[18F]FAPI-42 PET/CT in differentiated thyroid cancer: diagnostic performance, uptake values, and comparison with 2-[18F]FDG PET/CT.

PURPOSE: This study aimed to assess the diagnostic performance of [18F]FAPI-42 PET/CT and compare it with that of 2-[18F]FDG PET/CT in patients with differentiated thyroid cancer (DTC) with biochemical elevations in Tg or anti-Tg antibodies. METHODS: A total of 42 patients with DTC with biochemical elevations in Tg or anti-Tg antibodies underwent [18F]FAPI-42 PET/CT as part of this study; of which, 11 additionally underwent 2-[18F]FDG PET/CT within 7 days. Images were semi-quantitatively and visually interpreted, and the quantity, location, and uptake values of lesions were noted. The diagnostic capacity of [18F]FAPI-42 PET/CT and biomarkers affecting the uptake of [18F]FAPI-42 were evaluated. In addition, the diagnostic performance and uptake of [18F]FAPI-42 and 2-[18F]FDG were compared, and the correlation between lesion diameter and quantitative parameters was investigated. RESULTS: A total of 161 lesions were detected in 27 (64%) patients on [18F]FAPI-42 PET/CT. FAPI-positive local recurrence showed the highest uptake intensity, followed by lymphatic, other site-associated (bone and pleura), and pulmonary lesions (mean SUVmax, 4.7 versus 3.7 versus 3.0 versus 2.2, respectively; P < 0.0001). The levels of TSH, Tg, and Tg-Ab did not affect the uptake value of lesions (median SUVmax: 2.4 versus 3.2, P = 0.56; 2.9 versus 2.4, P = 0.0935; 2.8 versus 2.6, P = 0.0525, respectively). A total of 90 positive lesions were detected in 7 patients using both modalities. All positive lesions showed statistically higher uptake of 2-[18F]FDG than that of [18F]FAPI-42 (SUVmax, 2.6 versus 2.1; P = 0.026). However, the SUVmax of [18F]FAPI-42 was higher than that of 2-[18F]FDG in local recurrences and lymphatic lesions (SUVmax, 4.2 versus 2.9 and 3.9 versus 3.4, respectively; P > 0.05). CONCLUSION: [18F]FAPI-42 can be used for detecting lesions and reflecting FAP expression during local recurrence and metastasis in patients with DTC with biochemical elevations in Tg or anti-Tg antibodies. The diagnostic performance of [18F]FAPI-42 PET/CT is comparable with that of 2-[18F]FDG PET/CT in such patients.

CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma.

Recent studies have reported that MLST8 is upregulated in many malignant tumors. Nevertheless, the underlying molecular mechanism is still unclear. The aim of this work was to investigate how MLST8 contributes to the development and progression of clear cell renal cell carcinoma (ccRCC). MLST8 is an oncogenic protein in the TCGA database and ccRCC clinical specimens. We also ascertain that MLST8 interacts with FBXW7, which was universally regarded as an E3 ubiquitin ligase. MLST8 can be degraded and ubiquitinated by tumor suppressor FBXW7. FBXW7 recognizes a consensus motif (T/S) PXX (S/T/D/E) of MLST8 and triggers MLST8 degradation via the ubiquitin-proteasome pathway. Strikingly, the activated cyclin dependent kinase 1 (CDK1) kinase engages in the MLST8 phosphorylation required for FBXW7-mediated degradation. In vitro, we further prove that MLST8 is an essential mediator of FBXW7 inactivation-induced tumor growth, migration, and invasion. Furthermore, the MLST8 and FBXW7 proteins are negatively correlated in human renal cancer specimens. Our findings suggest that MLST8 is a putative oncogene that functions via interaction with FBXW7, and inhibition MLST8 could be a potential future target in ccRCC treatment.

Dual-task convolutional neural network based on the combination of the U-Net and a diffraction propagation model for phase hologram design with suppressed speckle noise.

