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1.
Front Oncol ; 11: 725137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765544

RESUMO

Metabolic dysfunctions enabling increased nucleotide biosynthesis are necessary for supporting malignant proliferation. Our investigations indicate that upregulation of fatty acid synthase (FASN) and de novo lipogenesis, commonly observed in many cancers, are associated with nucleotide metabolic dysfunction in lymphoma. The results from our experiments showed that ribonucleotide and deoxyribonucleotide pool depletion, suppression of global RNA/DNA synthesis, and cell cycle inhibition occurred in the presence of FASN inhibition. Subsequently, we observed that FASN inhibition caused metabolic blockade in the rate-limiting step of the oxidative branch of the pentose phosphate pathway (oxPPP) catalyzed by phosphogluconate dehydrogenase (PGDH). Furthermore, we determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. Through cell-free enzyme assays consisting of FASN and PGDH, we delineated that the PGDH-catalyzed ribulose-5-phosphate synthesis is enhanced in the presence of FASN and is suppressed by increasing concentrations of NADPH. Additionally, we observed that FASN and PGDH were colocalized in the cytosol. The results from these experiments led us to conclude that NADP-NADPH turnover and the reciprocal stimulation of FASN and PGDH catalysis are involved in promoting oxPPP and nucleotide biosynthesis in lymphoma. Finally, a transcriptomic analysis of non-Hodgkin's lymphoma (n = 624) revealed the increased expression of genes associated with metabolic functions interlinked with oxPPP, while the expression of genes participating in oxPPP remained unaltered. Together we conclude that FASN-PGDH enzymatic interactions are involved in enabling oxPPP and nucleotide metabolic dysfunction in lymphoma tumors.

2.
J Dent ; 116: 103892, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34798150

RESUMO

OBJECTIVES: We aimed to confirm whether autofluorescence emitted from teeth can predict tooth bleaching efficacy and establish a novel model combining natural color parameters and tooth autofluorescence data to improve the predictability of tooth bleaching. METHODS: A total of 61 tooth specimens were prepared from extracted human molars/premolars and immersed in 35% hydrogen peroxide for 1 h for tooth bleaching. The changes in laser-induced fluorescence (∆LIF) were assessed using Raman spectrometry. Tooth color and autofluorescence data were obtained using quantitative light-induced fluorescence (QLF) technology. Pearson correlation analyses were used to confirm the relationship between ∆LIF and autofluorescence. Intraclass correlation coefficients (ICC) were calculated to compare the conventional and new prediction models. Decision tree analysis was performed to evaluate clinical applicability. RESULTS: The yellowness-to-blueness value from fluorescence imaging showed a moderate correlation with ∆LIF (r= -0.409, p = 0.001). The degree of agreement between the actual efficacy and that predicted by our novel model was high (ICC=0.933, p = 0.002). Decision tree analysis suggested that tooth autofluorescence could be a key factor in prediction of tooth bleaching outcomes. CONCLUSIONS: Our findings showed that autofluorescence detected from QLF images may be used to predict tooth bleaching efficacy. Our proposed model appeared to improve the predictability of tooth bleaching.

