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1.
Sensors (Basel) ; 24(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38610424

RESUMO

Mural paintings, as the main components of painted cultural relics, have essential research value and historical significance. Due to their age, murals are easily damaged. Obtaining intact sketches is the first step in the conservation and restoration of murals. However, sketch extraction often suffers from problems such as loss of details, too thick lines, or noise interference. To overcome these problems, a mural sketch extraction method based on image enhancement and edge detection is proposed. The experiments utilize Contrast Limited Adaptive Histogram Equalization (CLAHE) and bilateral filtering to enhance the mural images. This can enhance the edge features while suppressing the noise generated by over-enhancement. Finally, we extract the refined sketch of the mural using the Laplacian Edge with fine noise remover (FNR). The experimental results show that this method is superior to other methods in terms of visual effect and related indexes, and it can extract the complex line regions of the mural.

2.
BMC Womens Health ; 24(1): 248, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637788

RESUMO

BACKGROUND: Idiopathic granulomatous mastitis (IGM) results in notable clinical symptoms and breast deformity. This study aimed to evaluate the clinical feasibility of microwave ablation (MWA) for the treatment of IGM through comparison with surgical excision. METHODS: From June 2016 to December 2020, a total of 234 consecutive patients admitted to the hospital were retrospectively included in this study. IGM was pathologically confirmed via breast biopsy in all included patients. These patients were divided into the MWA group (n = 91) and surgical group (n = 143) based on the type of treatment. Patients in both groups received oral prednisone prior to intervention. The clinical remission rate, recurrence rate, operative pain, complications, and BREAST Q score were compared between the two groups. RESULTS: There were 340 lesions in the MWA group, and 201 lesions in the surgical group were ultimately included. Significant differences in the complete remission rate (96.7% vs. 86.7%, p = 0.020), recurrence rate (3.3% vs. 13.3%, p = 0.020), operation time (48.7±14.6 min vs. 68.1±36.4 min, p < 0.001), postoperative pain (p < 0.001) and postoperative BREAST Q score (p < 0.001) were observed between the MWA and surgical groups. CONCLUSIONS: Microwave ablation is feasible for the treatment of IGM, due to its high curative rate and low recurrence rate. Because of the minimal invasiveness of MWA and sufficient preservation of the gland and contour of the breast, patients are more satisfied with the appearance of the breast. Therefore, for patients with complex conditions requiring surgery, MWA is a good alternative treatment.


Assuntos
Mastite Granulomatosa , Feminino , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Mastite Granulomatosa/cirurgia , Micro-Ondas/uso terapêutico , Ultrassonografia de Intervenção , Imunoglobulina M/uso terapêutico
3.
World J Surg Oncol ; 22(1): 104, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637834

RESUMO

OBJECTIVES: To investigate the clinicopathological characteristics and prognosis of patients with primary sarcoma of the uterine cervix. METHODS: We identified all patients with primary cervical sarcomas treated at our institution from 2002 to 2020 and analyzed the clinicopathological characteristics and prognosis. RESULTS: 34 patients were identified, 7 (20.6%) patients had leiomyosarcoma, 6 (17.6%) had carcinosarcoma, 5 (14.7%) had Ewing sarcoma, 4 (11.8%) had rhabdomyosarcoma, 4 (11.8%) had undifferentiated sarcoma, 2 (5.9%) had adenosarcoma, 2 (5.9%) had endometrial stromal sarcoma, 1 (2.9%) had dermatofibrosarcoma protuberans, 1 (2.9%) had alveolar soft tissue sarcoma and 2 (5.9%) had sarcoma not otherwise specified. The median age of the whole patients was 43.5 years (range, 13-63). The median age of patients with Ewing sarcoma or rhabdomyosarcoma was 22 years (range, 13-39) and 17 years (range, 13-36 years), respectively. The distribution by stage was: stage I in 21 (61.8%) patients, stage II in 4 (11.8%), stage III in 6 (17.6%) and stage IV in 3 (8.8%). Overall, 30 patients (88.2%) received surgical treatment. The median follow-up was 33.3 months (range 3.6-187.3 months). 11 patients died within 2 years after diagnosis, most of them were patients with carcinosarcoma or undifferentiated sarcoma (45.5%, 5/11). In the entire cohort, 2- and 5-year OS were 67.2% and 56.9%, respectively. 5-year OS was 25.0% for undifferentiated sarcoma, 50.0% for rhabdomyosarcoma, 50.0% for carcinosarcoma, 53.3% for Ewing sarcoma, 57.1% for leiomyosarcoma. CONCLUSION: Cervical sarcomas are rare neoplasms with multiple histological subtypes and follow an aggressive course. Prognosis may be associated with tumor histology and stage.