In this paper, a dual-task convolutional neural network based on the combination of the U-Net and a diffraction propagation model is proposed for the design of phase holograms to suppress speckle noise of the reconstructed images. By introducing a Fresnel transmission layer, based on angular spectrum diffraction theory, as the diffraction propagation model and incorporating it into U-Net as the output layer, the proposed neural network model can describe the actual physical process of holographic imaging, and the distributions of both the light amplitude and phase can be generated. Afterwards, by respectively using the Pearson correlation coefficient (PCC) as the loss function to modulate the distribution of the amplitude, and a proposed target-weighted standard deviation (TWSD) as the loss function to limit the randomness and arbitrariness of the reconstructed phase distribution, the dual tasks of the amplitude reconstruction and phase smoothing are jointly solved, and thus the phase hologram that can produce high quality image without speckle is obtained. Both simulations and optical experiments are carried out to confirm the feasibility and effectiveness of the proposed method. Furthermore, the depth of field (DOF) of the image using the proposed method is much larger than that of using the traditional Gerchberg-Saxton (GS) algorithm due to the smoothness of the reconstructed phase distribution, which is also verified in the experiments. This study provides a new phase hologram design approach and shows the potential of neural networks in the field of the holographic imaging and more.

Establishment and evaluation of a CT-based radiomic model for AIDS-associated pulmonary cryptococcosis.

BACKGROUND: Establish a CT-based diagnostic radiomic model for AIDS complicated with pulmonary cryptococcosis and evaluate the diagnostic efficacy of this model. METHODS: This retrospective study enrolled 98 AIDS patients with pulmonary cryptococcosis and 103 AIDS patients with other infections or neoplastic lesions, comprising a total of 699 lesions. Patients were randomly divided into a training group and test group at a ratio of 2.75:1. Features from all lesions, cavity lesions and solid nodule lesions were extracted, and two kinds of radiomic models (6 types) were established. ROC curves were drawn, and the sensitivity and specificity were calculated to compare the SVM model and LR model, radiologists' empirical diagnoses and the combination of these empirical diagnoses with the radiomic model. RESULTS: The AUCs of senior radiologist for all lesions and cavity lesions were lower than those of the SVM and LR models. The diagnostic efficacy of primary radiologist was lower than that of both of the other model types. The diagnostic efficacy of the LR model was relatively stable, with the highest diagnostic efficiency of the 3 model/radiologist groups. The AUCs of intermediate radiologist in combination with the LR radiomic model for all lesions, nodular lesions and cavity lesions were 0.88, 0.84, and 0.9, respectively, which were the highest among all models and radiologists. CONCLUSIONS: The CT-based radiomic LR model of AIDS-associated pulmonary cryptococcosis exhibits good diagnostic performance, which was similar to that of senior radiologists and higher than that of the primary radiologist. With the help of a radiomic model, radiologists can achieve improved diagnostic accuracy compared to that when only an empirical diagnosis is used.

[Effect of Social Support on Multimorbidity and Related Outcomes of Middle-Aged and Older Adults in China].

Objective: To analyze the current status of social support for middle-aged and older adults with multimorbidity and to explore the correlation between different dimensions of social support and multimorbidity and the related outcomes on the basis of China Health and Retirement Longitudinal Study (CHARLS) 2015 survey data so as to reveal the complex social background of multimorbidity and the impact of social support on multimorbidity. Methods: A total of 9168 valid samples, with an average age of 59.60 years, were included in the study. Using the social support-related variables of the respondents, we conducted factor analysis and constructed regression models of common factors of social support and multimorbidity-related outcomes, intending to analyze the impact of common factors of social support on multimorbidity in the middle-aged and older adults. Results: The multimorbidity of middle-aged and older adults in China was related to multiple factors of social support, and the differences were statistically significant. Logistic regression showed that social support in the form of activity/recreational facilities and medical resources was a protective factor of multimorbidity, that family emotional support and economic support had a positive effect on life satisfaction of comorbid patients, and that social support in the form of education, social life and housing conditions was negatively correlated with catastrophic medical expenditure of the comorbid population ( P<0.05). Conclusion: Social support for middle-aged and older adults in China is unevenly distributed. Social support in the form of activity/recreational facilities and medical resources may reduce the risks of multimorbidity among middle-aged and older adults. Good family economic and emotional support can improve the life satisfaction of middle-aged and older adults with multimorbidity. Social support in the form of education, social life and housing conditions may reduce the risk of catastrophic medical expenditure in middle-aged and older adults with multimorbidity.

