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1.
Cell Death Differ ; 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39164456

RESUMEN

The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.

2.
JCI Insight ; 9(8)2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38451719

RESUMEN

Mesenchymal stem cells (MSCs), suffering from diverse gene hits, undergo malignant transformation and aberrant osteochondral differentiation. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a nonreceptor protein tyrosine phosphatase, regulates multicellular differentiation, proliferation, and transformation. However, the role of SHP2 in MSC fate determination remains unclear. Here, we showed that MSCs bearing the activating SHP2E76K mutation underwent malignant transformation into sarcoma stem-like cells. We revealed that the SHP2E76K mutation in mouse MSCs led to hyperactive mitochondrial metabolism by activating mitochondrial complexes I and III. Inhibition of complexes I and III prevented hyperactive mitochondrial metabolism and malignant transformation of SHP2E76K MSCs. Mechanistically, we verified that SHP2 underwent liquid-liquid phase separation (LLPS) in SHP2E76K MSCs. SHP2 LLPS led to its dissociation from complexes I and III, causing their hyperactivation. Blockade of SHP2 LLPS by LLPS-defective mutations or allosteric inhibitors suppressed complex I and III hyperactivation as well as malignant transformation of SHP2E76K MSCs. These findings reveal that complex I and III hyperactivation driven by SHP2 LLPS promotes malignant transformation of SHP2E76K MSCs and suggest that inhibition of SHP2 LLPS could be a potential therapeutic target for the treatment of activated SHP2-associated cancers.


Asunto(s)
Transformación Celular Neoplásica , Células Madre Mesenquimatosas , Mitocondrias , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Células Madre Mesenquimatosas/metabolismo , Animales , Ratones , Mitocondrias/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Humanos , Mutación , Diferenciación Celular , Separación de Fases
3.
Am J Transl Res ; 16(1): 255-271, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38322576

RESUMEN

OBJECTIVES: Heterotopic ossification (HO), whether hereditary or traumatic, refers to the abnormal formation of bone in extraskeletal sites, often triggered by inflammation or flare-ups. Unfortunately, there are currently no effective treatments for HO. Metformin is well-known for its anti-diabetic, anti-inflammatory, anti-aging, and anti-cancer effects. However, its potential role in treating HO remains uncertain. METHODS: Metformin was dissolved into water and given to mice. All the mice in this study were examined by microCT and myeloid cell quantification using flow cytometry. Complex activity kit was used to examine the activity of mitochondrial complexes of myeloid cells. RESULTS: In this study, we discovered that metformin effectively inhibits genetic and traumatic HO formation and progression. Additionally, we observed a significant increase in myeloid cells in the genetic and traumatic HO mouse model compared to uninjured mice. Notably, metformin specifically reduced the infiltration of myeloid cells into the injured sites of the genetic and traumatic HO model mice. Further investigations revealed that metformin targets mitochondrial complex I and suppresses mitochondrial metabolism in myeloid cells. CONCLUSION: These findings suggest that metformin suppresses HO development by potentially downregulating the mitochondrial metabolism of myeloid cells, offering a promising therapeutic option for HO treatment.

4.
Biomedicines ; 11(4)2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37189851

RESUMEN

Hepatocellular carcinoma (HCC) is an aggressive and challenging disease to treat. Due to the lack of effective early diagnosis and therapy for the illness, it is crucial to identify novel biomarkers that can predict tumor behavior in HCC. In such cases, family with sequence similarity 210 member B (FAM210B) is abundant in various human tissues, but its regulatory mechanisms and role in various tissues remain unclear. In this study, we analyzed the expression pattern of FAM210B in HCC using public gene expression databases and clinical tissue samples. Our results confirmed that FAM210B was dysregulated in both HCC cell lines and HCC paraffin section samples. FAM210B depletion significantly increased the capacity of cells to grow, migrate, and invade in vitro, while overexpression of FAM210B suppressed tumor growth in a xenograft tumor model. Furthermore, we identified FAM210B's involvement in MAPK signaling and p-AKT signaling pathways, both of which are known oncogenic signaling pathways. In summary, our study provides a rational basis for the further investigation of FAM210B as a valuable biological marker for diagnosing and predicting the prognosis of HCC patients.

