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1.
Cells ; 13(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38334644

RESUMO

Cachexia is a condition characterized by substantial loss of body weight resulting from the depletion of skeletal muscle and adipose tissue. A considerable fraction of patients with advanced cancer, particularly those who have been diagnosed with pancreatic or gastric cancer, lung cancer, prostate cancer, colon cancer, breast cancer, or leukemias, are impacted by this condition. This syndrome manifests at all stages of cancer and is associated with an unfavorable prognosis. It heightens the susceptibility to surgical complications, chemotherapy toxicity, functional impairments, breathing difficulties, and fatigue. The early detection of patients with cancer cachexia has the potential to enhance both their quality of life and overall survival rates. Regarding this matter, blood biomarkers, although helpful, possess certain limitations and do not exhibit universal application. Additionally, the available treatment options for cachexia are currently limited, and there is a lack of comprehensive understanding of the underlying molecular pathways associated with this condition. Thus, this review aims to provide an overview of molecular mechanisms associated with cachexia and potential therapeutic targets for the development of effective treatments for this devastating condition.


Assuntos
Neoplasias da Mama , Caquexia , Masculino , Humanos , Caquexia/metabolismo , Atrofia Muscular/metabolismo , Qualidade de Vida , Músculo Esquelético/metabolismo , Neoplasias da Mama/patologia
2.
Nat Commun ; 15(1): 1353, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355624

RESUMO

There is strong evidence that obesity is a risk factor for poor semen quality. However, the effects of multigenerational paternal obesity on the susceptibility to cadmium (a reproductive toxicant)-induced spermatogenesis disorders in offspring remain unknown. Here, we show that, in mice, spermatogenesis and retinoic acid levels become progressively lower as the number of generations exposed to a high-fat diet increase. Furthermore, exposing several generations of mice to a high fat diet results in a decrease in the expression of Wt1, a transcription factor upstream of the enzymes that synthesize retinoic acid. These effects can be rescued by injecting adeno-associated virus 9-Wt1 into the mouse testes of the offspring. Additionally, multigenerational paternal high-fat diet progressively increases METTL3 and Wt1 N6-methyladenosine levels in the testes of offspring mice. Mechanistically, treating the fathers with STM2457, a METTL3 inhibitor, restores obesity-reduced sperm count, and decreases Wt1 N6-methyladenosine level in the mouse testes of the offspring. A case-controlled study shows that human donors who are overweight or obese exhibit elevated N6-methyladenosine levels in sperm and decreased sperm concentration. Collectively, these results indicate that multigenerational paternal obesity enhances the susceptibility of the offspring to spermatogenesis disorders by increasing METTL3-mediated Wt1 N6-methyladenosine modification.


Assuntos
Infertilidade Masculina , Análise do Sêmen , Masculino , Humanos , Camundongos , Animais , Sêmen/metabolismo , Obesidade/metabolismo , Pai , Infertilidade Masculina/genética , Dieta Hiperlipídica/efeitos adversos , Tretinoína , Metiltransferases
3.
Ann Surg Oncol ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347332

RESUMO

INTRODUCTION: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited. METHODS: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases. RESULTS: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients. CONCLUSIONS: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.