Pseudomonas aeruginosa antitoxin HigA functions as a diverse regulatory factor by recognizing specific pseudopalindromic DNA motifs.

Type II toxin-antitoxin (TA) systems modulate many essential cellular processes in prokaryotic organisms. Recent studies indicate certain type II antitoxins also transcriptionally regulate other genes, besides neutralizing toxin activity. Herein, we investigated the diverse transcriptional repression properties of type II TA antitoxin PaHigA from Pseudomonas aeruginosa. Biochemical and functional analyses showed that PaHigA recognized variable pseudopalindromic DNA sequences and repressed expression of multiple genes. Furthermore, we presented high resolution structures of apo-PaHigA, PaHigA-PhigBA and PaHigA-Ppa2440 complex, describing how the rearrangements of the HTH domain accounted for the different DNA-binding patterns among HigA homologues. Moreover, we demonstrated that the N-terminal loop motion of PaHigA was associated with its apo and DNA-bound states, reflecting a switch mechanism regulating HigA antitoxin function. Collectively, this work extends our understanding of how the PaHigB/HigA system regulates multiple metabolic pathways to balance the growth and stress response in P. aeruginosa and could guide further development of anti-TA oriented strategies for pathogen treatment.

[Subacute Thyroiditis Following HPV Vaccination: A Case Report].

Subacute thyroiditis (SAT) is the most common self-limiting thyroid disease causing pain. The etiology of the disease remains unknown, but it is usually related to viral infection or allergic reaction after viral infection. SAT after vaccination is extremely rare. The patient had a fever of no clearly defined cause about 8 hours after receiving the first dose of a 0.5 mL 9-valent human papillomavirus vaccine (Gardasil 9). The highest temperature was 37.8 ℃, accompanied by a pain in the neck, fatigue and the increasing pain when swallowing. After the patient was admitted to the hospital, physical examination revealed Ⅱ° enlargement of the thyroid gland, which was hard and tender, and no vascular murmur was heard. There was no redness, swelling or ulceration at the vaccination site, and no obvious abnormalities were observed in other physical examinations. Laboratory findings were as follows: C-reactive protein, 25.20 mg/L; erythrocyte sedimentation rate, 55 mm/1 h; leukocyte, 4.94×10 9 L -1; thyrotropin, 0.137 mU/L; free thyroxine, 22.32 pmol/L; antithyroglobulin antibody, 69.18 IU/mL; anti-thyroid peroxidase antibody, 21.66 IU/mL. Thyroid ultrasonography showed diffuse enlargement of bilateral thyroid with uneven internal echo. The patient was diagnosed with SAT. After 5 days of treatment with ibuprofen, the patient no longer had low fever and the neck pain was relieved. The patient was followed up till now, and had completed the vaccination of the three-dose 9-valent human papillomavirus vaccine. The function of thyroid was found to be normal in follow-up visits, and SAT did not recur.

Structural and Functional Insights into PpgL, a Metal-Independent ß-Propeller Gluconolactonase That Contributes to Pseudomonas aeruginosa Virulence.

Biofilm formation is a critical determinant in the pathopoiesis of Pseudomonas aeruginosa It could significantly increase bacterial resistance to drugs and host defense. Thus, inhibition of biofilm matrix production could be regarded as a promising attempt to prevent colonization of P. aeruginosa and the subsequent infection. PpgL, a periplasmic gluconolactonase, has been reported to be involved in P. aeruginosa quorum-sensing (QS) system regulation. However, the detailed function and catalysis mechanism remain elusive. Here, the crystal structure of PpgL is described in the current study, along with biochemical analysis, revealing that PpgL is a typical ß-propeller enzyme with unique metal-independent lactone hydrolysis activity. Consequently, comparative analysis of seven-bladed propeller lactone-catalyzing enzymes and mutagenesis studies identify the critical sites which contribute to the diverse catalytic and substrate recognition functions. In addition, the reduced biofilm formation and attenuated invasion phenotype resulting from deletion of ppgL confirm the importance of PpgL in P. aeruginosa pathogenesis. These results suggest that PpgL is a potential target for developing new agents against the diseases caused by P. aeruginosa.