Assuntos
Carcinossarcoma , Leiomiossarcoma , Rabdomiossarcoma , Sarcoma de Ewing , Sarcoma , Neoplasias do Colo do Útero , Neoplasias Uterinas , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Leiomiossarcoma/patologia , Sarcoma de Ewing/cirurgia , Neoplasias do Colo do Útero/cirurgia , Neoplasias Uterinas/diagnóstico , Sarcoma/cirurgia , Sarcoma/diagnóstico , Carcinossarcoma/patologia , Rabdomiossarcoma/cirurgia , Prognóstico
4.
J Adv Res ; 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38556044

RESUMO

INTRODUCTION: Breast cancer-related bone metastasis can lead to skeletal-related events (SREs), which decrease patient quality of life. Inhibition of osteoclastogenesis is a key treatment for SREs; however, the availability of clinical drugs remains limited, and all existing ones disrupt physiological bone formation, while exhibiting no effect on patient survival time. OBJECTIVES: This study aimed to identify a novel osteoclast inhibitor for the treatment of breast cancer-induced SREs. METHODS: The MDA-MB-231 breast cancer cell-induced bone loss model was used to investigate the therapeutic effects of erianin in vivo. Then, we evaluated the inhibitory effects of erianin on osteoclastogenesis and signalling in bone marrow-derived macrophages (BMMs) induced by conditioned medium from MDA-MB-231 breast cancer cells (231 CM) and receptor activator of nuclear factor-κB ligand (RANKL) in vitro. Next, a Cellular Thermal Shift Assay and siRNA-mediate knockdown were performed, to investigate the target of erianin during osteoclast formation. The effects of erianin on human osteoclastogenesis were evaluated using CD14+ monocytes obtained from patients with breast cancer. RESULTS: Erianin effectively improved breast cancer cells-induced bone destruction at doses of 2 and 20 mg/kg/day in vivo, while suppressing osteoclastogenesis and the upregulation of SRC-NFATc1, INTEGRIN ß3-MMP9 signals induced by 231 CM and RANKL in vitro. Furthermore, erianin interacted with NFATc1 but not SRC, and Nfatc1 knockdown eliminated the inhibitory effects of erianin on osteoclastogenesis. Notably, lower expression of NFATc1 positively correlated with longer survival in patients with cancer and a high risk of bone metastasis. We further revealed that 62.5-250 nM erianin suppresses NFATc1 and excessive osteoclastogenesis in CD14+ monocytes from patients with breast cancer. CONCLUSION: Erianin acts as an NFATc1 inhibitor that attenuates breast cancer-induced osteoclastogenesis and bone destruction.

5.
Int J Hematol ; 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38441775

RESUMO

OBJECTIVE: To describe the features of ETV6::ABL1 AML as well as the clinical treatment and outcomes. METHODS: Clinical data were collected from three patients diagnosed with ETV6::ABL1 AML at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital. Their clinical and laboratory features were analyzed, and the treatment process and outcomes were described. Ten reported cases of ETV6::ABL1 AML from the literature were also included for analysis. RESULTS: The median age of the patients was 34 years, and 2 patients were male. No patient had a history of blood disorders before diagnosis. After relapse, they were referred to our hospital, where the ETV6::ABL1 gene was detected. Unfortunately, Patient 1 died rapidly after leukemia relapse due to severe infection. Patients 2 and 3 received salvage therapy with a dasatinib-containing regimen, followed by allo-HSCT, and are currently alive and disease-free. CONCLUSION: ETV6::ABL1 is a rare but recurrent genetic aberration in AML, and the combined use of fluorescence in situ hybridization and PCR can better identify this fusion gene. Patients carrying ETV6::ABL1 have a high relapse rate and a poor prognosis. TKIs are a reasonable treatment option for this group, and allo-HSCT may be curative.

