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2.
Front Oncol ; 14: 1332522, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38863624

RESUMEN

Rearrangements involving the neurotrophic-tropomyosin receptor kinase (NTRK) gene family (NTRK1, NTRK2, and NTRK3) have been identified as drivers in a wide variety of human cancers. However, the association between NTRK rearranged thyroid carcinoma and clinicopathological characteristics has not yet been established. In our study, we retrospectively reviewed medical records of thyroid cancer patients and identified 2 cases with NTRK rearrangement, no additional molecular alterations were observed in either of these cases. The fusion of the rearrangement in both cases was ETV6(E4)::NTRK3(E14). By analyzing the clinicopathological features of these two cases, we found that both were characterized by multiple tumor nodules, invasive growth, and central lymph node metastases, indicating the follicular subtype of papillary thyroid carcinoma. Immunohistochemical staining profiles showed CD56-, CK19+, Galectin-3+, HBME1+. These clinicopathological features suggest the possibility of ETV6-NTRK3 rearranged thyroid carcinoma and highlight the importance of performing gene fusion testing by FISH or NGS for these patients.

3.
Pak J Pharm Sci ; 37(1(Special)): 235-243, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38747275

RESUMEN

Stimulus-responsive mesoporous silica nanoparticles (MSNs) have displayed great potentiality for controlled-release and targeted drug delivery. In the current work, a supercritical fluid method was utilized to successfully prepare cinnamon oil loaded into chitosan grafted MSNs (CO@CS-MSNs). The influencing factors of drug loads, such as pressure, temperature, impregnation time and depressure time, were investigated. The structure of CO@CS-MSNs was demonstrated with Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscope (TEM), scanning electron microscopy (SEM), thermogravimetry (TG) as well as X-ray diffraction (XRD). The drug release assays in vitro at various pH conditions displayed that CO@CS-MSNs had an excellent pH-responsive release behavior, which confirmed that CO was loaded successfully into the CO@CS-MSNs. The findings indicated that the supercritical fluid approach is a non-destructive and efficient approach for stimulus-responsive MSNs, which is expected to further expand its application range.


Asunto(s)
Dióxido de Carbono , Quitosano , Cinnamomum zeylanicum , Liberación de Fármacos , Nanopartículas , Dióxido de Silicio , Quitosano/química , Dióxido de Silicio/química , Nanopartículas/química , Concentración de Iones de Hidrógeno , Dióxido de Carbono/química , Porosidad , Cinnamomum zeylanicum/química , Portadores de Fármacos/química , Aceites Volátiles/química , Aceites Volátiles/administración & dosificación , Difracción de Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , Microscopía Electrónica de Rastreo , Preparaciones de Acción Retardada
4.
Ultrastruct Pathol ; 48(3): 221-233, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38619116

RESUMEN

The endoplasmic reticulum(ER)is the largest membranous network serving as a region for protein, lipid and steroid synthesis, transport and storage. Detailed information about ER-cisternae, ER-tubules and rough endoplasmic reticulum (rER) is scarce in human blood cells. This study describes a series of giant inclusions and Auer bodies in promyeloblasts in six patients with acute promyelocytic leukemia (APL), by light microscopy, transmission electron microscopy (TEM) and cytochemical stains. TEM revealed that giant inclusions and pro-Auer bodies were associated with rER and surrounded by tubular structures composed of degenerated or redundant membrane in promyeloblasts, which corresponded with elements of the ER system. This paper reveals that in the promyeloblasts of APL, ER is the source of and transforms progressively into giant inclusions and Auer bodies.


Asunto(s)
Retículo Endoplásmico , Cuerpos de Inclusión , Leucemia Promielocítica Aguda , Microscopía Electrónica de Transmisión , Humanos , Leucemia Promielocítica Aguda/patología , Cuerpos de Inclusión/ultraestructura , Masculino , Femenino , Retículo Endoplásmico/ultraestructura , Adulto , Persona de Mediana Edad , Adulto Joven , Adolescente , Células Precursoras de Granulocitos/ultraestructura , Células Precursoras de Granulocitos/patología
6.
Anal Chim Acta ; 1294: 342294, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38336410

