Efficacy and safety of fruquintinib as third- or further-line therapy for patients with advanced bone and soft tissue sarcoma: a multicenter retrospective study.

PURPOSE: Fruquintinib is an oral small-molecule angiogenesis inhibitor, markedly specifically inhibited vascular endothelial growth factor 2 (VEGFR2). This retrospective study aimed to evaluate the safety and efficacy of fruquintinib, or in combination with immunotherapy or chemotherapy in patients with bone and soft tissue sarcoma (STS), who have failed at least secondary-line treatment. PATIENTS AND METHODS: We performed a retrospective analysis of advanced bone and STS patients who received fruquintinib containing third- or further-line therapy in Shanghai Jiao Tong University Affiliated Sixth People's and the Affiliated Hospital of Jiangxi University of Traditional Chiese Medicine from September 2019 to February 2022. All of them had accepted at least anthracyclines-based chemotherapy. For the experimental group, 25 cases, the patients took a basic dose of fruquintinib 3-5 mg once a day for 21 days per 4 weeks as a cycle until the disease progression or intolerable toxicity. The other 20 patients in the control group received the best supportive care. The patients were evaluated by computed tomography (CT) or MRI once 2 months or symptoms worse. The DCR, progression-free survival (PFS), and adverse reactions of the drug were recorded and reviewed. RESULTS: The DCR in patients receiving fruquintinib therapy was 80.0%. The median PFS (mPFS) in the fruquintinib-containing therapy group was significantly longer than that in the control group (4.8 vs. 1.4 months; P < 0.001). The mPFS in the fruquintinib group, the fruquintinib-OI group and the fruquintinib-chemotherapy group were 3.2 months [95% confidence interval (CI), 2.0-7.9], 4.9 months (95% CI, 3.0-9.9) and 4.2 months (95% CI, 2.6-6.6) respectively, all of them were longer than the mPFS of 1.4 months (95% CI, 0.3-2.5) in the control group ( P < 0.001). CONCLUSION: Fruquintinib was reported for the first time to have favorable efficacy and safety as an optional treatment for patients with advanced bone and STS who failed in multi-line therapies.

Accumulation and Depuration of Cd and its Effect on the Expressions of Metallothionein and Apoptotic Genes in Litopenaeus vannamei.

We investigated cadmium (Cd) accumulation in muscles, gills and hepatopancreas of Litopenaeus vannamei following 48 h exposure to 5.25 mg/L, and depuration of Cd in these tissues on 1, 5 and 15 d post exposure. We also detected the expressions of metallothionein (MT), caspase-3 and p53 in hepatopancreas of shrimp exposed to 0, 5.25 and 10.5 mg/L Cd (the 24 h median lethal concentration, 24 h LC50) at 0, 3, 12, 24 and 48 h. Cd accumulated with high concentration in hepatopancreas, and low concentration in muscles. Cd depurated fast in hepatopancreas and gills. MT expression increased in a time-dependent manner after Cd exposure. The p53 and caspase-3 increased at 12 and 24 h in 10.5 mg/L group. In conclusion, the accumulation and depuration of Cd in three tissues were tissues-specific. The changes of the expressions of MT, p53 and caspase-3, were stress response of L. vannamei under Cd exposure.

Poor vitamin D status was associated with increased appendicular fat deposition in US Adults: Data from 2011-2018 National Health and Nutrition Examination Survey.