6.
Diabetol Metab Syndr ; 16(1): 58, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438889

RESUMO

BACKGROUND: The role of stress hyperglycemia ratio (SHR) on the prognosis of spontaneous intracerebral hemorrhage (ICH) in patients with different diabetic status has not been elucidated. This study aimed to evaluate the prognostic value of SHR and admission blood glucose (ABG) for the short- and long-term mortality in diabetic and nondiabetic populations with ICH. METHOD: Participants with ICH were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC-IV). The primary outcome was all-cause 30-day and 1-year mortality. The association of SHR and ABG with the primary outcomes in diabetic and nondiabetic cohorts were assessed by Cox proportional hazard regression. RESULTS: Overall, 1029 patients with a median age of 71.09 (IQR: 60.05-81.97) were included. Among them, 548 (53%) individuals were male, and 95 (19%) as well as 323 (31%) ones experienced the 30-day and 1-year mortality, respectively. After adjusting for confounding variables, individuals in quintile 5 of SHR had significantly higher risk of the 30-day and 1-year mortality than those in quintile 1 in the whole cohort (30-day mortality: HR 3.33, 95%CI 2.01-5.51; 1-year mortality: HR 2.09, 95% CI 1.46-3.00) and in nondiabetic patients (30-day mortality: HR 4.55, 95%CI 2.33-8.88; 1-year mortality: HR 3.06, 95%CI 1.93-4.86), but no significant difference was observed in diabetic patients. Similar results were observed for ABG as a categorical variable. As continuous variable, SHR was independently correlated with the 30-day and 1-year mortality in both of the diabetic and nondiabetic cohorts (30-day mortality: HR 2.63, 95%CI 1.50-4.60. 1-year mortality: HR 2.12, 95%CI 1.33-3.39), but this correlation was only observed in nondiabetic cohort for ABG (HR 1.00, 95%CI 0.99-1.01 for both of the 30-day and 1-year mortality). Moreover, compared with ABG, SHR can better improve the C-statistics of the original models regarding the 30-day and 1-year outcomes, especially in patients with diabetes (p < 0.001 in all models). CONCLUSION: SHR might be a more useful and reliable marker than ABG for prognostic prediction and risk stratification in critically ill patients with ICH, especially in those with diabetes.

7.
Children (Basel) ; 11(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38397250

RESUMO

A serious game titled "Crossing the Jungle" was developed in this study to train children's inhibition skills using the Stroop task. The effects of inhibitory control on children were tested by a pre-test, post-test, and one-month follow-up test. In the control groups, children were asked to play a commercial game instead. In experiment 1, 48 participants chose either the training or control game voluntarily, whereas, in experiment 2, 44 participants were randomly assigned to either group. In both experiments, children exposed to the serious game demonstrated training effects from the Stroop spatial task and near-transfer effects from the Flanker task. However, transferring effects were not produced by the Go/No-go task. As a result, although the serious game "Crossing the Jungle" does not improve response inhibition, children aged 9 to 12 who play it may benefit from improved interference inhibition abilities. This provides evidence for the mutual independence of interference inhibition and response inhibition in children at this stage.