RESUMEN

BACKGROUND: Tin and lead contamination is a global threat to marine ecosystems considering their species-specific toxicity, bioavailability and mobility. Hence simultaneous measurement of multiple tin and lead compounds at µg L-1 to pg L-1 levels in environmental water is always an indispensable but challengeable task. High performance liquid chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) is one of the most widely used choices for this purpose because of good sensitivity, strong separation power and good compatibility. Previous HPLC-ICP-MS methods based on a single elemental speciation strategy are low-efficiency and sensitivity-insufficient for a large set of unstable samples and interaction of multiple metal(loid)s down to ng L-1 levels. RESULTS: In this study, we developed a sensitive, efficient and environment-friendly analytical method for accurate quantification of inorganic and organic species of tin and lead simultaneously based on HPLC-ICP-MS with online integration of solid phase extraction (SPE). By using graphene oxide modified silica conditioned with 1 mM benzoic acid to enrich tin and lead species from 10 mL sample, detection limits were improved to 2-8 pg per liter due to satisfactory enrichment factors (522-2848 folds). The SPE-HPLC-ICP-MS method was applicable to quantification of ultra-trace tin and lead species at pg L-1 levels in uncontaminated seawater. Tributyltin was the only tin species detected at subnanograms per liter levels while Pb(II) was the only lead species detected at several nanograms per liter in thirteen coastal seawater samples collected in Hangzhou Bay, indicating light contamination of tin and lead. SIGNIFICANCE: Overall, the proposed SPE-HPLC-ICP-MS method is highly sensitive, efficient and environment-friendly that are fairly suitable to routine speciation analysis of tin and lead in environmental, food, and biological samples.


Asunto(s)
Plomo , Estaño , Espectrometría de Masas/métodos , Cromatografía Líquida de Alta Presión/métodos , Ecosistema , Agua de Mar , Extracción en Fase Sólida/métodos
7.
Ultrastruct Pathol ; 48(1): 56-65, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38037244

RESUMEN

The monocytes in acute monocytic leukemia (AML-M5b) were analyzed by scanning and transmission electron microscopy (SEM and TEM) to understand more fully their structure and origin. By SEM, monocytes exhibited localized expansions of the surface, some of which appeared to bud off as surface vesicles (SVs). Filopodial processes and pseudopodia were also present. TEM demonstrated that the SVs were composed of a double-membrane at the pole away from the cell body, and a single membrane nearer to the cell body. In the peripheral cytoplasm, intracellular vesicles (IVs) had the appearance of vacuoles and were enclosed by single membranes. Most SVs were characterized by a notch as a rER edge and an expanded head. Filopodial processes had the same thickness of 40 nm as the SV walls, which suggested a close developmental relationship between the two. Pseudopodia between SVs were irregular in size. Rod-like rER cisternae were prominent in the peripheral cytoplasm and some showed a close physical juxtaposition as to suggest a transition from rER to IVs to SVs. Ultrastructural cytochemistry demonstrated activity of 5'-nucleotidase over rER, SVs, filopodial processes and pseudopodia, and a patchy reaction over other areas of plasma membrane. Overall, the results indicated that rER transforms into SVs, filopodial processes and pseudopodia, as a way of integrating cytoplasmic membranes into the plasma membrane.


Asunto(s)
Monocitos , Orgánulos , Microscopía Electrónica , Citoplasma , Membrana Celular
8.
Front Public Health ; 11: 1191881, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37927885

RESUMEN

Background: Non-melanoma skin cancer (NMSC) is a prevalent skin malignancy. It has been indicated in many studies that trihalomethanes (THMs) exposure has a strong association with tumors but has not been associated with NMSC. Our investigation aims to explore the association between THMs exposure and NMSC. Methods: Cross-sectional data from the 2011 to 2020 National Health and Nutrition Examination Survey (NHANES) was collected. Poisson regression and subgroup analyses were performed to evaluate the association between individual THMs components and NMSC. Fitted smoothing curves and generalized additive models were also used. Results: This study involved 5,715 individuals, 98 (1.7%) of whom self-reported NMSC. After adjusting for covariates, Poisson regression showed that higher blood TBM levels were associated with an increased likelihood of NMSC (OR = 1.03; 95% CI: 1.01-1.05, p = 0.002). However, the correlation between the blood levels of TCM, DBCM, and BDCM and the likelihood of NMSC was not statistically significant (all p > 0.05). Subgroup analysis and interaction tests showed no significant differences between blood TBM concentration and the likelihood of NMSC, indicating that age, gender, and race were significantly independent of this positive association (all p < 0.05). Conclusions: Our results implied that among adults older than 65 years old in the U.S., elevated blood TBM concentrations were positively associated with NMSC. More prospective investigations are required to validate this relationship with the early prevention of NMSC.