3.
Korean J Radiol ; 22(12): 2017-2025, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34668353

RESUMO

OBJECTIVE: To evaluate the accuracy and clinical efficacy of a hybrid Greulich-Pyle (GP) and modified Tanner-Whitehouse (TW) artificial intelligence (AI) model for bone age assessment. MATERIALS AND METHODS: A deep learning-based model was trained on an open dataset of multiple ethnicities. A total of 102 hand radiographs (51 male and 51 female; mean age ± standard deviation = 10.95 ± 2.37 years) from a single institution were selected for external validation. Three human experts performed bone age assessments based on the GP atlas to develop a reference standard. Two study radiologists performed bone age assessments with and without AI model assistance in two separate sessions, for which the reading time was recorded. The performance of the AI software was assessed by comparing the mean absolute difference between the AI-calculated bone age and the reference standard. The reading time was compared between reading with and without AI using a paired t test. Furthermore, the reliability between the two study radiologists' bone age assessments was assessed using intraclass correlation coefficients (ICCs), and the results were compared between reading with and without AI. RESULTS: The bone ages assessed by the experts and the AI model were not significantly different (11.39 ± 2.74 years and 11.35 ± 2.76 years, respectively, p = 0.31). The mean absolute difference was 0.39 years (95% confidence interval, 0.33-0.45 years) between the automated AI assessment and the reference standard. The mean reading time of the two study radiologists was reduced from 54.29 to 35.37 seconds with AI model assistance (p < 0.001). The ICC of the two study radiologists slightly increased with AI model assistance (from 0.945 to 0.990). CONCLUSION: The proposed AI model was accurate for assessing bone age. Furthermore, this model appeared to enhance the clinical efficacy by reducing the reading time and improving the inter-observer reliability.

4.
Ann Surg Treat Res ; 101(4): 206-213, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34692592

RESUMO

Purpose: Postoperative pain and delayed wound healing are the main complications following anal surgery associated with poor quality of life. Hyaluronic acid (HA) supports tissue regeneration and rapid wound healing by promoting cell proliferation and migration. We investigated the effects of HA on perianal wound healing in a rat model. Methods: Forty-eight 8-week-old Sprague-Dawley rats with perianal wounds created by biopsy punch were divided into 3 groups: simple dressing with gauze (control), dressing with topical HA film, and dressing with topical HA gel. HA agents were not reapplied postoperatively. Wound healing was evaluated by measuring the healed area, and histological analyses were randomly performed using hematoxylin and eosin and Masson trichrome staining. Results: Fewer mean days were required for complete wound healing in the HA film and HA gel groups than in the control group (11.6 vs. 11.9 vs. 13.8 days, respectively; P = 0.010). The healed area in the HA film group on day 11 was larger than that in the HA gel and control groups (80.2% vs. 61.9% vs. 53.2%, respectively; P < 0.001). Histologically, the HA film group showed accelerated reepithelialization, a rapid transition to lymphocyte-predominant inflammation, and increased fibroblastic proliferation and collagen deposition compared to the other groups. There was no treatment-related toxicity in the HA application groups. Conclusion: Topical application of HA film to perianal wounds improves the wound healing rate in a rat model. This finding suggests a potential benefit of HA film application in promoting wound healing after anal surgery in humans.

5.
J Craniofac Surg ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643597

RESUMO

INTRODUCTION: In case of zygomaticomaxillary fibrous dysplasia (FD), surgical treatment is often required due to visual disturbance, exophthalmos, and also necessary for cosmetic reasons. However, it is not easy to determine the timing and method of operation. The objective of our study is to define a new surgical option, for the treatment of FD of zygomaticomaxillary area. MATERIALS AND METHODS: Five patients affected by FD of their zygomaticomaxillary area who underwent surgery with a core extirpation were included in this study. A retrospective chart review and pre- and post-operative analysis of computed tomography scan were performed. RESULTS: All patients underwent core extirpation surgery and zygoma reduction was combined in 2 patients. All patients showed the cessation of the increase of external size postoperatively and results of the operation were well maintained over the follow-up period of 1 year. CONCLUSIONS: In this article, we present our experiences in the management of FD using the core extirpation with or without zygoma reduction, focusing on surgical indication, techniques, and results. Although there are limitations due to selective operative indication, the procedure can be usefully performed to prevent external growth and avoid repetitive surgery.