8.
Tissue Cell ; 87: 102323, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38412577

RESUMO

BACKGROUND: Peiminine (PMI) is an active alkaloid sourced from Fritillaria thunbergii, which has been shown to suppress the development of a variety of tumors. Whereas, the roles and precise mechanism of PMI in breast cancer (BC) development remain not been clarified. METHODS: The cytotoxic effect of PMI on MCF-10A and BC cell lines (MCF-7 and BT-549) were assessed by MTT and LDH release assay. Cell proliferation was evaluated by EdU staining. Levels of Malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH) activity and iron assay were measured by Enzyme linked immunosorbent assay (ELISA) kits, respectively. Transmission Electron Microscope was performed to observe mitochondrial morphological structure. Immunofluorescence, immunohistochemistry, and western blot were conducted to examine protein levels, respectively. Xenograft model was used to confirm cellular findings. RESULTS: PMI treatment reduced the viability and enhanced LDH level of MCF-7 and BT-549 cells in a time- and concentration-dependent manner, and further suppressed cell proliferation in vitro and tumor growth in vivo. Subsequently, PMI administration resulted in significant increases of ROS, MDA and iron levels, reduction of GSH activity as well as mitochondrial shrinkage and GPX4 reduction, while all these phenomena could be rescued by ferrostatin-1. Mechanistically, PMI treatment led to promoted Nrf2 expression and its nuclear translocation, as well as it's downstream protein HO-1 and NQO1 expressions. Notably, ML-385, a Nrf2 specific inhibitor, greatly reversed the anti-tumor effects and pro-ferroptosis role of PMI in BC cells. CONCLUSION: Taking these finding together, PMI could stimulate ferroptosis to inhibit BC tumor growth by activating Nrf2-HO-1 signaling pathway.


Assuntos
Neoplasias da Mama , Cevanas , Ferroptose , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Transdução de Sinais , Ferro
9.
Adv Sci (Weinh) ; 11(14): e2304046, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38311581

RESUMO

Sonodynamic therapy (SDT), a tumor treatment modality with high tissue penetration and low side effects, is able to selectively kill tumor cells by producing cytotoxic reactive oxygen species (ROS) with ultrasound-triggered sonosensitizers. N-type inorganic semiconductor TiO2 has low ROS quantum yields under ultrasound irradiation and inadequate anti-tumor activity. Herein, by using atomic layer deposition (ALD) to create a heterojunction between porous TiO2 and CoOx, the sonodynamic therapy efficiency of TiO2 can be improved. Compared to conventional techniques, the high controllability of ALD allows for the delicate loading of CoOx nanoparticles into TiO2 pores, resulting in the precise tuning of the interfaces and energy band structures and ultimately optimal SDT properties. In addition, CoOx exhibits a cascade of H2O2→O2→·O2 - in response to the tumor microenvironment, which not only mitigates hypoxia during the SDT process, but also contributes to the effect of chemodynamic therapy (CDT). Correspondingly, the synergistic CDT/SDT treatment is successful in inhibiting tumor growth. Thus, ALD provides new avenues for catalytic tumor therapy and other pharmaceutical applications.


Assuntos
Peróxido de Hidrogênio , Nanopartículas , Humanos , Espécies Reativas de Oxigênio , Catálise , Hipóxia
10.
Int J Biol Macromol ; 263(Pt 2): 130310, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38382774

RESUMO

L-threo-p-nitrophenylserine (component 2) is an important intermediate during synthesis of chloramphenicol. However, its biosynthesis is limited by enzyme activity and stereoselectivity. In this study, we achieved a breakthrough in the high-efficiency production of 2 by employing engineered Chitiniphilus shinanonensis L-threonine transaldolase (ChLTTA) in conjunction with a by-product elimination system within a one-pot reaction. Notably, a novel visual stepwise high-throughput screening method was developed for the directed evolution of ChLTTA, leveraging its characteristic color. The engineered mutant F70D/F59A (Mu6 variant) emerged as a star performer, exhibiting a remarkable 2.6-fold increase in catalytic efficiency over the wild-type ChLTTA, coupled with an outstanding 91.5 % diastereoisomer excess (de). Molecular dynamics (MD) simulations unraveled the mechanism responsible for the enhanced catalytic performance observed in the Mu6 variant. Meanwhile, the Mu6 variant was coupled with Saccharomyces cerevisiae ethanol dehydrogenase (ScADH) and Candida boidinii formate dehydrogenase (CbFDH) to create a high-efficiency cascade system (E.coli/pRSF-Mu6-ScADH-CbFDH). Under optimized conditions, this cascade system demonstrated unparalleled performance, yielding 201.5 mM of 2 with an impressive conversion of 95.9 % and a de value of 94.5 %. This achievement represents the highest reported yield to date. This study offers a novel insight into the sustainable and efficient production of chloramphenicol intermediate.