4.
Mol Pharm ; 21(2): 944-956, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38270082

RESUMO

T cell immunoglobulin and mucin domain-3 (TIM3; HAVCR2) is a transmembrane protein that exerts negative regulatory control over T cell responses. Studies have demonstrated an upregulation of TIM3 expression in tumor-infiltrating lymphocytes (TILs) in cancer patients. In this investigation, a series of monoclonal antibodies targeting TIM3 were produced by hybridoma technology. Among them, C23 exhibited favorable biological properties. To enable specific binding, we developed a 124I/125I-C23 radio-tracer via N-bromosuccinimide (NBS)-mediated labeling of the monoclonal antibody C23. Binding affinity and specificity were assessed using the 293T-TIM3 cell line, which overexpresses TIM3, and the parent 293T cells. Furthermore, biodistribution and in vivo imaging of 124I/125I-C23 were examined in HEK293TIM3 xenograft models and allograft models of 4T1 (mouse breast cancer cells) and CT26 (mouse colon cancer cells). Micro-PET/CT imaging was conducted at intervals of 4, 24, 48, 72, and/or 96 h post intravenous administration of 3.7-7.4 MBq 124I-C23 in the respective model mice. Additionally, immunohistochemistry (IHC) staining of TIM3 expression in dissected tumor organs was performed, along with an assessment of the corresponding expression of Programmed Death 1 (PD1), CD3, and CD8 in the tumors. The C23 monoclonal antibody (mAb) specifically binds to TIM3 protein with a dissociation constant of 23.28 nM. The 124I-C23 and 125I-C23 radio-tracer were successfully prepared with a labeling yield of 83.59 ± 0.35% and 92.35 ± 0.20%, respectively, and over 95.00% radiochemical purity. Stability results indicated that the radiochemical purity of 124I/125I-C23 in phosphate-buffered saline (PBS) and 5% human serum albumin (HSA) was still >80% after 96 h. 125I-C23 uptake in 293T-TIM3 cells was 2.80 ± 0.12%, which was significantly higher than that in 293T cells (1.08 ± 0.08%), and 125I-C23 uptake by 293T-TIM3 cells was significantly blocked at 60 and 120 min in the blocking groups. Pharmacokinetics analysis in vivo revealed an elimination time of 14.62 h and a distribution time of 0.4672 h for 125I-C23. Micro-PET/CT imaging showed that the 124I-C23 probe uptake in the 293T-TIM3 model significantly differed from that of the negative control group and blocking group. In the humanized mouse model, the 124I-C23 probe had obvious specific uptake in the 4T1 and CT26 models and maximum uptake at 24 h in tumor tissues (SUVmax (the maximum standardized uptake value) in 4T1 and CT26 humanized TIM3 murine tumor models: 0.59 ± 0.01 and 0.76 ± 0.02, respectively). Immunohistochemistry of tumor tissues from these mouse models showed comparable TIM3 expression. CD3 and CD8 cells and PD-1 expression were also observed in TIM3-expressing tumor tissues. The TIM3-targeting antibody C23 showed good affinity and specificity. The 124I/125I-C23 probe has obvious targeting specificity for TIM3 in vitro and in vivo. Our results suggest that 124I/125I-C23 is a promising tracer for TIM3 imaging and may have great potential in monitoring immune checkpoint drug efficacy.


Assuntos
Radioisótopos do Iodo , Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Camundongos , Animais , Tomografia por Emissão de Pósitrons/métodos , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Distribuição Tecidual , Anticorpos Monoclonais/química , Compostos Radiofarmacêuticos/farmacocinética , Mucinas/metabolismo , Linhagem Celular Tumoral
5.
Food Sci Biotechnol ; 33(1): 103-113, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38186616

RESUMO

A strain designated Acinetobacter indicus WMB-7 with the ability to hydrolyze phthalate esters (PAEs) was isolated from the fermented grains of Baijiu. The genome of the strain was sequenced with a length of 3,256,420 bp and annotated with 3183 genes, of which 36 hydrolases encoding genes were identified. The hydrolases were analyzed by protein structure modeling and molecular docking, and 14 enzymes were docked to the ligand di-butyl phthalate with the catalytic active regions, and showed binding affinity. The 14 enzymes were expressed in E. coli and 5 of them showed the ability for PAEs hydrolysis. Enzyme GK020_RS15665 showed high efficiency for PAEs hydrolysis and could efficiently hydrolyze di-butyl phthalate under an initial concentration of 1000 mg/L with a half-life of 4.24 h. This work combined a series of methods for identifying PAEs hydrolases and offered a molecular basis for PAEs degradation of A. indicus strains from Baijiu. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01334-w.

6.
Clin Epigenetics ; 16(1): 14, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38245781

RESUMO

BACKGROUND: Epigenetics plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Some studies have reported that YAP is involved in inflammatory response and can regulate target genes through epigenetic modifications. JMJD3, a histone H3K27me3 demethylase, is associated with some inflammatory diseases. In this study, we investigated the role of YAP in the development of IBD and the underlying epigenetic mechanisms. RESULTS: YAP expression was significantly increased in both in vitro and in vivo colitis models as well as in patients with IBD. Epithelial-specific knockout of YAP aggravates disease progression in dextran sodium sulfate (DSS)-induced murine colitis. In the TNF-α-activated cellular inflammation model, YAP knockdown significantly increased JMJD3 expression. Coimmunoprecipitation experiments showed that YAP and EZH2 bind to each other, and chromatin immunoprecipitation-PCR (ChIP-PCR) assay indicated that silencing of YAP or EZH2 decreases H3K27me3 enrichment on the promoter of JMJD3. Finally, administration of the JMJD3 pharmacological inhibitor GSK-J4 alleviated the progression of DSS-induced murine colitis. CONCLUSION: Our findings elucidate an epigenetic mechanism by which YAP inhibits the inflammatory response in colitis through epigenetic silencing of JMJD3 by recruiting EZH2.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Humanos , Camundongos , Colite/induzido quimicamente , Colite/genética , Metilação de DNA , Epigênese Genética , Histonas/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/genética , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo
7.
Eur J Med Chem ; 266: 116134, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38266552