5.
Oncol Lett ; 25(5): 176, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37033103

RESUMEN

Breast cancer is the most common malignancy and ranks second among the causes of tumor-associated death in females. The recurrence and drug resistance of breast cancer are intractable due to the presence of breast cancer stem cells (BCSCs), which are adequate to initiate tumor formation and refractory to conventional remedies. Runt-related transcription factor 2 (RUNX2), a pivotal transcription factor in mammary gland and bone development, has also been related to metastatic cancer and BCSCs. State-of-the-art research has indicated the retention of RUNX2 expression in a more invasive subtype of breast cancer, and in particular, triple-negative breast cancer development and drug resistance are associated with estrogen receptor signaling pathways. The present review mainly focused on the latest updates on RUNX2 in BCSCs and their roles in breast cancer progression and drug resistance, providing insight that may aid the development of RUNX2-based diagnostics and treatments for breast cancer in clinical practice.

6.
Artículo en Chino | WPRIM (Pacífico Occidental) | ID: wpr-1029563

RESUMEN

Objective:To evaluate the clinical efficacy and safety of endoscopic submucosal dissection (ESD) for early colorectal cancer and its precancerous lesions by using novel lifting clip-assisted traction.Methods:From March to July 2021, 42 patients with colorectal lesions who received ESD at the Digestive Endoscopy Center of Shanghai Tenth People's Hospital were included in the retrospective study. Nineteen patients were enrolled as the observation group using the novel lifting clip, and 23 others in the control group without the help of an auxiliary method. The operation time, the hospital stay, hospital expenses and the incidence of complications of the two groups were compared.Results:All 42 patients successfully received ESD. The operation time of the observation group was significantly shorter than that of the control group [31.00 (21.00, 58.00) min VS 60.00 (30.00, 75.00) min, Z=-2.04, P=0.04]. The postoperative hospital stay of the observation group was significantly shorter than that of the control group [2.00 (1.00, 2.00) d VS 2.00 (2.00, 3.00) d, Z=-1.99, P=0.04]. The hospital cost was lower than that of the control group, but the difference was not statistically significant (19 331.42 ± 3 481.20 yuan VS 19 802.40 ± 2 548.50 yuan, t=-0.49, P=0.63). No intraoperative perforation occurred in either group. There was no significant difference in intraoperative blood loss between the observation group and the control group [0.00 (0.00, 5.00) mL VS 3.00 (0.00, 7.00) mL, Z=-1.42, P=0.16]. There was 1 case of postoperative abdominal pain in the observation group, 2 cases of postoperative abdominal pain and 1 case of fever in the control group. There was no significant difference in the overall incidence of postoperative complications between the observation group and the control group [5.3% (1/19) VS 13.0% (3/23), χ2=0.73, P=0.39]. Conclusion:The novel lifting clip-assisted colorectal ESD is safe and effective, which can significantly shorten the ESD operation time and postoperative hospital stay without increasing the economic burden of patients.

8.
Bone Res ; 10(1): 62, 2022 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-36289197

RESUMEN

Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.