Asunto(s)
Neoplasias Cutáneas , Trihalometanos , Adulto , Humanos , Anciano , Encuestas Nutricionales , Estudios Transversales , Estudios Prospectivos , Neoplasias Cutáneas/epidemiología
10.
iScience ; 26(6): 106917, 2023 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-37378343

RESUMEN

The role of SET domain containing 7 (SETD7) during human hematopoietic development remains elusive. Here, we found that deletion of SETD7 attenuated the generation of hematopoietic progenitor cells (HPCs) during the induction of hematopoietic differentiation from human embryonic stem cells (hESCs). Further analysis specified that SETD7 was required for lateral plate mesoderm (LPM) specification but dispensable for the generation of endothelial progenitor cells (EPCs) and HPCs. Mechanistically, rather than depending on its histone methyltransferase activity, SETD7 interacted with ß-catenin at lysine residue 180 facilitated its degradation. Diminished SETD7 expression led to the accumulation of ß-catenin and the consequent activation of the Wnt signaling pathway, which altered LPM patterning and facilitated the production of paraxial mesoderm (PM). Taken together, the findings indicate that SETD7 is related to LPM and PM patterning via posttranslational regulation of the Wnt/ß-catenin signaling pathway, providing novel insights into mesoderm specification during hematopoietic differentiation from hESCs.

11.
Comput Biol Med ; 160: 106961, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37156222

RESUMEN

Endoscopic medical imaging in complex curved intestinal structures are prone to uneven illumination, low contrast and lack of texture information. These problems may lead to diagnostic challenges. This paper described the first supervised deep learning based image fusion framework to enable the polyp region highlight through a global image enhancement and a local region of interest (ROI) with paired supervision. Firstly, we conducted a dual attention based network in global image enhancement. The Detail Attention Maps was used to preserve more image details and the Luminance Attention Maps was used to adjust the global illumination of the image. Secondly, we adopted the advanced polyp segmentation network ACSNet to obtain the accurate mask image of lesion region in local ROI acquisition. Finally, a new image fusion strategy was proposed to realize the local enhancement effect of polyp image. Experimental results show that our method can highlight the local details of the lesion area better and reach the optimal comprehensive performance with comparing with 16 traditional and state-of-the-art enhancement algorithms. And 8 doctors and 12 medical students were asked to evaluate our method for assisting clinical diagnosis and treatment effectively. Furthermore, the first paired image dataset LHI was constructed, which will be made available as an open source to research communities.


Asunto(s)
Algoritmos , Aumento de la Imagen , Humanos , Procesamiento de Imagen Asistido por Computador
12.
Mol Neurobiol ; 60(6): 3534-3552, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36892728

RESUMEN

Aging is one of the key mechanisms of vascular dysfunction and contributes to the initiation and progression of ischemic stroke (IS). Our previous study demonstrated that ACE2 priming enhanced the protective effects of exosomes derived from endothelial progenitor cells (EPC-EXs) on hypoxia-induced injury in aging endothelial cells (ECs). Here, we aimed to investigate whether ACE2-enriched EPC-EXs (ACE2-EPC-EXs) could attenuate brain ischemic injury by inhibiting cerebral EC damage through their carried miR-17-5p and the underlying molecular mechanisms. The enriched miRs in ACE2-EPC-EXs were screened using the miR sequencing method. EPC-EXs, ACE2-EPC-EXs, and ACE2-EPC-EXs with miR-17-5p deficiency (ACE2-EPC-EXsantagomiR-17-5p) were administered to transient middle cerebral artery occlusion (tMCAO)-operated aged mice or coincubated with hypoxia/reoxygenation (H/R)-treated aging ECs. The results showed that (1) the level of brain EPC-EXs and their carried ACE2 were significantly decreased in aged mice compared to in young mice, and (2) after tMCAO, aged mice displayed increases in brain cell senescence, infarct volume, and neurological deficit score (NDS) and a decrease in cerebral blood flow (CBF). (3) Compared with EPC-EXs, ACE2-EPC-EXs were enriched with miR-17-5p and more effective in increasing ACE2 and miR-17-5p expression in cerebral microvessels, accompanied by obvious increases in cerebral microvascular density (cMVD) and cerebral blood flow (CBF) and decreases in brain cell senescence, infarct volume, neurological deficit score (NDS), cerebral EC ROS production, and apoptosis in tMCAO-operated aged mice. Moreover, silencing of miR-17-5p partially abolished the beneficial effects of ACE2-EPC-EXs. (4) In H/R-treated aging ECs, ACE2-EPC-EXs were more effective than EPC-EXs in decreasing cell senescence, ROS production, and apoptosis and increasing cell viability and tube formation. In a mechanistic study, ACE2-EPC-EXs more effectively inhibited PTEN protein expression and increased the phosphorylation of PI3K and Akt, which were partially abolished by miR-17-5p knockdown. Altogether, our data suggest that ACE-EPC-EXs have better protective effects on ameliorating aged IS mouse brain neurovascular injury by inhibiting cell senescence, EC oxidative stress, apoptosis, and dysfunction by activating the miR-17-5p/PTEN/PI3K/Akt signaling pathway.