RESUMO

PURPOSE: Claudin 18.2 (CLDN18.2), due to its highly selective expression in tumor cells, has made breakthrough progress in clinical research and is expected to be integrated into routine tumor diagnosis and treatment. METHODS: In this research, we obtained an scFv-Fc fusion protein (SF106) targeting CLDN18.2 through hybridoma technology. The scFv-Fc fusion protein was labeled with radioactive isotopes (124I and 177Lu) to generate the radio-probes. The targeting and specificity of the radio-probes were tested in cellular models, and its diagnostic and therapeutic potential was further evaluated in tumor-bearing models. RESULTS: The molecular probes [124I]I-SF106 and [177Lu]Lu-DOTA-SF106 possess high radiochemical purity (RCP, 98.18 ± 0.93 % and 97.05 ± 1.1 %) and exhibit good stability in phosphate buffer saline and 5 % human serum albumin (92.44 ± 4.68 % and 91.03 ± 2.42 % at 120 h). [124I]I-SF106 uptake in cells expressing CLDN18.2 was well targeted and specific, and the dissociation constant was 17.74 nM [124I]I-SF106 micro-PET imaging showed that the maximum standardized uptake value (SUVmax) was significantly higher than CLDN18.2-negative tumors (1.83 ± 0.02 vs. 1.23 ± 0.04, p < 0.001). The maximum uptake was attained in tumors expressing CLDN18.2 at 48 h after injection. [124I]I-SF106 and [177Lu]Lu-DOTA-SF106 dosimetric study showed that the effective dose in humans complies with the medical safety standards required for their clinical application. The results of treatment experiments showed that 3 MBq of [177Lu]Lu-DOTA-SF106 in CLDN18.2-expressing tumor-bearing mice could significantly inhibit tumor growth. CONCLUSION: These results indicate that radionuclide-labeled scFv-Fc molecular probes ([124I]I-SF106 and [177Lu]Lu-DOTA-SF106) provide a new possibility for the diagnosis and treatment of CLDN18.2-positive cancer patients in clinical practice.


Assuntos
Neoplasias , Compostos Radiofarmacêuticos , Humanos , Camundongos , Animais , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Albumina Sérica Humana , Radioisótopos do Iodo , Sondas Moleculares , Linhagem Celular Tumoral , Claudinas
8.
Theranostics ; 14(2): 699-713, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169608

RESUMO

Background: Radiotherapy (RT) may trigger systemic antitumor immunity, manifesting as regression of non-irradiated lesions (abscopal effect). Intracellular adhesion molecule-1 (ICAM-1) is a key molecule involved in the abscopal effect of RT. However, the specific function of ICAM-1 in CD8+ T cells during antitumor immune responses remains unclear. Herein, we investigated whether noninvasive imaging of ICAM-1 can be used to annotate CD8+ T-cell function, thereby better selecting combinational therapy to enhance the antitumor immunity induced by RT. Methods: Using knockout mouse models, we investigated the role of ICAM-1 expressed on CD8+ T cells in the antitumor immunity of RT and conducted drug screening guided by ICAM-1-targeted noninvasive imaging. Results: The systemic antitumor effect of RT relies on the expression of ICAM-1 on CD8+ T cells. ICAM-1 expression is essential for CD8+ T-cell activation, proliferation, and effector function. Noninvasive annotation of the proliferation and effector function of CD8+ T cells by ICAM-1-targeted imaging identified VS-6063, a focal adhesion kinase inhibitor, as a new adjuvant to augment systemic antitumor immunity of RT in an immunologically "cold" tumor model. Mechanistically, VS-6063 overcomes the physical barriers in tumors and promotes the migration and infiltration of CD8+ T cells primed by RT into distant tumors. Conclusion: Our findings highlight that molecular imaging of ICAM-1 levels provides a dynamic readout of the proliferation and effector function of tumor-infiltrating CD8+ T cells, which facilitates the high-throughput exploitation of new combinational drugs to maximize the systemic antitumor effect of RT.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Camundongos , Animais , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias/radioterapia , Neoplasias/metabolismo , Adjuvantes Imunológicos/farmacologia , Camundongos Knockout
9.
Heliyon ; 10(1): e22810, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38148801