9.
Am J Transl Res ; 14(7): 4591-4605, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35958497

RESUMEN

OBJECTIVE: To explore the synergistic effect and metabolic mechanism of chronic arsenic exposure and PTPN11 gain-of-function mutation on tumorigenesis. METHODS: Arsenic-transformed Ptpn11+/+ (WT-As) and Ptpn11D61G/+ -mutant (D61G-As) mouse embryonic fibroblasts (MEFs) were established by chronic treatment of low-dose arsenic. We used cell counting, plate colony and soft agar colony formation, and a nude mouse xenograft model to detect malignant transformation and tumorigenesis in vitro and in vivo. To detect mitochondrial oxidative phosphorylation (OXPHOS), we used Seahorse real-time cell metabolic analysis as well as adenosine triphosphate (ATP) and ROS production assays. Lastly, we examined mTOR signaling pathway changes by western blotting. RESULTS: Low-dose arsenic exposure promoted WT MEFs proliferation and exacerbated malignancy driven by Ptpn11D61G/+ mutation. Additionally, Ptpn11D61G/+ -mutant MEFs exhibited increased mitochondrial metabolism and low-dose arsenic amplified this malignant metabolic activity. Mechanistically, the mTOR signaling pathway was activated in Ptpn11D61G/+ -mutant MEFs and was further phosphorylated in arsenic-treated MEFs expressing Ptpn11D61G/+ . Critically, tumorigenesis induced by the synergistic effect of low-dose arsenic and Ptpn11D61G/+ mutation was prevented by mTOR pathway inhibition via rapamycin. CONCLUSION: This study found that metabolic reprogramming, particularly mitochondrial hyperactivation, is a core mechanism underlying tumorigenesis induced by the synergistic effect of Ptpn11D61G/+ mutation and arsenic exposure. Furthermore, these findings suggested mTOR is a therapeutic target for Ptpn11-associated cancers.

10.
Front Cell Dev Biol ; 10: 857045, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35756991

RESUMEN

Bone marrow microenvironment (BMM) has been proven to have benefits for both normal hematopoietic stem cell niche and pathological leukemic stem cell niche. In fact, the pathological leukemia microenvironment reprograms bone marrow niche cells, especially mesenchymal stem cells for leukemia progression, chemoresistance and relapse. The growth and differentiation of MSCs are modulated by leukemia stem cells. Moreover, chromatin abnormality of mesenchymal stem cells is sufficient for leukemia initiation. Here, we summarize the detailed relationship between MSC and leukemia. MSCs can actively and passively regulate the progression of myelogenous leukemia through cell-to-cell contact, cytokine-receptor interaction, and exosome communication. These behaviors benefit LSCs proliferation and survival and inhibit physiological hematopoiesis. Finally, we describe the recent advances in therapy targeting MSC hoping to provide new perspectives and therapeutic strategies for leukemia.

11.
Front Immunol ; 13: 868813, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35514975

RESUMEN

Breast cancer development and progression rely not only on the proliferation of neoplastic cells but also on the significant heterogeneity in the surrounding tumor microenvironment. Its unique microenvironment, including tumor-infiltrating lymphocytes, complex myeloid cells, lipid-associated macrophages, cancer-associated fibroblasts (CAFs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a crucial role in the occurrence, growth, and metastasis of breast cancer. However, a detailed understanding of the complex microenvironment in breast cancer remains largely unknown. The unique pattern of breast cancer microenvironment cells has been poorly studied, and neither has the supportive role of these cells in pathogenesis been assessed. Single-cell multiomics biotechnology, especially single-cell RNA sequencing (scRNA-seq) reveals single-cell expression levels at much higher resolution, finely dissecting the molecular characteristics of tumor microenvironment. Here, we review the recent literature on breast cancer microenvironment, focusing on scRNA-seq studies and analyzing heterogeneity and spatial location of different cells, including T and B cells, macrophages/monocytes, neutrophils, and stromal cells. This review aims to provide a more comprehensive perception of breast cancer microenvironment and annotation for their clinical classification, diagnosis, and treatment. Furthermore, we discuss the impact of novel single-cell omics technologies, such as abundant omics exploration strategies, multiomics conjoint analysis mode, and deep learning network architecture, on the future research of breast cancer immune microenvironment.