Assuntos
Treonina , Transaldolase , Cloranfenicol , Escherichia coli/genética
11.
BMC Cancer ; 24(1): 242, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383340

RESUMO

PURPOSE: To explore the association between preoperative WBC count and the long-term survival outcomes and clinical outcomes in different stage patients who underwent surgical resection for colorectal cancer (CRC). PATIENTS AND METHODS: A cohort of 8121 Chinese patients who underwent surgical resection for CRC from January 1, 2008 to December 31, 2014 were enrolled as part of the retrospective cohort were retrospectively analyzed. Based on that the preoperative WBC optimal cut-off value was 7*109/L (7,000/µL), the high preoperative WBC group and the low preoperative WBC group was defined. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. The impact of preoperative WBC count on overall survival (OS) and disease-free survival (DFS) was investigated using the Kaplan-Meier method and Univariate Cox proportional hazards models in different stage subgroup respectively. RESULTS: After IPTW, the clinical characters in the high preoperative WBC count group and the low preoperative WBC count group were balanced. Kaplan-Meier analysis showed that the 5-year OS rate were significantly lower in the high preoperative WBC count group overall, in stage II and IV. The 5-year DFS rate was significantly lower overall, in stage II and III in the high preoperative WBC count group. High preoperative WBC count was associated with poorer OS overall in stage II and stage IV. CONCLUSIONS: This study suggests that preoperative WBC count is an independent risk factor for survival in patients undergoing colorectal surgery and may need to consider the stage of cancer when applied to predict long-term adverse outcome prognosis.


Assuntos
Neoplasias Colorretais , Leucopenia , Humanos , Estudos Retrospectivos , Prognóstico , Contagem de Leucócitos , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença
12.
Acta Pharmacol Sin ; 45(4): 790-802, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38191913

RESUMO

Osteoporosis results from overactivation of osteoclasts. There are currently few drug options for treatment of this disease. Since the successful development of allosteric inhibitors, phosphatases have become attractive therapeutic targets. Protein phosphatase 1, regulatory subunit 15 A (PPP1R15A), is a stress-responsive protein, which promotes the UPR (unfolded protein response) and restores protein homeostasis. In this study we investigated the role of PPP1R15A in osteoporosis and osteoclastogenesis. Ovariectomy (OVX)-induced osteoporosis mouse model was established, osteoporosis was evaluated in the left femurs using micro-CT. RANKL-stimulated osteoclastogenesis was used as in vitro models. We showed that PPP1R15A expression was markedly increased in BMMs derived from OVX mice and during RANKL-induced osteoclastogenesis in vitro. Knockdown of PPP1R15A or application of Sephin1 (a PPP1R15A allosteric inhibitor in a phase II clinical trial) significantly inhibited osteoclastogenesis in vitro. Sephin1 (0.78, 3.125 and 12.5 µM) dose-dependently mitigated the changes in NF-κB, MAPK, and c-FOS and the subsequent nuclear factor of activated T cells 1 (NFATc1) translocation in RANKL-stimulated BMMs. Both Sephin1 and PPP1R15A knockdown increased the phosphorylated form of eukaryotic initiation factor 2α (eIF2α); knockdown of eIF2α reduced the inhibitory effects of Sephin1 on NFATc1-luc transcription and osteoclast formation. Furthermore, Sephin1 or PPP1R15A knockdown suppressed osteoclastogenesis in CD14+ monocytes from osteoporosis patients. In OVX mice, injection of Sephin1 (4, 8 mg/kg, i.p.) every two days for 6 weeks significantly inhibited bone loss, and restored bone destruction and decreased TRAP-positive cells. This study has identified PPP1R15A as a novel target for osteoclast differentiation, and genetic inhibition or allosteric inhibitors of PPP1R15A, such as Sephin1, can be used to treat osteoporosis. This study revealed that PPP1R15A expression was increased in osteoporosis in both human and mice. Inhibition of PPP1R15A by specific knockdown or an allosteric inhibitor Sephin1 mitigated murine osteoclast formation in vitro and attenuated ovariectomy-induced osteoporosis in vivo. PPP1R15A inhibition also suppressed pathogenic osteoclastogenesis in CD14+ monocytes from osteoporosis patients. These results identify PPP1R15A as a novel regulator of osteoclastogenesis and a valuable therapeutic target for osteoporosis.