The aim of the study was to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and regional body fat deposition in 2011-2018 National Health and Nutrition Examination Survey participants aged 18 to 59 years. We hypothesized that serum 25(OH)D concentrations were negatively associated with total, appendicular, and truncal fat deposition. Serum 25(OH)D concentration was categorized into sufficient (≥75.0 nM), insufficient (50.0-74.9 nM), and deficient (<50.0 nM) groups. Fat mass (FM) was measured by dual-energy X-ray absorptiometry, and FM index (FMI) was calculated by dividing FM (kg) with height2 (m2). Multivariant linear regression and Granger causal analysis were performed to assess the causal relationship between vitamin D status and regional FMIs. Overall serum 25(OH)D concentrations were negatively associated with total (ß = -0.029, standard error [SE] = 0.002), trunk (ß = -0.015, SE = 0.001), arms (ß = -0.004, SE = 3.09 × 10-4), and legs (ß = -0.010, SE = 0.001) FMIs in all participants (P < .001, respectively); however, after stratified by vitamin D status and BMI, the negative associations were only observed in individuals with vitamin D deficiency and obesity. The causal analysis indicated that serum 25(OH)D concentrations may causally reduce the arms (F = 4.917, probability [P] = 0.007), legs (F = 5.783, P = 0.003), and total (F = 3.202, P = 0.041) FMIs except for trunk FMI but not vice versa. In conclusion, poor vitamin D status was associated with increased total and appendicular body fat deposition in US adults, particularly in participants with obesity.

Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway.

Anti-angiogenesis therapy has shown significant anti-tumor effects against a variety of cancers. But resistance to antiangiogenic drugs, intrinsic and evasive, is frequently found in patients during treatment. Here, we report that dihydroartemisinin (DHA), a derivative of the Chinese medicine artemisinin, enhances antiangiogenic drug-induced cytotoxicity in osteosarcoma (OS) cells. Proteomics analysis revealed that DHA treatment significantly affected the activity of the collagen-modifying enzyme lysyl oxidase-like 2 (LOXL2), a regulatory gene associated with poor prognosis of OS. Furthermore, we found that DHA reduced the expression of vascular endothelial growth factor (VEGFA) by downregulating LOXL2. This mechanism was confirmed by QRT-PCR, western blot, and ELISA assays. Correspondingly, vector-enforced expression of LOXL2 markedly reduced VEGFA secretion. Untargeted metabolomic analysis revealed that the lipid metabolism that confers antiangiogenic drug resistance, was also interfered with by DHA. Thus, DHA not only exerts antitumor effects in OS cells directly but also synergizes with the antiangiogenic drug by regulating vascular endothelial growth factor A (VEGFA) expression and lipid metabolism.

The long non-coding RNA CRNDE promotes osteosarcoma proliferation and migration by sponging miR-136-5p/MRP9 axis.

Background: The long-noncoding RNA colorectal neoplasia differentially expressed (CRNDE) gene has been found to be upregulated in several solid tumors. Whether CRNDE affects osteosarcoma (OS) and its underling mechanism remains unknown. Methods: Tumor tissues and corresponding normal tissues were collected from 45 patients with OS. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied to determine lncRNA CRNDE level in the tissues. Participants were divided into a high CRNDE group and a low CRNDE group according to the median value of lncRNA CRNDE expression detected by in situ hybridization (ISH). The differences between high and low expression of lncRNA CRNDE in patients were compared clinically by chi-square test. Kaplan-Meier survival analysis was applied to analyze the relationship between lncRNA CRNDE expression and patient survival. Subsequently, silencing or overexpression of lncRNA CRNDE were performed in MG63 and 143B cell lines, qRT-PCR was applied to verify the expression of lncRNA CRNDE, miR-136-5p, and MRP9; dual-luciferase reporter assay was used to evaluate the targeting relationship between miR-136-5p, lncRNA CRNDE, and Cell Counting Kit-8 (CCK8), wound-healing, and Transwell assays were used to analyze for cell proliferation, migration, and invasion, respectively, and western blot was used to detect expression in cells. Results: The expression of CRNDE in OS tissues was higher than that in normal tissues. High lncRNA CRNDE expression was significantly associated with clinical stage, lung metastasis, and poor prognosis in OS patients. Additionally, overexpression of lncRNA CRNDE promoted proliferation and migration of OS cells. Bioinformatics analysis showed that lncRNA CRNDE competitively inhibited miR-136-5p through acting as a competitive endogenous RNA (ceRNA). It was also revealed that miR-136-5p is a binding target gene of lncRNA CRNDE and that MRP9 is involved in this process as a downstream target gene of miR-136-5p. Conclusions: The lncRNA CRNDE promotes the proliferation and migration of OS cells by regulating the miR-136-5p/MRP9 pathway, and lncRNA CRNDE can be a significant marker of OS prognosis.

Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine Biosynthetic Pathway.

Osteosarcoma (OS) is the most common primary bone sarcoma, chemoresistance becomes an obstacle to its treatment. Metabolic reprogramming is a hallmark of malignancy, targeting the metabolic pathways might provide a reasonable therapeutic strategy for OS. Here we demonstrated that Ailanthone (AIL), a major component of the Chinese medicine Ailanthus altissima, significantly suppressed OS cell growth in vitro and in vivo. Furthermore, AIL dose-dependently inhibited cell migration and invasion, induced cell cycle arrest and apoptosis in OS cells. Combined transcriptomics, proteomics and metabolomics analyses revealed that AIL induced widespread changes in metabolic programs in OS cells, while the serine biosynthetic pathway (SSP) was the most significantly altered pathway. qRT-PCR and Western blot assay confirmed that the transcript and protein levels of the SSP genes (PHGDH, PSAT1 and PSPH) were downregulated dose-dependently by AIL. In addition, we found out that many downstream pathways of the SSP including the one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism were downregulated after AIL treatment. In the revere test, PHGDH overexpression but not exogenous serine supplementation clearly attenuated the effects of AIL on OS cells. Taken together, AIL exerts antitumor effects on OS through mediating metabolic reprogramming, at least in part, by suppressing the SSP. Our findings suggest that AIL could emerge as a potential therapeutic strategy in OS.

FAT1 and MSH2 Are Predictive Prognostic Markers for Chinese Osteosarcoma Patients Following Chemotherapeutic Treatment.

Osteosarcoma is characterized by diverse genetic mutations, including single-nucleotide variants (SNVs), which can complicate clinical outcomes of the treatment. This study identified key mutations or polymorphisms in genes that correlate with osteosarcoma prognoses. A total of 110 patients with osteosarcoma were assigned to "good" or "poor" cohorts depending on their 5-year disease-free survival (DFS) after surgery and chemotherapeutic treatment. We performed next-generation sequencing analysis of tumor tissues for prognosis-associated SNVs in 315 tumorigenesis-related genes, followed by modeling of clinical outcomes for these patients using random forest classification via a support vector machine (SVM). Data from the Chinese Millionome Database were used to compare SNV frequency in osteosarcoma patients and healthy people. SVM screening identified 17 nonsynonymous SNVs located in 15 genes, of which rs17224367 and rs3733406 (located in MSH2 and FAT1, respectively) were strongly correlated with osteosarcoma prognosis. These results were verified in a 26-patient validation cohort, confirming that these SNVs could be used to predict prognosis. These results demonstrated that two SNVs located in MSH2 and FAT1 are associated with prognosis of osteosarcoma patients. © 2022 American Society for Bone and Mineral Research (ASBMR).

[Enhancement pattern of thyroid carcinoma with contrast-enhanced ultrasound].

OBJECTIVE: To investigate the enhancement pattern of thyroid carcinoma with contrast-enhanced ultrasound (CEUS) for the diagnostic value. METHODS: Thirty-one cases with thirty-five thyroid Occupied were retrospectively reviewed. The final diagnosis was confirmed by biopsy pathology. Contrast agent SonoVue and contrast pulse sequencing (CPS) technique were used in this study. RESULTS: Thirty-five thyroid carcinoma presented three enhancement patterns with CEUS. Type I: twenty-three lesions enhanced in a pattern of ring with centripetal fill-in, however, the central part of no contrast agent filling. Type II: five lesions enhanced regularly and homogeneously. Type III: seven lesions enhanced irregularly and homogeneously. Thyroid benign and malignant lesions perfusion time curve, compared to papillary thyroid carcinoma with nodular goiter in the AT, TTP and WT indicators P < 0.05; papillary thyroid carcinoma and thyroid adenoma, compared to WT alone an indicator of P < 0.05. CONCLUSIONS: Identification of the different enhancement patterns of thyroid carcinoma could improve the diagnostic ability of CEUS.