Prognostic nomogram for bladder cancer with brain metastases: a National Cancer Database analysis.

BACKGROUND: This study aimed to establish and validate a nomogram for predicting brain metastasis in patients with bladder cancer (BCa) and assess various treatment modalities using a primary cohort comprising 234 patients with clinicopathologically-confirmed BCa from 2004 to 2015 in the National Cancer Database. METHODS: Machine learning method and Cox model were used for nomogram construction. For BCa patients with brain metastasis, surgery of the primary site, chemotherapy, radiation therapy, palliative care, brain confinement of metastatic sites, and the Charlson/Deyo Score were predictive features identified for building the nomogram. RESULTS: For the original 169 patients considered in the model, the areas under the receiver operating characteristic curve (AUC) were 0.823 (95% CI 0.758-0.889, P < 0.001) and 0.854 (95% CI 0.785-0.924, P < 0.001) for 0.5- and 1-year overall survival respectively. In the validation cohort, the nomogram displayed similar AUCs of 0.838 (95% CI 0.738-0.937, P < 0.001) and 0.809 (95% CI 0.680-0.939, P < 0.001), respectively. The high and low risk groups had median survivals of 1.91 and 5.09 months for the training cohort and 1.68 and 8.05 months for the validation set, respectively (both P < 0.0001). CONCLUSIONS: Our prognostic nomogram provides a useful tool for overall survival prediction as well as assessing the risk and optimal treatment for BCa patients with brain metastasis.

Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy.

Bladder cancer (BC) is a disease arising from the malignant cells of the urinary bladder. Myeloid-derived suppressor cells (MDSCs) expand broadly and have strong immunosuppressive activities in the cancer microenvironment. Determining how to inhibit the negative effects of MDSCs requires immediate attention. In this study, we found that granulocytic-MDSCs (G-MDSCs), which constitute one of the two types of MDSCs, were significantly increased in BC tissues compared with those in the adjacent bladder tissues. There was a robust negative correlation between the G-MDSCs and the CD8+ T cells in the BC tissues. In this study, we attempted to identify pharmacological approaches to eliminate MDSCs and restore T cell anti-tumor activities. It is necessary to explore a method to eliminate the detrimental effects of MDSCs. Cisplatin, a chemotherapy medication used to treat BC, not only rapidly kills proliferating cancer cells but also affects the tumor immune microenvironment. However, the mechanism underlying this phenomenon is largely unknown. In this study, we found that Cisplatin directly inhibited the proliferation and induced the apoptosis of T24 cells (a BC cell line), as well as decreased the percentage of the G-MDSCs in the population of peripheral blood mononuclear cells (PBMCs), which restored the expansion of the CD8+ T cells. In the C3H/He mouse BC model, Cisplatin treatment inhibited the progression of BC and effectively decreased the proportion of G-MDSCs. These results suggest that Cisplatin treatment enhances the anti-tumor function of CD8+ T cells by decreasing G-MDSCs. This finding provides a new perspective for Cisplatin treatment to prevent the progression of BC, particularly in patients with abnormally high levels of G-MDSCs.

Self-retaining barbed suture reduces warm ischemia time during laparoscopic partial nephrectomy.