Asunto(s)
Neoplasias de la Mama , Fibroblastos Asociados al Cáncer , Neoplasias de la Mama/patología , Fibroblastos Asociados al Cáncer/metabolismo , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Análisis de la Célula Individual , Microambiente Tumoral
12.
Helicobacter ; 27(4): e12895, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35437862

RESUMEN

BACKGROUND: Macrophages, as innate immune cells, were reported to participate in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis. However, the role and mechanism of macrophage dysfunction in H. pylori-associated pediatric gastritis remain unclear. MATERIALS AND METHODS: An RNA-sequencing assay was used to examine the differential gene expression in normal gastric antrum, non-H. pylori-infected tissue, and H. pylori-infected pediatric gastritis tissue. qPCR assays were applied to verify the expression of target genes. HE staining was performed to identify the occurrence of inflammation in the normal gastric antrum, non-H. pylori-infected tissue, and H. pylori-infected pediatric gastritis tissue. Western blotting was used to measure the expression of SHP2 in pediatric gastritis tissue. The metabolic profile of macrophages was determined via Seahorse metabolic analysis. Flow cytometry analysis was used to examine the level of reactive oxygen species (ROS). RESULTS: We found that H. pylori -infected gastritis tissue exhibited many differentially expressed genes (DEGs) compared to gastritis tissue without H. pylori infection. Moreover, H. pylori -infected gastritis tissue showed many DEGs annotated with an overactive immune response. We identified that tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), which encodes SHP2, was significantly increased in macrophages of H. pylori -infected gastritis tissue. Furthermore, we revealed that SHP2 could activate the glycolytic function of macrophages to promote H. pylori -induced inflammation. The transcription factor SPI1 , as the downstream molecule of SHP2, could be responsible for the regulation of metabolism-associated gene expression and inflammation. CONCLUSION: Our study illustrated the molecular landscape of H. pylori-infected gastritis tissue in children and suggested that the SHP2/SPI1axis could be a novel therapeutic target in H. pylori-induced pediatric gastritis.


Asunto(s)
Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Niño , Mucosa Gástrica/patología , Gastritis/patología , Glucólisis , Humanos , Inflamación/patología , Macrófagos/metabolismo
13.
Sensors (Basel) ; 21(12)2021 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-34204575

RESUMEN

Advanced heart monitors, especially those enabled by the Internet of Health Things (IoHT), provide a great opportunity for continuous collection of the electrocardiogram (ECG), which contains rich information about underlying cardiac conditions. Realizing the full potential of IoHT-enabled cardiac monitoring hinges, to a great extent, on the detection of disease-induced anomalies from collected ECGs. However, challenges exist in the current literature for IoHT-based cardiac monitoring: (1) Most existing methods are based on supervised learning, which requires both normal and abnormal samples for training. This is impractical as it is generally unknown when and what kind of anomalies will occur during cardiac monitoring. (2) Furthermore, it is difficult to leverage advanced machine learning approaches for information processing of 1D ECG signals, as most of them are designed for 2D images and higher-dimensional data. To address these challenges, a new sensor-based unsupervised framework is developed for IoHT-based cardiac monitoring. First, a high-dimensional tensor is generated from the multi-channel ECG signals through the Gramian Angular Difference Field (GADF). Then, multi-linear principal component analysis (MPCA) is employed to unfold the ECG tensor and delineate the disease-altered patterns. Obtained principal components are used as features for anomaly detection using machine learning models (e.g., deep support vector data description (deep SVDD)) as well as statistical control charts (e.g., Hotelling T2 chart). The developed framework is evaluated and validated using real-world ECG datasets. Comparing to the state-of-the-art approaches, the developed framework with deep SVDD achieves superior performances in detecting abnormal ECG patterns induced by various types of cardiac disease, e.g., an F-score of 0.9771 is achieved for detecting atrial fibrillation, 0.9986 for detecting right bundle branch block, and 0.9550 for detecting ST-depression. Additionally, the developed framework with the T2 control chart facilitates personalized cycle-to-cycle monitoring with timely detected abnormal ECG patterns. The developed framework has a great potential to be implemented in IoHT-enabled cardiac monitoring and smart management of cardiac health.