RESUMO

Objective: To evaluate the image quality of low-dose temporal bone computed tomography (CT) in otitis media and mastoiditis patients by using deep learning reconstruction (DLR). Materials and methods: A total of ninety-seven temporal bones from 53 consecutive adult patients who had suspected otitis media and mastoiditis and underwent temporal bone CT were prospectively enrolled. All patients underwent high resolution CT protocol (group A) and an additional low-dose protocol (group B). In group A, high resolution data were reconstructed by filter back projection (FBP). In group B, low-dose data were reconstructed by DLR mild (B1), DLR standard (B2) and DLR strong (B3). The objective image quality was analyzed by measuring the CT value and image noise on the transverse image and calculating the signal-to-noise ratio (SNR) on incudomallear joint, retroauricular muscle, vestibule and subcutaneous fat. Subjective image quality was analyzed by using a five-point scale to evaluate nine anatomical structures of middle and inner ear. The number of temporal bone lesions which involved in five structures of middle ear were assessed in group A, B1, B2 and B3 images. Results: There were no significant differences in the CT values of the four reconstruction methods at four structures (all p > 0.05). The DLR group B1, B2 and B3 had significantly less image noise and a significantly higher SNR than group A at four structures (all p < 0.001). The group B1 had comparable subjective image quality as group A in nine structures (all p > 0.05), however, the group B3 had lower subjective image quality than group A in modiolus, spiral osseous lamina and stapes (all p < 0.001), the group B2 had lower subjective image quality than group A in modiolus and spiral osseous lamina (both p < 0.05). The number of temporal bone lesions which involved in five structures for group A, B1 and B2 images were no significant difference (all p > 0.05), however, the number of temporal bone lesions which involved in mastoid for group B3 images were significantly more than group A (p < 0.05). The radiation dose of high resolution CT protocol and low-dose protocol were 0.55 mSv and 0.11 mSv, respectively. Conclusion: Compared with high resolution CT protocol, in the low-dose protocol of temporal bone CT, DLR mild and standard could improve the objective image quality, maintain good subjective image quality and satisfy clinical diagnosis of otitis media and mastoiditis patients.

10.
Int J Pharm ; 651: 123756, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38160990

RESUMO

BACKGROUND AND PURPOSE: Some kinds of antibody-drug conjugate (ADC) with high affinity to Nectin-4 have demonstrated breakthrough progress in the third-line setting for bladder cancer. However, many patients are still difficult to benefit from treatment based on the heterogeneity of tumour. As the most advanced auxiliary treatment technology, treatment visualization can most intuitively predict the effectiveness of drug treatment, and timely detect the occurrence of drug resistance. Among them, nuclear medicine molecular probes play an important role in this field. METHODS: 124/125I-EV was prepared by labelling Enfortumad Vedetin (EV), an ADC drugs widely used in clinic targeted Nectin-4, with Na124/125I using N-bromine succinimide as oxidant. The radiochemical purity was analyzed via radio-TLC and bioactivity was measured by enzyme-linked immunosorbent assay. Cell uptake assay and small-animal PET imaging were performed to verified the specificity and targeting. KEY RESULTS: 124/125I-EV was prepared with high labeling yield and radiochemical purity. ELISA assays demonstrated that 124I-EV maintained the same high bioactivity as EV with significantly higher uptake in SW780 cells (Nectin-4 positive, 4.05 ± 0.32 %IA/5 × 105 cells at 8 h) than that in T24 cells (Nectin-4 negative, 1.34 ± 0.18 %IA/5 × 105 cells, p < 0.001). In PET imaging, 124I-EV had a significantly higher accumulation in SW780 tumour than that in T24 tumour and the uptake in SW780 tumour could be specifically blocked when co-injected with cold EV. The signal-to-noise ratio at the tumour site gradually increased with time, and peaked at 72 h. CONCLUSION AND IMPLICATIONS: 124I-EV was successfully prepared with high specificity and binding affinity of Nectin-4. This radioactive probe completely simulates the internal circulation of ADC drugs and tumour uptake and retention, which will greatly improve the clinical application of ADC therapy.