Asunto(s)
Lesiones Encefálicas , Células Progenitoras Endoteliales , Exosomas , MicroARNs , Ratones , Animales , Células Progenitoras Endoteliales/metabolismo , MicroARNs/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Exosomas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Lesiones Encefálicas/metabolismo , Hipoxia/metabolismo , Infarto/metabolismo , Apoptosis
13.
Br J Haematol ; 201(4): 690-703, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36708268

RESUMEN

JAK2V617F is the most frequent mutation in BCR-ABL-negative myeloproliferative neoplasms (MPNs). It is an important but not the only determinant of MPN phenotype. We performed high-throughput sequencing on JAK2V617F+ essential thrombocythaemia (ET) and polycythaemia vera (PV) patient samples to unveil factors involved in phenotypic heterogeneity and to identify novel therapeutic targets for MPN. Two concurrent mutations that may affect phenotype were identified, including mutations in SH2B3, which is primarily prevalent in PV, and SF3B1, which is more commonly mutated in ET. Next, we conducted transcriptomic analysis at the haematopoietic stem cell (HSC) and megakaryocyte (MK)-erythroid progenitor (MEP) levels. Inflammatory signalling pathways were elevated in both ET HSCs and MEPs, unlike in PV HSCs and MEPs. Notably, Wnt/ß-catenin signalling was uniquely upregulated during ET haematopoietic differentiation from HSC to MEP, and inhibiting Wnt/ß-catenin signalling blocked MK differentiation in vitro. Consistently, Wnt/ß-catenin inhibitor administration decreased platelet counts in JAK2V617F+ MPN mice by blocking MEPs and MK progenitors and by inhibiting maturation of MKs, while in wild-type mice, Wnt/ß-catenin inhibitor did not significantly reduce platelet counts. In conclusion, our findings provide new insights into the mechanisms underlying phenotypic differentiation of JAK2V617F+ PV and ET and indicate Wnt/ß-catenin signalling as a potential therapeutic target for MPN.


Asunto(s)
Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Animales , Ratones , beta Catenina , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genética , Mutación , Fenotipo , Janus Quinasa 2/genética
14.
Insect Sci ; 30(1): 95-108, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35510515

RESUMEN

Diaphorina citri is an important vector of Citrus Huanglongbing (HLB) disease. After feeding on young host plant shoots, the population of D. citri can increase significantly. Females also only lay eggs on young shoots. However, there are few studies on the mechanism of this phenomenon. Exogenous nutrient signals can affect the insulin signaling system of D. citri after feeding on young shoots. In this study, the expression of upstream factors DcILP1, DcILP2, and DcIR in the insulin signaling system of D. citri was upregulated after feeding on young shoots. After being silenced by RNA interference technology, the results showed that the number of oviposited eggs of D. citri was significantly decreased and the ovarian development was inhibited with severe vacuolation. In addition, detection using quantitative reverse transcription-polymerase chain reaction showed that the upstream regulatory gene DcRheb of the target of rapamycin (TOR) pathway and the downstream reproduction-related DcVg gene were also significantly downregulated. These results suggest that feeding upon young shoots may upregulate the expression levels of upstream factors DcILP1, DcILP2, and DcIR in the insulin signaling system. The signal will be through upregulating the expression of DcRheb, an upstream gene of the TOR signaling pathway. This in turn influences yolk metabolism, which eventually causes the ovaries of female D. citri to mature and therefore initiate oviposition behavior.