OBJECTIVE: To evaluate the efficacy and safety of self-retaining barbed suture in renorrhaphy during laparoscopic partial nephrectomy by comparing surgical outcomes in a prospective randomized manner. MATERIAL AND METHODS: From July 2014 to July 2015, a total of 60 patients with T1 renal tumor were randomized into two equal groups: self-retaining barbed suture (SRBS) and conventional absorbable polyglactin suture (non-SRBS group). All patients were treated by retroperitoneal laparoscopic partial nephrectomy. One surgeon with high volume experience performed all procedures. The patient demographics and perioperative outcomes were compared. RESULTS: The patient demographics and tumor characteristics were comparable. The mean tumor size and R.E.N.A.L. scores were comparable between the two groups. LPN was successfully accomplished in all patients without open conversion. The warm ischemia and renorrhaphy times were significantly shorter in the SRBS group (18.8 ± 8.2 vs. 22.9 ± 7.3 min, P = .04; 10.4 ± 3.7 vs. 13.8 ± 5.6 min, P = .01). The minor complication rate was 13.3% vs. 10.0%, which was comparable. No major complication occurred. CONCLUSIONS: The randomized controlled trial demonstrates that SRBS for renorrhaphy during retroperitoneal laparoscopic partial nephrectomy is safe and efficient. Application of barbed suture simplifies the parenchymal repair procedure and reduces warm ischemia time in comparison with conventional suture.

microRNA-495 promotes bladder cancer cell growth and invasion by targeting phosphatase and tensin homolog.

Accumulating evidence has linked deregulation of microRNA-495 (miR-495) to tumorigenesis; however, its function in tumor progression is controversial. This work was undertaken to explore the expression and biological roles of miR-495 in bladder cancer. The expression of miR-495 was examined in 67 pairs of bladder cancer and adjacent normal bladder tissues. The roles of miR-495 in bladder cancer cell proliferation and invasion in vitro and tumorigenesis in vivo were determined. Direct target gene(s) mediating the activity of miR-495 in bladder cancer cells was identified. It was found that miR-495 was expressed at greater levels in bladder tissues and cell lines. High expression of miR-495 was significantly associated with larger tumor size, advanced TNM stage, and lymph node metastasis. Overexpression of miR-495 significantly promoted bladder cancer cell proliferation and invasion, whereas inhibition of miR-495 suppressed cell proliferation and invasion. PTEN, a well-defined tumor suppressor was identified to be a target gene of miR-495. A significant inverse correlation between miR-495 and PTEN expression was noted in bladder cancer tissues (r = -0.3094, P = 0.0125). Overexpression of miR-495 led to reduction of PTEN expression in bladder cancer cells. Rescue experiments showed that enforced expression of PTEN impaired miR-495-mediated bladder cancer proliferation and invasion. In vivo mouse studies demonstrated that overexpression of miR-495 accelerated the growth of subcutaneous bladder cancer xenografts, which was associated with downregulation of PTEN. Overall, these findings indicate that miR-495 upregulation contributes to bladder cancer cell growth, invasion, and tumorigenesis by targeting PTEN and offer a potential therapeutic target for bladder cancer.

Long-term use of ciclosporin on kidney transplant recipients surviving more than 10 years.

OBJECTIVE: To evaluate the long-term use of ciclosporin on kidney transplant recipients who survived more than 10 years. METHODS: We reviewed cadaveric kidney transplant patients who had survived 10 years or longer in this study. Patients were divided into five groups based on their ciclosporin concentration at one year: group 1 (> 250 ng/ml), group 2 (200-250 ng/ml), group 3 (150-200 ng/ml), group 4 100-150 ng/ml) and group 5 (< 100 ng/ml). Lab parameters were compared among these groups over time. RESULTS: There were no differences in lab parameters among the five groups. At five years, systolic blood pressures (SBP), TG, CH, DB, TB were significantly higher in groups 3, 4, and 5. Uric acid was also higher but albumin was lower in group 5 compared to those in all other groups. Prevalence of proteinuria in both groups 4 and 5 were lower. At 10 years, SBP in group 3 was lower while both uric acid and ALT in all groups were decreased. CONCLUSION: In patients who survived for more than 10 years after kidney transplantation, serum lipid levels were markedly elevated, indicating the increase of cardiovascular risk factors for patients, which might impact long-term survival benefit.

Corrigendum: Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fendo.2023.1214334.].

Comparison of 18 F-FAPI and 18 F-FDG PET/CT in a Patient With Fibrous Dysplasia.