Asunto(s)
Fibrilación Atrial , Electrocardiografía , Corazón , Humanos , Internet , Monitoreo Fisiológico
14.
Cancer Cell Int ; 21(1): 337, 2021 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-34217295

RESUMEN

BACKGROUND: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), posing a major challenge to developing effective treatment of lung adenocarcinoma (LUAD). The strategy of combining EGFR-TKI with other synergistic or sensitizing therapeutic agents are considered a promising approach in the era of precision medicine. Moreover, the role and mechanism of SHP2, which is involved in cell proliferation, cytokine production, stemness maintenance and drug resistance, has not been carefully explored in lung adenocarcinoma (LUAD). METHODS: To evaluate the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 inhibition was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing was performed to explore the mechanism of SHP2 promoted stemness. RESULTS: This study demonstrated that high SHP2 expression level correlates with poor outcome of LUAD patients, and SHP2 expression is enriched in Osimertinib resistant LUAD cells. SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. SHP2 facilitates the secretion of CXCL8 cytokine from the EGFR T790M mutant LUAD cells, through a CXCL8-CXCR1/2 positive feedback loop that promotes stemness and tumorigenesis. Our results further show that SHP2 mediates CXCL8-CXCR1/2 feedback loop through ERK-AKT-NFκB and GSK3ß-ß-Catenin signaling in EGFR T790M mutant LUAD cells. CONCLUSIONS: Our data revealed that SHP2 inhibition enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may help provide an alternative therapeutic option to enhance the clinical efficacy of osimertinib in EGFR T790M mutant LUAD patients.

15.
Arch Gerontol Geriatr ; 94: 104334, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33516077

RESUMEN

Using the Pearlin stress process model, the present study aimed to test if there was an association between caregiving intensity and caregiver burden, to analyze what type of association existed, and to test if different indicators of social support moderated such association among caregivers of people with dementia. Data from the baseline assessment of the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) (N = 637) were used. Caregiver burden (12-item Zarit caregiver burden scale), caregiving intensity (caregiving hours), and social support (Lubben social network, received support, satisfaction with support, and negative interactions) were the main measurements. Separate multivariate regression models were conducted with Stata 16. The results showed that the relationship between caregiving hours and caregiver burden was a nonlinear inversed U shape after controlling all of the socio-demographic variables. Further analyses showed that when caregiving hours reached 14 hours per day, the levels of burden were the highest. In addition, received support, satisfaction with support, and social network significantly buffered the relationship between caregiving hours and caregiver burden when they were examined separately. However, only social network played a significant buffering role when examining the four social support indicators simultaneously. These findings suggest the need for programs and practices that emphasize the importance of identifying, gaining, and strengthening positive aspect of social support, especially in how to broaden a caregiver's social network while caring for a family member with dementia.


Asunto(s)
Enfermedad de Alzheimer , Cuidadores , Carga del Cuidador , Costo de Enfermedad , Humanos , Apoyo Social
16.
Am J Emerg Med ; 40: 148-158, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32063427

RESUMEN

OBJECTIVE: To develop a novel model for predicting Emergency Department (ED) prolonged length of stay (LOS) patients upon triage completion, and further investigate the benefit of a targeted intervention for patients with prolonged ED LOS. MATERIALS AND METHODS: A two-step model to predict patients with prolonged ED LOS (>16 h) was constructed. This model was initially used to predict ED resource usage and was subsequently adapted to predict patient ED LOS based on the number of ED resources using binary logistic regressions and was validated internally with accuracy. Finally, a discrete event simulation was used to move patients with predicted prolonged ED LOS directly to a virtual Clinical Decision Unit (CDU). The changes of ED crowding status (Overcrowding, Crowding, and Not-Crowding) and savings of ED bed-hour equivalents were estimated as the measures of the efficacy of this intervention. RESULTS: We screened a total of 123,975 patient visits with final enrollment of 110,471 patient visits. The overall accuracy of the final model predicting prolonged patient LOS was 67.8%. The C-index of this model ranges from 0.72 to 0.82. By implementing the proposed intervention, the simulation showed a 12% (1044/8760) reduction of ED overcrowded status - an equivalent savings of 129.3 ED bed-hours per day. CONCLUSIONS: Early prediction of prolonged ED LOS patients and subsequent (simulated) early CDU transfer could lead to more efficiently utilization of ED resources and improved efficacy of ED operations. This study provides evidence to support the implementation of this novel intervention into real healthcare practice.