Asunto(s)
Citrus , Hemípteros , Femenino , Animales , Insulina , Oviposición , Péptidos , Interferencia de ARN , Hemípteros/genética , Enfermedades de las Plantas
15.
Graefes Arch Clin Exp Ophthalmol ; 261(1): 213-222, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35969325

RESUMEN

PURPOSE: To determine age-and sex-related changes in periocular morphology in Caucasians using a standardized protocol. METHODS: Healthy Caucasian volunteers aged 18-35 and 60-90 years old were recruited from the Department of Ophthalmology, Faculty of Medicine and University Hospital, Cologne, between October 2018 and May 2020. Volunteers with facial asymmetry, facial deformities, history of facial trauma, facial surgery, botox injection, eyelid ptosis, strabismus, or nystagmus, were excluded. Standardized three-dimensional facial photos of 68 young volunteers and 73 old volunteers were taken in this clinical practice. Position changes of endocanthion, pupil center, and exocanthion were analyzed in different age and gender groups, including palpebral fissure width (PFW): distance between endocanthions (En-En), pupil centers (Pu-Pu), exocanthions (Ex-Ex), endocanthion and nasion (En-Na), pupil center and nasion (Pu-Na), exocanthion and nasion (Ex-Na), endocanthion and pupil center (Pu-En), exocanthion and pupil center (Pu-Ex), and palpebral fissure inclination (PFI); angle of endocanthions to nasion (En-Na-En), pupils to nasion (Pu-Na-Pu), exocanthions to nasion (Ex-Na-Ex); endocanthion inclination (EnI), and exocanthion inclination (ExI). RESULTS: PFW, En-En, Ex-Na, Pu-Ex, PFI, ExI, and Ex-Na-Ex were significantly different between the young and old groups (p ≤ 0.004). There were sex-related differences in PFW, Ex-Ex, En-Na, Pu-Na, Ex-Na, Pu-En, PFI, and EnI between both groups (p ≤ 0.041). CONCLUSION: The position change of the pupil is minimal relative to age; it is preferred to establish the reference plane to describe periocular changes. The endocanthion tends to move temporally and inferiorly, while the exocanthion tends to shift nasally and inferiorly with age.


Asunto(s)
Blefaroptosis , Estrabismo , Humanos , Antropometría , Párpados/anatomía & histología , Pupila
16.
Ophthalmol Ther ; 12(1): 111-123, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36245061

RESUMEN

INTRODUCTION: In this study, we measured the volume of customized tumor models in the periocular area using three-dimensional (3D) stereophotogrammetry and evaluated the reproducibility of these measurements. METHODS: Five tumor models of different colors and sizes were placed in different periocular positions, and 3D facial images were obtained from 68 healthy adult volunteers. Subsequently, the volumes of the tumor models were measured, and the intra- and interrater reproducibility was assessed. RESULTS: The gray 6 mm model revealed the highest reliable measurements in both Caucasians (intra- and interrater intraclass correlation coefficients of 0.981 and 0.899, mean absolute difference of 1.446 and 3.327 mm3, relative error measurement of 3.497% and 8.120%, technical error of measurement of 1.450 and 3.105 mm3, and relative technical error of measurement of 3.506% and 7.580%) and Asians (0.968 and 0.844, 1.974 and 4.067 mm3, 4.772% and 9.526%, 2.100 and 4.302 mm3, and 5.076% and 10.076%, respectively). The highest reliability of measurements in the lateral upper eyelid (0.88 and 0.95, 4.042 and 3.626 mm3, 9.730% and 9.020%, 5.714 and 3.358 mm3, and 9.730% and 8.350%, respectively) and medial upper eyelid (0.81 and 0.89, 4.313 and 4.226 mm3, 9.730% and 9.020%, 6.098 and 4.069 mm3, and 9.730% and 8.350%, respectively) with eyes closed was evident in Caucasians, while the same trend (0.841 and 0.815, 2.828 and 3.757 mm3, 9.860% and 9.840%, 4.052 and 4.308 mm3, and 9.860% and 9.740%, respectively) was observed in Asians in the medial canthus with eyes closed. CONCLUSIONS: This study confirms, for the first time, the high reliability of periocular tumor volume measurements using 3D stereophotogrammetry, suggesting its feasibility for eyelid tumor measurement. Further trials are required to investigate its clinical use for documentation and follow-up of different eyelid tumors.