ABSTRACT: A 16-year-old woman presented with an acute headache on the left side. A head CT scan revealed bone destruction in the skull. Subsequent 18 F-FDG and 18 F-FAPI PET/CT scans were performed within a week. The 18 F-FDG PET/CT indicated mild uptake in the regions of bone destruction, whereas the 18 F-FAPI PET/CT displayed significant tracer accumulation. The patient was ultimately diagnosed with fibrous dysplasia.

Renal hypouricemia complicated with kidney stone: a case report.

Renal hypouricemia (RHUC) is a rare autosomal recessive disorder characterized by impaired renal tubular uric acid reabsorption and abnormally high uric acid clearance, which may be manifested by reduced serum uric acid (SUA) levels and elevated fractional excretion of uric acid (FE-UA >10%). Most RHUC patients are often asymptomatic or have accidentally decreased SUA levels during health examinations, while others develop kidney stones and exercise-induced acute kidney injury (EIAKI). We now report a case of RHUC complicated with an asymptomatic kidney stone, and we identified a heterozygous mutation of c.269G > A (p.R90H) and a novel heterozygous mutation of c.674C > G (p.T225R) in the SLC22A12 gene in the patient through whole exon gene detection (NGS method). This case offers valuable insights into the mechanisms, clinical management, and prognosis of RHUC and its associated complications.

Development of a predictive nomogram for intermediate-risk differentiated thyroid cancer patients after fixed 3.7GBq (100mCi) radioiodine remnant ablation.

Objectives: The objective of this study was to develop a predictive nomogram for intermediate-risk differentiated thyroid cancer (DTC) patients after fixed 3.7GBq (100mCi) radioiodine remnant ablation (RRA). Methods: Data from 265 patients who underwent total thyroidectomy with central lymph node dissection (CND) and received RRA treatment at a single institution between January 2018 and March 2023 were analyzed. Patients with certain exclusion criteria were excluded. Univariate and multivariate logistic regression analyses were performed to identify risk factors for a non-excellent response (non-ER) to RRA. A nomogram was developed based on the risk factors, and its performance was validated using the Bootstrap method with 1,000 resamplings. A web-based dynamic calculator was developed for convenient application of the nomogram. Results: The study included 265 patients with intermediate-risk DTC. Significant differences were found between the ER group and the non-ER group in terms of CLNM>5, Hashimoto's thyroiditis, sTg level, TgAb level (P < 0.05). CLNM>5 and sTg level were identified as independent risk factors for non-ER in multivariate analysis. The nomogram showed high accuracy, with an area under the curve (AUC) of 0.833 (95% CI = 0.770-0.895). The nomogram's predicted probabilities aligned closely with actual clinical outcomes. Conclusions: This study developed a predictive nomogram for intermediate-risk DTC patients after fixed 3.7GBq (100mCi) RRA. The nomogram incorporates CLNM>5 and sTg levels as risk factors for a non-ER response to RRA. The nomogram and web-based calculator can assist in treatment decision-making and improve the precision of prognosis information. Further research and validation are needed.

Systemic immune-inflammation index and all-cause and cause-specific mortality in sarcopenia: a study from National Health and Nutrition Examination Survey 1999-2018.

Background: Sarcopenia, common in the elderly, often linked to chronic diseases, correlates with inflammation.The association between SII and mortality in sarcopenia patients is underexplored, this study investigates this relationship in a U.S. adult cohort. Methods: We analyzed 1999-2018 NHANES data, focusing on 2,974 adults with sarcopenia. Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Using a weighted sampling design, participants were grouped into three groups by the Systemic Immune-Inflammation Index (SII). We used Cox regression models, adjusting for demographic and clinical variables, to explore SII's association with all-cause and cause-specific mortality in sarcopenia, performing sensitivity analyses for robustness. Results: Over a median follow-up of 9.2 years, 829 deaths occurred. Kaplan-Meier analysis showed significant survival differences across SII groups. The highest SII group showed higher hazard ratios (HRs) for all-cause and cause-specific mortality in both crude and adjusted models. The highest SII group had a higher HR for all-cause(1.57, 1.25-1.98), cardiovascular(1.61, 1.00-2.58), cancer(2.13, 1.32-3.44), and respiratory disease mortality(3.21, 1.66-6.19) in fully adjusted models. Subgroup analyses revealed SII's association with all-cause mortality across various demographics, including age, gender, and presence of diabetes or cardiovascular disease. Sensitivity analyses, excluding participants with cardiovascular diseases, those who died within two years of follow-up, or those under 45 years of age, largely reflected these results, with the highest SII group consistently demonstrating higher HRs for all types of mortality in both unadjusted and adjusted models. Conclusion: Our study is the first to demonstrate a significant relationship between SII and increased mortality risks in a sarcopenia population.