6.
J Biol Chem ; 297(4): 101170, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34492268

RESUMO

Elevated intracellular levels of dNTPs have been shown to be a biochemical marker of cancer cells. Recently, a series of mutations in the multifunctional dNTP triphosphohydrolase (dNTPase), sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), have been reported in various cancers. Here, we investigated the structure and functions of SAMHD1 R366C/H mutants, found in colon cancer and leukemia. Unlike many other cancer-specific mutations, the SAMHD1 R366 mutations do not alter cellular protein levels of the enzyme. However, R366C/H mutant proteins exhibit a loss of dNTPase activity, and their X-ray structures demonstrate the absence of dGTP substrate in their active site, likely because of a loss of interaction with the γ-phosphate of the substrate. The R366C/H mutants failed to reduce intracellular dNTP levels and restrict HIV-1 replication, functions of SAMHD1 that are dependent on the ability of the enzyme to hydrolyze dNTPs. However, these mutants retain dNTPase-independent functions, including mediating dsDNA break repair, interacting with CtIP and cyclin A2, and suppressing innate immune responses. Finally, SAMHD1 degradation in human primary-activated/dividing CD4+ T cells further elevates cellular dNTP levels. This study suggests that the loss of SAMHD1 dNTPase activity induced by R366 mutations can mechanistically contribute to the elevated dNTP levels commonly found in cancer cells.


Assuntos
Neoplasias do Colo , Leucemia , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Proteína 1 com Domínio SAM e Domínio HD , Substituição de Aminoácidos , Linhagem Celular , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Ciclina A2/química , Ciclina A2/genética , Ciclina A2/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Endodesoxirribonucleases/química , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Humanos , Leucemia/enzimologia , Leucemia/genética , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/química , Proteína 1 com Domínio SAM e Domínio HD/genética , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Relação Estrutura-Atividade
7.
J Craniofac Surg ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545055

RESUMO

ABSTRACT: Osteoma is a benign, slow growing lesion that consists of compact or cancellous bone. Three types of osteomas could be classified: the central osteoma arising from the endosteum, the peripheral osteoma from the periosteum, and the extraskeletal soft tissue osteoma. In the craniofacial region, peripheral osteomas of the zygoma are quite rare. A literature review identified 7 cases of zygomatic arch and 3 cases of zygomatic body. This is the first report of zygomatic osteoma that was endoscopically removed. This report presents a rare case of osteoma of the zygoma and its endoscopic approach. The authors were able to confirm that endoscopic approach of this zygomatic osteoma was safe and effective surgical choice.

8.
BMC Pediatr ; 21(1): 379, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479534

RESUMO

OBJECTIVE: A significant number of patients with KS have cleft palate (CP) or submucous cleft palate (SMCP) and show delayed speech development. However, few reports have discussed the characteristics of CP in KS and the outcomes of postoperative speech development. The purpose of this study was to investigate the characteristics and surgical outcomes of CP in patients with KS, and to discuss the importance of the diagnosis of CP or SMCP. METHODS: We conducted a retrospective study on patients with clinically diagnosed KS who underwent palatoplasty. Clinical and surgical data were collected from patients' medical records, and velopharyngeal function was evaluated using nasopharyngoscopy and speech analysis. RESULTS: In 11 cases, 5 patients had CP (45.5%) and 6 had SMCP (54.5%). Four patients who were genetically tested had a pathogenic variant of KMT2D. Seven of nine patients (77.8%) who underwent conventional palatoplasty showed velopharyngeal insufficiency and hypernasality. All patients who underwent pharyngeal flap surgery achieved velopharyngeal competency. Statistical analysis revealed a statistically significant difference in postoperative results between non-syndromic and KS patients. CONCLUSION: Patients with SMCP may be more common than previously reported. The results showed that it is difficult to produce optimal results with conventional palatoplasty; therefore, pharyngeal flap surgery should be considered as a treatment to obtain favorable results. Pharyngeal flap surgery in patients with KS should be carefully designed based on speech evaluation and nasopharyngoscopic findings.