Assuntos
Carcinoma de Células de Transição , Imunoconjugados , Radioisótopos do Iodo , Iodo , Neoplasias da Bexiga Urinária , Animais , Humanos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Nectinas
11.
BMC Musculoskelet Disord ; 24(1): 960, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38082325

RESUMO

BACKGROUND: To analyze the factors affecting the loss of correction effect in patients with congenital scoliosis after one stage posterior hemivertebra resection, orthosis, fusion and internal fixation. METHODS: Thirty-nine patients with congenital scoliosis (CS) who underwent one-stage posterior hemivertebra resection, orthosis, fusion and internal fixation were retrospectively included in Hebei Children's Hospital General demographic information of patients was collected. Preoperative and postoperative imaging indicators were compared, Including cobb Angle of the main curvature of the spine, segmental Cobb Angle, compensatory cephalic curve, compensatory curve on the caudal side, segmental kyphosis, coronal balance, sagittal balance, thoracic kyphosis, lumbar lordosis, and apical vertebra translation. Correlation analysis is used to evaluate the factors affecting the loss of judgment and correction effect, and the correlation indicators are included in the multi-factor Logistics regression. RESULTS: In terms of radiographic indicators in the coronal plane, compared to preoperative values, significant improvements were observed in postoperative Cobb Angle of main curve (8.00°±4.62° vs. 33.30°±9.86°), Segmental Cobb angle (11.87°±6.55° vs. 31.29°±10.03°), Compensatory cephalic curve (6.22°±6.33° vs. 14.75°±12.50°), Compensatory curve on the caudal side (5.58°±3.43° vs. 12.61°±8.72°), coronal balance (10.95 mm ± 8.65 mm vs. 13.52 mm ± 11.03 mm), and apical vertebra translation (5.96 mm ± 5.07 mm vs. 16.55 mm ± 8.39 mm) (all P < 0.05). In the sagittal plane, significant improvements were observed in Segmental kyposis Angle (7.60°±9.36° vs. 21.89°±14.62°, P < 0.05) as compared to preoperative values. At the last follow-up, Segmental kyphosis Angle (6.09°±9.75° vs. 21.89°±14.62°, P < 0.05), Thoracic kyphosis (26.57°±7.68° vs. 24.06°±10.49°, P < 0.05) and Lumbar lordosis (32.12°±13.15° vs. 27.84°±16.68°, P < 0.05) had statistical significance compared with the preoperative department. The correlation analysis showed that the correction effect of the main curve Cobb angle was correlated with fixed segment length (rs=-0.318, P = 0.048), postoperative segment Cobb angle (rs=-0.600, P < 0.001), preoperative apical vertebra translation (rs = 0.440, P = 0.005), and spinal cord malformation (rs=-0.437, P = 0.005). The correction effect of segmental kyphosis was correlated with age (rs = 0.388, P = 0.037). The results of the multivariate logistic regression analysis revealed that postoperative segmental Cobb angle > 10° (OR = 0.011, 95%CI:0.001-0.234, P = 0.004), associated spinal cord anomalies (OR = 24.369, 95%CI:1.057-561.793, P = 0.046), and preoperative apical translation > 10 mm (OR = 0.012, 95%CI:0.000-0.438, P = 0.016) were influential factors in the progression of the main curve Cobb angle. CONCLUSION: The one-stage posterior hemivertebra resection and short-segment corrective fusion with internal fixation are effective means to treat congenital scoliosis. However, attention should be paid to the loss of correction and curve progression during follow-up. Patients with spinal cord malformation and a large preoperative apical vertebra translation have a greater risk of losing the correction after surgery.