Precision USPIO-PEG-SLex Nanotheranostic Agent Targeted Photothermal Therapy for Enhanced Anti-PD-L1 Immunotherapy to Treat Immunotherapy Resistance.

Background: The anti-Programmed Death-Ligand 1 (termed aPD-L1) immune checkpoint blockade therapy has emerged as a promising treatment approach for various advanced solid tumors. However, the effect of aPD-L1 inhibitors limited by the tumor microenvironment makes most patients exhibit immunotherapy resistance. Methods: We conjugated the Sialyl Lewis X with a polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO-PEG) to form UPS nanoparticles (USPIO-PEG-SLex, termed UPS). The physicochemical properties of UPS were tested and characterized. Transmission electron microscopy and ICP-OES were used to observe the cellular uptake and targeting ability of UPS. Flow cytometry, mitochondrial membrane potential staining, live-dead staining and scratch assay were used to verify the in vitro photothermal effect of UPS, and the stimulation of UPS on immune-related pathways at the gene level was analyzed by sequencing. Biological safety analysis and pharmacokinetic analysis of UPS were performed. Finally, the amplification effect of UPS-mediated photothermal therapy on aPD-L1-mediated immunotherapy and the corresponding mechanism were studied. Results: In vitro experiments showed that UPS had strong photothermal therapy ability and was able to stimulate 5 immune-related pathways. In vivo, when the PTT assisted aPD-L1 treatment, it exhibited a significant increase in CD4+ T cell infiltration by 14.46-fold and CD8+ T cell infiltration by 14.79-fold, along with elevated secretion of tumor necrosis factor-alpha and interferon-gamma, comparing with alone aPD-L1. This PTT assisted aPD-L1 therapy achieved a significant inhibition of both primary tumors and distant tumors compared to the alone aPD-L1, demonstrating a significant difference. Conclusion: The nanotheranostic agent UPS has been introduced into immunotherapy, which has effectively broadened its application in biomedicine. This photothermal therapeutic approach of the UPS nanotheranostic agent enhancing the efficacy of aPD-L1 immune checkpoint blockade therapy, can be instructive to address the challenges associated with immunotherapy resistance, thereby offering potential for clinical translation.

SUMO-specific protease 2 suppresses cell migration and invasion through inhibiting the expression of MMP13 in bladder cancer cells.

BACKGROUND: SUMO-specific protease 2 (SENP2) is a de-SUMOylation protease family member which has an indispensable role in the regulation of NF-κB transcriptional activation and Wnt signaling. However, whether SENP2 plays a role in tumor metastasis is completely unknown. METHODS: Real-time PCR and Western blot was used to detect the expression of SENP2 in human bladder cancer samples and cell lines. Small interfering RNA (siRNA) was used to silencing the expression of SENP2. Matrigel-coated invasion chambers were used to detect the invasion ability of SENP2 in bladder cancer cells. RESULTS: SENP2 was down-regulated in bladder cancer samples. SENP2 inhibited bladder cancer cells migration and invasion in vitro. Transcriptional analysis of several genes associated with tumor metastasis and invasion demonstrated that SENP2 selectively down-regulated MMP13 in bladder cancer cells. Further analysis indicated that silencing of MMP13 rescued the invasive phenotype in SENP2 expressing T24 cells. CONCLUSION: SENP2 functions as a tumor metastasis suppressor in bladder cancer. The effects of SENP2 on bladder cancer invasion are partially mediated by inhibiting the expression of MMP13.