Asunto(s)
Servicio de Urgencia en Hospital , Tiempo de Internación/estadística & datos numéricos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Triaje
17.
Artículo en Inglés | WPRIM (Pacífico Occidental) | ID: wpr-921378

RESUMEN

OBJECTIVES@#A study was conducted to investigate the clinical effects of oral digital design on the aesthetic restoration of anterior teeth of cleft lip/palate patients.@*METHODS@#Nine adult cleft lip/palate patients who need aesthetic restoration of anterior teeth were recruited. Digital information of patients' dental arches, the surrounding soft tissue and face were captured by digital camera and scanner. The aesthetic analysis and design were conducted using keynote and 3shape software and were demonstrated to the patients. The optimized treatment plan was ensured by communicating with the patients. Digital wax-up models were exported and printed into resin diagnostic models, which were then utilized in the treatment process to guide the doctors and the technicians in tooth preparation and in making the final restorations, respectively. The adhesive procedure was completed after satisfactory try-in. Aesthetics assessment was conducted in accordance with the anterior esthetic evaluation form. The scores of patient's satisfaction were recorded on a questionnaire containing six items of aesthetic index and doctor-patient communication. Patients were interviewed and examined after 1, 3, 6, and 12 months, respectively, and the clinical effects of restorations were evaluated.@*RESULTS@#All nine patients had satisfactory clinical results. The aesthetic defects of the patients were effectively addressed. All treatments met the requirements of the preoperative digital designs. The patients' scores were all above 90 on the satisfaction scale. At 12 months after the operation, the clinical effects of restorations of all cases achieved A class in each evaluation indicator.@*CONCLUSIONS@#For cleft lip/palate patients with esthetic defect in the anterior teeth, the digital design plays an important role in optimizing the treatment plan and guides the whole treatment process. This design can help clinicians achieve predictable satisfactory aesthetic results.


Asunto(s)
Adulto , Humanos , Labio Leporino , Fisura del Paladar , Estética , Diente
18.
Cell ; 183(2): 490-502.e18, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33002410

RESUMEN

The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.


Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células A549 , Animales , Niño , Preescolar , Femenino , Mutación con Ganancia de Función/genética , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Células Madre Embrionarias de Ratones , Mutación/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Transducción de Señal , Dominios Homologos src/genética
19.
Journal of Experimental Hematology ; (6): 1321-1325, 2020.
Artículo en Chino | WPRIM (Pacífico Occidental) | ID: wpr-827118