12.
ACS Pharmacol Transl Sci ; 6(12): 1829-1840, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38093841

RESUMO

Recent global clinical trials have shown that CLDN18.2 is an ideal target for the treatment of gastric cancer and that patients with high CLDN18.2 expression can benefit from targeted therapy. Therefore, accurate and comprehensive detection of CLDN18.2 expression is important for patient screening and guidance in anti-CLDN18.2 therapy. Phage display technology was used to screen CLDN18.2-specific peptides from 100 billion libraries. 293TCLDN18.1 cells were used to exclude nonspecific binding and CLDN18.1 binding sequences, while 293TCLDN18.2 cells were used to screen CLDN18.2-specific binding peptides. The monoclonal clones obtained from phage screening were sequenced, and peptides were synthesized based on the sequencing results. Binding specificity and affinity were assessed with a fluorescein isothiocyanate (FITC)-conjugated peptide. A 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated peptide was also synthesized for 68Ga radiolabeling. The in vitro and in vivo stability, partition coefficients, in vivo molecular imaging, and biodistribution were also characterized. Overall, 54 monoclonal clones were selected after phage display screening. Subsequently, based on the cell ELISA results, CLDN18.2 preference monoclonal clones were selected for deoxyribonucleic acid (DNA) sequencing, and four 7-peptide sequences were obtained after sequence comparison; among them, a peptide named T37 was further validated in vitro and in vivo. The T37 peptide specifically recognized CLDN18.2 but not CLDN18.1 and bound strongly to CLDN18.2-positive cell membranes. The 68Ga-DOTA-T37 probe exhibits good in vitro properties and high stability as a hydrophilic probe; it has high biological safety, and positron emission tomography/computed tomography (PET/CT) studies have shown that it can specifically target CLDN18.2 protein and CLDN18.2-positive tumors in mice. 68Ga-DOTA-T37 demonstrated the superiority and feasibility of using a CLDN18.2-specific probe in PCT/CT imaging, which deserves further development and exploitation.

13.
Artigo em Inglês | MEDLINE | ID: mdl-38062170

RESUMO

PURPOSE: Gastric cancer (GC), one of the most prevalent and deadliest tumors worldwide, is often diagnosed at an advanced stage with limited treatment options and poor prognosis. The development of a CLDN18.2-targeted radioimmunotherapy probe is a potential treatment option for GC. METHODS: The CLDN18.2 antibody TST001 (provided by Transcenta) was conjugated with DOTA and radiolabeled with the radioactive nuclide 177Lu. The specificity and targeting ability were evaluated by cell uptake, imaging and biodistribution experiments. In BGC823CLDN18.2/AGSCLDN18.2 mouse models, the efficacy of [177Lu]Lu-TST001 against CLDN18.2-expressing tumors was demonstrated, and toxicity was evaluated by H&E staining and blood sample testing. RESULTS: [177Lu]Lu-TST001 was labeled with an 99.17%±0.32 radiochemical purity, an 18.50 ± 1.27 MBq/nmol specific activity and a stability of ≥ 94% after 7 days. It exhibited specific and high tumor uptake in CLDN18.2-positive xenografts of GC mouse models. Survival studies in BGC823CLDN18.2 and AGSCLDN18.2 tumor-bearing mouse models indicated that a low dose of 5.55 MBq and a high dose of 11.10 MBq [177Lu]Lu-TST001 significantly inhibited tumor growth compared to the saline control group, with the 11.1 MBq group showing better therapeutic efficacy. Histological staining with hematoxylin and eosin (H&E) and Ki67 immunohistochemistry of residual tissues confirmed tumor tissue destruction and reduced tumor cell proliferation following treatment. H&E showed that there was no significant short-term toxicity observed in the heart, spleen, stomach or other important organs when treated with a high dose of [177Lu]Lu-TST001, and no apparent hematotoxicity or liver toxicity was observed. CONCLUSION: In preclinical studies, [177Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.

14.
Front Oncol ; 13: 1288383, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38115906

RESUMO

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.

15.
Food Chem X ; 20: 100970, 2023 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-38144740

RESUMO

Sauce-flavor baijiu (SFB) is a traditional Chinese distilled liquor crafted through a distinctive brewing process, involving seven rounds of stack fermentation (SF) and pit fermentation (PF). To date, there remains a knowledge gap regarding the microbial succession and flavor throughout all rounds of SFB with distinctive northern characteristics. Through LEfSe analysis, Saccharopolyspora, Virgibacillus, Thermoascus and Thermomyces, and Lactobacillus and Issatchenkia were found to be the most differentially representative genera in SF and PF, respectively. A total of 93 volatile flavor compounds were found in base baijius through the gas-chromatography mass spectrometry. Moreover, 29 volatile flavor substances with significant difference in base baijius of different rounds were revealed using the OPLS-DA model and VIP values and Spearman correlation analysis shows that bacteria have a greater impact on differential flavor compounds than fungi. This study provides a new perspective and insight into the brewing of northern SFB.