Assuntos
Anormalidades Múltiplas , Fissura Palatina , Anormalidades Múltiplas/cirurgia , Fissura Palatina/diagnóstico , Fissura Palatina/cirurgia , Face/anormalidades , Doenças Hematológicas , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Doenças Vestibulares
9.
J Craniofac Surg ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34538784

RESUMO

BACKGROUND: The pharyngeal flap is one of the most common secondary surgeries for the correction of velopharyngeal insufficiency (VPI) for patients with cleft palate and/or cleft lip and palate. This study aimed to demonstrate the effectiveness of the precision pharyngeal flap surgery performed by the senior author. MATERIALS AND METHODS: Children with VPI, who underwent precision pharyngeal flap, were retrospectively examined. All surgical procedures were performed by the senior author. The flap size was individually configured based on the patients' preoperative nasopharyngoscopic analysis and speech function evaluation. Pre- and post-operative velopharyngeal functions were assessed using perceptual speech evaluation and nasometric analysis; factors affecting surgical outcomes were determined. RESULTS: Of 138 patients, 112 (women: 53, men: 59) were included in analyses, according to the inclusion and exclusion criteria. The median follow-up period was 21 months (range: 9-120). Postoperative perceptual speech evaluation revealed improved velopharyngeal function in 108 (96.4%). There were no reports of postoperative hyponasality (preoperative, 1.8% versus postoperative, 0%; P = 0.053). Other parameters of perceptual speech evaluation (hypernasality, nasal emission, articulation error, and intelligibility) showed significant improvement postoperatively (P < 0.01). Postoperative nasalance scores revealed sufficient postoperative resonance rating in 96% of patients. No patients experienced postoperative complications (bleeding, airway obstruction, and surgical wound dehiscence). CONCLUSIONS: Individually configured pharyngeal flaps designed based on preoperative nasopharyngoscopic examination coupled with precise surgical techniques led to the high surgery success rate for VPI treatment.

10.
PLoS One ; 16(8): e0255822, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34358264

RESUMO

Noninvasive techniques for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) have shown limited diagnostic performance. MicroRNAs (miRNAs) are useful biomarkers for diagnosing and monitoring the progression and treatment response to several diseases. Here, we evaluated whether serum exosomal miRNAs could be used for the diagnosis and prognosis of NAFLD severity. Exosomal miRNAs were isolated from the sera of 41 patients with NAFLD (diagnosed using liver biopsy) for microarray profiling. The degree of NAFLD severity was determined using inflammation, steatosis, and ballooning scores and the NAFLD activity score (NAS). Correlations between miRNA expression, clinical and biochemical parameters, and mRNA expression were analyzed. Overall, 25, 11, 13, and 14 miRNAs correlated with the inflammation score, steatosis score, ballooning score, and NAS, respectively, with 33 significant correlations observed between 27 miRNAs and six clinical variables. Eight miRNAs (let-7b-5p, miR-378h, -1184, -3613-3p, -877-5p, -602, -133b, and 509-3p) showed anticorrelated patterns with the corresponding mRNA expression. In fibrosis, 52 and 30 interactions corresponding to high miRNA-low mRNA and low miRNA-high mRNA expression, respectively, were observed. The present results therefore suggest that serum exosomal miRNAs can be used to evaluate NAFLD severity and identify potential targets for NAFLD treatment.

11.
Photodiagnosis Photodyn Ther ; 36: 102470, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34333145

RESUMO

Wound dehiscence is a common complication following vertical bone augmentation of implant dentistry. If the implanted titanium mesh becomes exposed, the exposed titanium mesh should be removed with the contaminated grafts before a clinical graft infection develops. However, no generally accepted evaluation methods have been suggested to determine the removal timing or the extent of contaminated bone grafts to be removed. Quantitative light-induced fluorescence (QLF) technology has been used for various oral bacterial condition such as dental caries, plaque, peri-implantitis, and osteomyelitis. This paper reports two patients with wound dehiscence within the third week after vertical bone augmentation with autogenous particulate bone on the posterior maxilla. With conservative treatment, a QLF technology was applied to determine whether to remove the mesh. The exposed mesh of the first patient was removed when red-fluorescence was observed the red fluorescence by QLF. However, the other case did not show red fluorescence during the fifth week after dehiscence, and secondary healing was achieved without complications. The remaining bone grafts were well integrated into the sound cortico-cancellous complex sufficient to support the dental implant. Based on these clinical, radiological, and histological results, we discussed the rationale of QLF application on wound dehiscence after the bone graft in implant dentistry.