Assuntos
Guanabenzo , Osteoporose , Animais , Feminino , Humanos , Camundongos , Diferenciação Celular , Guanabenzo/análogos & derivados , Guanabenzo/uso terapêutico , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos , Osteogênese , Osteoporose/tratamento farmacológico , Ovariectomia , Proteína Fosfatase 1/metabolismo , Proteína Fosfatase 1/farmacologia , Ligante RANK/metabolismo
13.
Heliyon ; 10(1): e23500, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38192826

RESUMO

HOXC6 plays an essential part of the carcinogenesis of solid tumors, but its functional relevance within the immune contexture in patients with colorectal cancer (CRC) is still uncertain. We intended to investigate the predictive value of HOXC6 expression for survival outcomes and its correlation with immune contexture in CRC patients by utilizing the Cancer Genome Atlas database (n = 619). Validation was performed in cohorts from Zhongshan Hospital (n = 200) and Shanghai Cancer Center (n = 300). Immunohistochemical (IHC) staining was utilized to compare the levels of immunocytes infiltrating the tumor between the groups with high and low expression of HOXC6. Elevated levels of HOXC6 expression in CRC tissues were linked to malignant progression and poor prognosis. HOXC6 as a risk factor for survival of CRC patients was confirmed. Receiver operating characteristic analysis confirmed its diagnostic value, and a reliable prognostic nomogram was constructed. KEGG analysis and GSEA showed that HOXC6 participated in immune regulation, and its expression was tightly linked to the abundance of infiltrating immunocytes. HOXC6 was upregulated in patients diagnosed with CRC within the two cohorts, and high HOXC6 levels were correlated with a worse prognosis. The high-HOXC6 expression group showed increased infiltration of Treg cells, CD68+ macrophages, CD66b+ neutrophils, and CD8+ T-cells and elevated levels of PD-L1 and PD-1, but decreased levels of granzyme B and perforin. These findings suggest that HOXC6 abundance in patients with CRC determines a poor prognosis, promotes an immunoevasive environment, and directs CD8+ T-cell dysfunction. HOXC6 is expected to become a prospective biomarker for the outcome of CRC.

14.
Nat Struct Mol Biol ; 31(2): 323-335, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38177676

RESUMO

Through targeting essential cellular regulators for ubiquitination and serving as a major platform for discovering proteolysis-targeting chimera (PROTAC) drugs, Cullin-2 (CUL2)-RING ubiquitin ligases (CRL2s) comprise an important family of CRLs. The founding members of CRLs, the CUL1-based CRL1s, are known to be activated by CAND1, which exchanges the variable substrate receptors associated with the common CUL1 core and promotes the dynamic assembly of CRL1s. Here we find that CAND1 inhibits CRL2-mediated protein degradation in human cells. This effect arises due to altered binding kinetics, involving CAND1 and CRL2VHL, as we illustrate that CAND1 dramatically increases the dissociation rate of CRL2s but barely accelerates the assembly of stable CRL2s. Using PROTACs that differently recruit neo-substrates to CRL2VHL, we demonstrate that the inhibitory effect of CAND1 helps distinguish target proteins with different affinities for CRL2s, presenting a mechanism for selective protein degradation with proper pacing in the changing cellular environment.


Assuntos
Proteínas Culina , Ubiquitina , Humanos , Ubiquitina/metabolismo , Proteínas Culina/metabolismo , Especificidade por Substrato , Proteínas de Transporte/metabolismo , Ubiquitinação , Ubiquitina-Proteína Ligases/metabolismo , Fatores de Transcrição/metabolismo
16.
Pathol Res Pract ; 253: 155039, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38134838

