 microg/mL of PDF resulted in an approximately 75% growth reduction. This was accompanied by a G(1) cell cycle arrest, shown by cell cycle analysis. Concurrently, DNA-PK activity in IFN-alpha(2b)/PDF-treated cells was almost three-fold higher than controls. CONCLUSIONS: The combination of IFN-alpha(2b) (10 000 IU/mL) and PDF (200 microg/mL) reduced growth by approximately 75% in T24 cells. This appears to be due to a synergistic potentiation of these two agents, inducing a G(1) arrest with DNA-PK activation. Therefore, the IFN-alpha(2b)/PDF combination could trigger DNA-PK activation that may act on the cell cycle to cease cancer cell growth.