12.
Cancers (Basel) ; 13(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34439352

RESUMO

Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

13.
Front Bioeng Biotechnol ; 9: 681253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336800

RESUMO

Rare sugars are regarded as functional biological materials due to their potential applications as low-calorie sweeteners, antioxidants, nucleoside analogs, and immunosuppressants. D-Allose is a rare sugar that has attracted substantial attention in recent years, owing to its pharmaceutical activities, but it is still not widely available. To address this limitation, we continuously produced D-allose from D-allulose using a packed bed reactor with commercial glucose isomerase (Sweetzyme IT). The optimal conditions for D-allose production were determined to be pH 8.0 and 60°C, with 500 g/L D-allulose as a substrate at a dilution rate of 0.24/h. Using these optimum conditions, the commercial glucose isomerase produced an average of 150 g/L D-allose over 20 days, with a productivity of 36 g/L/h and a conversion yield of 30%. This is the first report of the successful continuous production of D-allose from D-allulose by commercial glucose isomerase using a packed bed reactor, which can potentially provide a continuous production system for industrial applications of D-allose.

14.
Br J Cancer ; 125(7): 983-993, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34253873

RESUMO

BACKGROUND: Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. METHODS: Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. RESULTS: Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. CONCLUSIONS: This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

15.
Sci Rep ; 11(1): 14639, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282172

RESUMO

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676-0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724-0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

16.
Korean J Orthod ; 51(4): 282-292, 2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34275884

RESUMO

Objective: To quantitatively analyze the effect of nicotine on orthodontic tooth movement (OTM) and bone remodeling in rats using micro-computed tomography and tartrate-resistant acid phosphatase immunostaining. Methods: Thirty-nine adult male Sprague-Dawley rats were randomized into three groups: group A, 0.5 mL normal saline (n = 9, 3 per 3, 7, and 14 days); group B, 0.83 mg/kg nicotine (n = 15, 5 per 3, 7, and 14 days); and group C, 1.67 mg/kg nicotine (n = 15, 5 per 3, 7, and 14 days). Each animal received daily intraperitoneal injections of nicotine/saline from the day of insertion of identical 30-g orthodontic force delivery systems. A 5-mm nickel-titanium closed-coil spring was applied between the left maxillary first molar (M1) and the two splinted incisors. The rate of OTM and volumetric bone changes were measured using micro-computed tomography. Osteoclasts were counted on the mesial alveolar bone surface of the distobuccal root of M1. Six dependent outcome variables, including the intermolar distance, bone volume fraction, bone mineral density, trabecular thickness, trabecular volume, and osteoclast number, were summarized using simple descriptive statistics. Nonparametric Kruskal-Wallis tests were used to evaluate differences among groups at 3, 7, and 14 days of OTM. Results: All six dependent outcome variables showed no statistically significant among group-differences at 3, 7, and 14 days. Conclusions: The findings of this study suggest that nicotine does not affect OTM and bone remodeling, although fluctuations during the different stages of OTM in the nicotine groups should be elucidated in further prospective studies.

17.
Nat Commun ; 12(1): 4582, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321470

RESUMO

SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO2 to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function, a phenotype that is reversed by the phosphomimetic T592E mutation. Collectively, our observations clearly establish that lack of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity in non-cycling immune cells, an effect that is antagonized by cyclin/CDK-dependent phosphorylation of T592 in cycling cells.