17.
Am J Transl Res ; 15(12): 6959-6969, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38187000

RESUMEN

OBJECTIVE: To investigate the effects of focused ultrasound ablation (FUSA) versus conventional myomectomy on pelvic adhesions and fertility in the treatment of uterine fibroids. METHODS: The clinical data of 114 patients with uterine fibroids admitted to Northwest Women's and Children's Hospital from February 2020 to January 2023 were retrospectively analyzed, among which 61 cases were treated with FUSA and 53 cases received myomectomy. The length of surgery, bleeding, hospitalization days, incidence of pelvic adhesions, and ovarian reserve function indexes (FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone) and E2 (Estradiol)) were compared between the two groups. RESULTS: Compared to the myomectomy group, the FUSA group had shorter operation time (P<0.001), no bleeding (P<0.001), less hospitalization (P<0.001), lower incidence of pelvic adhesion (P = 0.020), and less impairment of ovarian reserve function (Increased FSH, LH and E2, all P<0.001). Logistic regression analysis showed that the maximum diameter of leiomyoma ≥5 cm (P = 0.008), the number of pregnancies ≥3 (P = 0.003) and intraoperative hemorrhage (P = 0.004) were independent risk factors for pelvic adhesion. CONCLUSIONS: FUSA is a safe and effective non-invasive method for the treatment of uterine fibroids that reduces postoperative complications and protects fertility potential, especially for female patients with fertility concerns. Future studies need to overcome existing limitations to improve reliability of evidence.

18.
Nat Commun ; 13(1): 6578, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-36323669

RESUMEN

Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.


Asunto(s)
N-Metiltransferasa de Histona-Lisina , Neoplasias , Humanos , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Elementos de Facilitación Genéticos , Histonas/metabolismo , ARN Bicatenario , Piroptosis , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Interferones/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo
19.
Front Plant Sci ; 13: 1039094, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36388468

RESUMEN

Highly efficient genetic transformation technology is greatly beneficial for crop gene function analysis and precision breeding. However, the most commonly used genetic transformation technology for woody plants, mediated by Agrobacterium tumefaciens, is time-consuming and inefficient, which limits its utility for gene function analysis. In this study, a simple, universal, and highly efficient genetic transformation technology mediated by A. rhizogenes K599 is described. This technology can be applied to multiple citrus genotypes, and only 2-8 weeks were required for the entire workflow. Genome-editing experiments were simultaneously conducted using 11 plasmids targeting different genomic positions and all corresponding transformants with the target knocked out were obtained, indicating that A. rhizogenes-mediated genome editing was highly efficient. In addition, the technology is advantageous for investigation of specific genes (such as ACD2) for obtaining "hard-to-get" transgenic root tissue. Furthermore, A. rhizogenes can be used for direct viral vector inoculation on citrus bypassing the requirement for virion enrichment in tobacco, which facilitates virus-induced gene silencing and virus-mediated gene expression. In summary, we established a highly efficient genetic transformation technology bypassing tissue culture in citrus that can be used for genome editing, gene overexpression, and virus-mediated gene function analysis. We anticipate that by reducing the cost, required workload, experimental period, and other technical obstacles, this genetic transformation technology will be a valuable tool for routine investigation of endogenous and exogenous genes in citrus.

20.
Eur J Med Res ; 27(1): 179, 2022 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-36109828

RESUMEN

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is considered one of the most common types of soft tissue sarcoma (STS). Current studies have shown that the prognosis of UPS is related to some of its clinical characteristics, but no survival prediction model for the overall survival (OS) of UPS patients has been reported. The purpose of this study is to construct and validate a nomogram for predicting OS in UPS patients at 3, 5 years after the diagnosis. METHODS: According to the inclusion and exclusion criteria, 1079 patients with UPS were screened from the SEER database and randomly divided into the training cohort (n = 755) and the validation cohort (n = 324). Patient demographic and clinicopathological characteristics were first described, and the correlation between the two groups was compared, using the Kaplan-Meier method and Cox regression analysis to determine independent prognostic factors. Based on the identified independent prognostic factors, a nomogram for OS in UPS patients was established using R language. The nomogram's performance was then validated using multiple indicators, including the area under the receiver operating characteristic curve (AUC), consistency index (C-index), calibration curve, and decision curve analysis (DCA). RESULTS: Both the C-index of the OS nomogram in the training cohort and the validation cohort were greater than 0 .75, and both the values of AUC were greater than 0.78. These four values were higher than their corresponding values in the TNM staging system, respectively. The calibration curves of the Nomogram prediction model and the TNM staging system were well fitted with the 45° line. Decision curve analysis showed that both the nomogram model and the TNM staging system had clinical net benefits over a wide range of threshold probabilities, and the nomogram had higher clinical net benefits than the TNM staging system as a whole. CONCLUSION: With good discrimination, accuracy, and clinical practicability, the nomogram can individualize the prediction of 3-year and 5-year OS in patients with UPS, which can provide a reference for clinicians and patients to make better clinical decisions.


Asunto(s)
Nomogramas , Sarcoma , Estudios de Cohortes , Humanos , Estadificación de Neoplasias , Pronóstico
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