16.
J Chem Phys ; 159(24)2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38146833

RESUMO

New six-dimensional ab initio potential energy surfaces (PESs) for the N2-CO2 complex, which involve the stretching vibration of N2 and the Q3 normal mode for the ν3 asymmetric stretching vibration of CO2, were constructed using the CCSD(T)-F12/AVTZ method with midpoint bond functions. Two vibrational averaged 4D interaction potentials were obtained by integrating over the two intramolecular coordinates. It was found that both PESs possess two equivalent T-shaped global minima as well as two in-plane and one out-of-plane saddle points. Based on these PESs, rovibrational bound states and energy levels were calculated applying the radial discrete variable representation/angular finite basis representation method and the Lanczos algorithm. The splitting of the energy levels between oN2-CO2 and pN2-CO2 for the intermolecular vibrational ground state is determined to be only 0.000 09 cm-1 due to the higher barriers. The obtained band origin shift is about +0.471 74 cm-1 in the N2-CO2 infrared spectra with CO2 at the ν3 zone, which coincides with the experimental data of +0.483 74 cm-1. The frequencies of the in-plane geared-bending for N2-CO2 at the ν3 = 0 and 1 states of CO2 turn out to be 21.6152 and 21.4522 cm-1, the latter reproduces the available experimental 21.3793 cm-1 value with CO2 at the ν3 zone. The spectral parameters fitted from the rovibrational energy levels show that this dimer is a near prolate asymmetric rotor. The computed microwave transitions as well as the infrared fundamental and combination bands for the complex agree well with the observed data.

17.
Endocr Pract ; 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38122932

RESUMO

OBJECTIVE: To investigate the usefulness of ultrasound (US) for the localization of ectopic hyperparathyroidism and compare it with 99mTc-sestamibi (99mTc-MIBI), 4-dimensional computed tomography (4D-CT), and 11C-choline positron emission tomography/ computed tomography (PET/CT). METHODS: Of the 527 patients with surgically confirmed primary hyperparathyroidism, 79 patients with ectopic hyperparathyroidism were enrolled. The diagnostic performance of US, 99mTc-MIBI, US + MIBI, 4D-CT, and 11C-choline PET/CT was calculated, and the factors affecting the sensitivity of US and 99mTc-MIBI were analyzed. RESULTS: Eighty-three ectopic parathyroid lesions were found in 79 patients. The sensitivity was 75.9%, 81.7%, 95.1%, 83.3%, and 100% for US, 99mTc-MIBI, US + MIBI, 4D-CT, and 11C-choline PET/CT, respectively. The difference in sensitivity among these different modalities did not achieve statistical significance (P > .05). The US sensitivity was significantly higher for ectopic lesions in the neck region than for those in the anterior mediastinum/chest wall (85.9% vs. 42.1%, P < .001). The 99mTc-MIBI and 4D-CT sensitivity was not significantly different between these two groups (84.1% vs. 94.6%, P = .193 and 81.3% vs. 85.7%, P = 1). The 11C-choline PET/CT sensitivity was 100% in both groups. CONCLUSIONS: US is a valuable tool for the localization of ectopic hyperparathyroidism, especially for ectopic lesions in the neck region.

18.
Molecules ; 28(24)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38138509

RESUMO

Dendrobium huoshanense is a famous edible and medicinal herb, and polysaccharides are the main bioactive component in it. In this study, response surface methodology (RSM) combined with a Box-Behnken design (BBD) was used to optimize the enzyme-assisted extraction (EAE), ultrasound-microwave-assisted extraction (UMAE), and hot water extraction (HWE) conditions and obtain the polysaccharides named DHP-E, DHP-UM, and DHP-H. The effects of different extraction methods on the physicochemical properties, structure characteristics, and bioactivity of polysaccharides were compared. The differential thermogravimetric curves indicated that DHP-E showed a broader temperature range during thermal degradation compared with DHP-UM and DHP-H. The SEM results showed that DHP-E displayed an irregular granular structure, but DHP-UM and DHP-H were sponge-like. The results of absolute molecular weight indicated that polysaccharides with higher molecular weight detected in DHP-H and DHP-UM did not appear in DHP-E due to enzymatic degradation. The monosaccharide composition showed that DHPs were all composed of Man, Glc, and Gal but with different proportions. Finally, the glycosidic bond types, which have a significant effect on bioactivity, were decoded with methylation analysis. The results showed that DHPs contained four glycosidic bond types, including Glcp-(1→, →4)-Manp-(1→, →4)-Glcp-(1→, and →4,6)-Manp-(1→ with different ratios. Furthermore, DHP-E exhibited better DPPH and ABTS radical scavenging activities. These findings could provide scientific foundations for selecting appropriate extraction methods to obtain desired bioactivities for applications in the pharmaceutical and functional food industries.