Assuntos
Ciclo Celular/fisiologia , HIV-1/fisiologia , Proteína 1 com Domínio SAM e Domínio HD/genética , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Sumoilação/fisiologia , Substituição de Aminoácidos , Células HEK293 , Infecções por HIV/virologia , Humanos , Lisina , Mutação , Fosforilação , Proteína 1 com Domínio SAM e Domínio HD/química , Células U937
18.
J Pathol Transl Med ; 55(4): 247-264, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34233112

RESUMO

Although the understanding of appendiceal mucinous neoplasms (AMNs) and their relationship with disseminated peritoneal mucinous disease have advanced, the diagnosis, classification, and treatment of AMNs are still confusing for pathologists and clinicians. The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (GPSG-KSP) proposed a multicenter study and held a workshop for the "Standardization of the Pathologic Diagnosis of the Appendiceal Mucinous Neoplasm" to overcome the controversy and potential conflicts. The present article is focused on the diagnostic criteria, terminologies, tumor grading, pathologic staging, biologic behavior, treatment, and prognosis of AMNs and disseminated peritoneal mucinous disease. In addition, GPSG-KSP proposes a checklist of standard data elements of appendiceal epithelial neoplasms to standardize pathologic diagnosis. We hope the present article will provide pathologists with updated knowledge on how to handle and diagnose AMNs and disseminated peritoneal mucinous disease.

19.
PLoS Pathog ; 17(7): e1009671, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34293041

RESUMO

Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial.


Assuntos
Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Cães , Infecções por HIV/tratamento farmacológico , Humanos , Ratos , Ratos Sprague-Dawley , Replicação Viral/efeitos dos fármacos
20.
Mod Pathol ; 34(9): 1728-1737, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34193964

RESUMO

To date, there have been no studies comparing the molecular subtypes of Index gastric cancers (IGCs) and metachronous gastric cancers (MGCs). We evaluated a cohort of 42 patients with 43 IGCs and 45 MGCs. Molecular subtyping was performed by immunohistochemistry of mismatch repair (MMR) proteins, E-cadherin, p53, and Epstein-Barr virus- (EBV-) in situ hybridization (ISH). Gastric adenocarcinomas were classified into 5 subtypes: EBV-associated, MMR deficient (MMRD), E-cadherin aberrant, p53-aberrant [p53(+)], and p53 non-aberrant [p53(neg)]. All IGCs had been successfully treated by either surgery (19%) or endoscopic resection (81%). The mean interval between IGCs and MGCs was 85 months. Among the IGCs, EBV-associated, MMRD, E-cadherin-aberrant, p53(+), and p53(neg) molecular subtypes represented 2 (5%), 4 (9%), 2 (5%), 21 (49%), and 14 (32%) of the cases, respectively. Two cases had concomitant p53(+) and aberrant E-cadherin molecular subtypes. Among metachronous cancers, EBV-associated, MMRD, E-cadherin-aberrant, p53(+), and p53(neg) molecular subtypes represented 3 (7%), 11 (24%), 0 (0%), 22 (49%), and 9 (20%) cases. Concomitant p53(+) was observed in 1 EBV-associated and 2 MMRD MGCs. Although, there was no significant difference in the frequency of most molecular subtypes in IGCs and MGCs, the number of MMRD gastric cancers more than doubled in the MGC group. Half of the MGCs had a divergent molecular subtype compared to that of the IGCs. Notably, the interval between the development of IGCs and MGCs was significantly longer in patients with divergent molecular subtypes (P = 0.010). All 4 patients with MMRD IGC developed MMRD MGCs. Although the concept of mucosal field cancerization may explain the matching molecular subtypes in early-developing MGCs, the presence of divergent subtypes in late-occurring MGCs suggests a shift in the carcinogenic mechanism affecting the residual mucosa possibly related to Helicobacter pylori eradication.

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