RESUMEN

OBJECTIVE@#To investigate the clinical characteristics of essential thrombocytopenia (ET) patients with positive mutations including JAK2, CALR, MPL, or negative mutations.@*METHODS@#A total of 66 newly diagnosed ET cases from January 2016 to December 2018 in Department of Hematology, Huaian No.1 People's Hospital affiliated to Nanjing Medical University were analyzed. Statistical analysis data included the patient's sex, age, symptoms, thrombosis and embolism events, spleen omegaly, platelet count (Plt), leukocyte (WBC) count, hemoglobin (Hb), fibrinogen (FIB), thrombus elastic diagram (TEG), serum potassium, blood glucose (GLU), lactate dehydrogenase (LDH), JAK2, CALR and MPL mutations, treatment options, and efficacy.@*RESULTS@#All the patients were not MPL-positive, and divided in three groups: JAK2 mutation (46 cases, 69.7%), CALR mutation (9 cases, 13.6%) and gene negative mutation (11 cases, 16.7%) group. The average age of patients in the JAK2 mutation group was 63.2 years old, and significantly higher than that in the CALR mutation group (51.8 year) and gene negative group (50.2 year) (P<0.05). Compared with the JAK2 mutation group and gene negative group, the CALR mutation group had lower WBC count (6.3×10/L vs 13.79×10/L) (P=0.003) (6.3×10/L vs 9.70×10/L) (P=0.009). Also the Hb level of patients in CALR mutation group was lower than the JAK2 mutation group (121.22 g/L vs 136.2 g/L) (P=0.036). However, there was higher tumor burden in the CALR mutation group, compared with the gene negative mutation group (300.11 U/L vs 227.4 U/L) (P=0. 033). There was no significant difference among the three groups, such as the Plt counts, serum potassium level, GLU level and FIB level (P>0.05). In addition, thrombus and embolism appeared in 30.3% (20/66) cases. 18.2% (12/66) cases were complicated with hyperkalemia, which significantly correlated with Plt counts (r=0.518). TEG was performed in 34 patients, of which 41.2% (14/34) had abnormal TEG and 55.9% (19/34) were accompanied by Plt count > 1 000 ×10/L, but there was no significant correlation between them (r=0.134). After routine clinical treatment, all the 66 cases achieved partial or complete hematological remission, but the disease usually repeated. Until now 4.5% (3/66) cases had been converted to myelofibrosis (MF) all with JAK2 mutation, but without advancing to acute myeloid leukemia.@*CONCLUSION@#ET patients with JAK2 mutation have higher incidence, moreover were in older age. However, the patients with CALR mutations display lower WBC count and Hb level, but higher tumor burden. In short, the multiple gene mutations of ET showed different clinical features closely relates with the prognosis, thus providing guidance for the clinical diagnosis and treatment.


Asunto(s)
Anciano , Humanos , Persona de Mediana Edad , Calreticulina , Genética , Janus Quinasa 2 , Genética , Mutación , Mielofibrosis Primaria , Trombocitemia Esencial , Trombocitopenia
20.
Journal of Experimental Hematology ; (6): 1985-1990, 2020.
Artículo en Chino | WPRIM (Pacífico Occidental) | ID: wpr-880003

RESUMEN

OBJECTIVE@#To investigate the clinical significance of the targeted next-generation sequencing assay for patients with suspected myeloid malignancies.@*METHODS@#A total of 39 hematopenia patients with suspected myeloid malignamies in Department of Hematology of The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University from January 2018 to April 2019 were treated, 20 hot spot genes of myelodysplastic syndrome (MDS) were detected.@*RESULTS@#Regarding the diagnostic type, there were 7 cases of idiopathic cytopenia of undetermined significance (ICUS), 8 cases of clonal cytopenias of undetermined significance (CCUS) and 24 cases of myeloid myeloid malignancies which included 18 cases of MDS, 4 cases of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and 2 cases of acute myeloid leukemia. Positive mutation was detected in 70.8% (17/24) of myeloid malignancy patients , and 72.7% (16/22) in MDS and MDS/MPN patients. The main mutation types were ASXL1, TET2 and RUNX1. Compared with gene negative group, there were no significant differences in sex, age (<60 years old or ≥60 years old), proportion of bone marrow blast cells (<5% or≥5%) and cytogenetics (good, medium and poor) (P>0.05). Furthermore, all 8 CCUS patients showed positive mutation, and the incidence of double or multiple mutation in CCUS group was significantly lower than that of the MDS and MDS/MPN group (37.5% vs 54.5%) (P=0.002). The mutation types between the two groups were similar, and there was no significant difference in variant allele frequency (P>0.05).@*CONCLUSION@#Our results suggest that there are high rates of double or multiple mutations in myeloid malignancies, especially in patients with MDS and MDS/MPN. Targeted sequencing assay can improve the diagnosis of myeloid malignancies, and guide clinical treatment.


Asunto(s)
Humanos , Persona de Mediana Edad , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Enfermedades Mielodisplásicas-Mieloproliferativas , Pacientes
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