RESUMO

The current criteria for utilizing MDM2 Fluorescence In Situ Hybridization (FISH) in adipose-derived tumors were first introduced in 2015 and have been widely adopted. However, these criteria may fail to identify some atypical lipomatous tumors / well-differentiated liposarcoma (ALT/WDL) with mature adipocytic morphology in clinical practice, possibly due to the fact that the existing criteria are primarily based on biopsy cases. Hence, a criterion based on resection cases is needed. In this study, we included 87 adipose tissue tumors with mature adipocytic morphology which were first resected, as well as 9 consultation cases and 25 recurrent resection cases. The final diagnosis was based on MDM2 amplification status. Among the 87 first-time resection cohort, MDM2 FISH amplification was observed in only 2 (5%) of the 39 superficial cases. Marginal infiltration was significantly different in both the MDM2 FISH negative and positive groups (p < 0.05). Of the 37 intramuscular tumors, 17 (46%) showed MDM2 FISH amplification. The MDM2 amplification positive group had a larger tumor size than MDM2 amplification negative group (p = 0.042). Tumors of larger size (≥11 cm) were highly correlated with MDM2 amplification (p = 0.003), but still, 35.3% of the MDM2 amplification-positive cases had tumor sizes less than 11 cm. Eight (66.7%) out of twelve retroperitoneal/ pelvic cases were MDM2 FISH positive. Among the 25 recurrent cases, twenty (80%) of them had MDM2 FISH amplification. In conclusion, we recommend MDM2 FISH for: 1. superficial cases with marginal infiltration based on adequate margin sampling; 2. all intramuscular tumors, retroperitoneal/pelvic tumors and recurrent tumors, both in resection cases and biopsy cases.


Assuntos
Lipoma , Lipossarcoma , Neoplasias Retroperitoneais , Humanos , Lipossarcoma/diagnóstico , Lipossarcoma/genética , Lipossarcoma/patologia , Hibridização in Situ Fluorescente , Amplificação de Genes , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Recidiva Local de Neoplasia/diagnóstico , Lipoma/diagnóstico , Biomarcadores Tumorais
17.
J Agric Food Chem ; 72(1): 461-474, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38153324

RESUMO

l-threo-p-methylsulfonylphenylserine (compound 1b) is the main intermediate of florfenicol, and its efficient synthesis has been the subject of current research. Herein, Burkholderia diffusa l-threonine transaldolase (BuLTTA) was rationally designed based on the sequence-structure-function relationship. A mutant M4 (Asn35Ser/Thr352Asn) could produce 35.5 mM 1b with 88.8% conversion and 93.8% diastereoselectivity, 314 and 129% of the values observed for wild-type BuLTTA. Molecular dynamics simulations indicated that the shortened distance between key active site residues and the transition state (PLP-1b) and the improved hydrogen bond force enhanced the catalytic performance of the M4 variant. Then, the mutant M4 was combined with K. kurtzmanii alcohol dehydrogenase (KkADH) to eliminate the BuLTTA-inhibiting byproduct acetaldehyde, and a cosubstrate was added to regenerate the ADH cofactor NADH. Under optimized conditions, the yield of 1b reached 115.2 mM with a conversion of 96% and a diastereoselectivity of 95.5%. This work provides a new strategy for the efficient and sustainable production of 1b.


Assuntos
Tianfenicol , Treonina , Transaldolase , Acetaldeído
18.
BMC Musculoskelet Disord ; 24(1): 861, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37919727

RESUMO

BACKGROUND: Lipids are critical in bone metabolism, and several studies have highlighted their importance. This study aimed to investigate the relationship between apolipoprotein B (apo B) and bone mineral density (BMD) at different skeletal sites (lumbar spine, femoral neck, and total femur) and to compare the influence of apo B with other traditional lipid markers. METHODS: The study included participants from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2016 who had complete data for apo B and BMD at the three skeletal sites. We used weighted multivariate regression analysis, subgroup analysis, and interaction tests to examine associations. Restricted cubic spline (RCS) was used to examine the non-linear relationship. RESULTS: A total of 4,258 adults were included in the study. Multivariate linear regression analysis showed that the relationship between apo B and BMD varied by skeletal site: a negative association was found with lumbar spine BMD [ß = -0.054, 95%CI: (-0.073, -0.035)]. In contrast, a positive association was found with femoral neck BMD [ß = 0.031, 95%CI: (0.011, 0.051)] and no significant association between apo B and total femur BMD. CONCLUSIONS: Our findings suggest that apo B is associated with BMD in a site-specific manner.


Assuntos
Densidade Óssea , Colo do Fêmur , Adulto , Humanos , Absorciometria de Fóton , Apolipoproteínas B , Colo do Fêmur/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Inquéritos Nutricionais
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