Assuntos
Antioxidantes , Dendrobium , Humanos , Antioxidantes/farmacologia , Antioxidantes/química , Dendrobium/química , Peso Molecular , Monossacarídeos/análise , Polissacarídeos/farmacologia , Polissacarídeos/química
19.
Brain Sci ; 13(12)2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38137105

RESUMO

BACKGROUND AND AIMS: The immune-inflammatory cascade and pyroptosis play an important role in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). The maintenance of immune homeostasis is inextricably linked to the Notch signaling pathway, but whether myeloid Notch1 affects microglia polarization as well as neuronal pyroptosis in CIRI is not fully understood. This study was designed to clarify the role of myeloid Notch1 in CIRI, providing new therapeutic strategies for ischemic stroke. METHODS AND RESULTS: Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to middle cerebral artery occlusion (MCAO). After 3 days of CIRI, we evaluated the neurological deficit score and cerebral infarction volume. Immunofluorescence staining was used to detect the expression of Notch1 and microglial subtype markers. Cerebral infiltrating macrophages were detected by flow cytometry. RT-qPCR was used to detect pro-inflammatory cytokines. Western blot was used to detect the expression of pyroptosis related proteins. The Notch1-siRNA transfected BV2 cells were co-cultured with HT22 cells to investigate the potential mechanisms by which microglial Notch1 affects neuronal pyroptosis induced by anoxia/reoxygenation in vitro. We found that Notch1 was activated in cerebral microglia/macrophages after CIRI. Myeloid Notch1 deficiency decreased the cerebral infarct volume (24.17 ± 3.29 vs. 36.17 ± 2.27, p < 0.001), neurological function scores (2.33 ± 0.47 vs. 3.17 ± 0.37, p < 0.001) and the infiltration of peripheral monocytes/macrophages (3.26 ± 0.53 vs. 5.67 ± 0.57, p < 0.01). Strikingly, myeloid-specific Notch1 knockout alleviated pyroptosis. Compared with microglia M1, increased microglia M2 were detected in the ischemic penumbra. In parallel in vitro co-culture experiments, we found that Notch1 knockdown in microglial BV2 cells inhibited anoxia/reoxygenation-induced JAK2/STAT3 activation and pyroptosis in hippocampal neuron HT22 cells. CONCLUSIONS: Our findings elucidate the underlying mechanism of the myeloid Notch1 signaling pathway in regulating neuronal pyroptosis in CIRI, suggesting that targeting myeloid-specific Notch1 is an effective strategy for the treatment of ischemic stroke.

20.
Int J Biol Macromol ; 254(Pt 2): 127887, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37935288

RESUMO

A cleaner and safer environment is one of the most important requirements in the future. It has become increasingly urgent and important to fabricate novel environmentally-friendly materials to remove various hazardous pollutants. Compared with traditional materials, chitosan is a more environmentally friendly material due to its abundance, biocompatibility, biodegradability, film-forming ability and hydrophilicity. As an abundant of -NH2 and -OH groups on chitosan molecular chain could chelate with all kinds of metal ions efficiently, chitosan-based materials hold great potential as a versatile supporting matrix for metal oxide nanomaterials (MONMs) (TiO2, ZnO, SnO2, Fe3O4, etc.). Recently, many chitosan/metal oxide nanomaterials (CS/MONMs) have been reported as adsorbents, photocatalysts, heterogeneous Fenton-like agents, and sensors for potential and practical applications in environmental remediation and monitoring. This review analyzed and summarized the recent advances in CS/MONMs composites, which will provide plentiful and meaningful information on the preparation and application of CS/MONMs composites for wastewater treatment and help researchers to better understand the potential of CS/MONMs composites for environmental remediation and monitoring. In addition, the challenges of CS/MONM have been proposed.

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