Gill transcriptome alterations in Macrobrachium rosenbergii under copper exposure.

Copper is one of common contaminants in estuaries and coastal zones, which may cause physiological dysfunction in aquatic organisms. However, molecular response triggered by Cu have remained largely unknown in freshwater prawn Macrobrachium rosenbergii. In the present study, we performed transcriptomic analysis to characterize molecular mechanisms of copper immunotoxicity in gills from M. rosenbergii. A large number of potential simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs) loci in the transcriptome were identified. 19,417 and 8989 differentially expressed genes (DEGs) were obtained at 3 h and 48 h after exposure, respectively. Most of these DEGs were down-regulated implying that gene expressions were largely inhibited by Cu, which might lead to impairments of biological functions. Functional enrichment analysis of these DEGs revealed that immune, detoxification and apoptosis were the differentially regulated processes by Cu stress. 12 DGEs involved in immune response and heavy metal detoxification were discovered and validated by qRT-PCR. The results indicated that the M. rosenbergii might counteract the toxicity of Cu at the transcriptomic level by increasing expressions of immune- and heavy metal detoxification-related genes, and these selected genes could be used as molecular indicators for Cu stress. Our study firstly reported the stress response at transcriptional level in M. rosenbergii during Cu exposure. The genes and pathways identified here not only give us new insight into molecular mechanisms underlying Cu toxicity effects in prawn, but facilitate biomarker identification and stress-resistant breeding studies.

Case study of 3D fingerprints applications.

Human fingers are 3D objects. More information will be provided if three dimensional (3D) fingerprints are available compared with two dimensional (2D) fingerprints. Thus, this paper firstly collected 3D finger point cloud data by Structured-light Illumination method. Additional features from 3D fingerprint images are then studied and extracted. The applications of these features are finally discussed. A series of experiments are conducted to demonstrate the helpfulness of 3D information to fingerprint recognition. Results show that a quick alignment can be easily implemented under the guidance of 3D finger shape feature even though this feature does not work for fingerprint recognition directly. The newly defined distinctive 3D shape ridge feature can be used for personal authentication with Equal Error Rate (EER) of ~8.3%. Also, it is helpful to remove false core point. Furthermore, a promising of EER ~1.3% is realized by combining this feature with 2D features for fingerprint recognition which indicates the prospect of 3D fingerprint recognition.

Combined use of choledochoscope and duodenoscope in treatment of bile peritonitis after removal of T-tube.

BACKGROUND: Biliary leakage after removal of a T-tube has significant morbidity and mortality. Its etiology is multifactorial. The treatment and outcome of this complication vary. In the present study we evaluated the procedures and efficacy of combined use of choledochoscope and duodenoscope in the treatment of bile peritonitis after T-tube removal. METHODS: The procedures and results of 11 cases of biliary leakage after removal of T-tube who had been treated from January 1998 to June 2004 by combined use of choledochoscope and duodenoscope were analyzed retrospectively. RESULT: After the treatment, 9 patients were cured, and 2 were reoperated on and cured. CONCLUSIONS: Biliary leakage after removal of T-tube can be cured successfully by combined use of choledochoscope and duodenoscope. Importantly, the method is simple, effective and safe, and mostly reoperation can be avoided.

Phase-synchronization decay of fixational eye movements.

In nonstationary noisy systems the traditional cross-correlation method may not appropriately detect all cases of interdependencies between coupled systems. The phase-synchronization method was previously found useful in detecting synchronization in several systems. We here applied the phase-synchronization decay to study the synchronization between six combinations of binocular fixational eye movement components. We found that only two components were synchronized: the right and left horizontal with each other and the right and left vertical. Furthermore, the vertical-vertical components were much more synchronized than the horizontal.

Scaling of horizontal and vertical fixational eye movements.

Eye movements during fixation of a stationary target prevent the adaptation of the visual system to continuous illumination and inhibit fading of the image. These random, involuntary, small movements are restricted at long time scales so as to keep the target at the center of the field of view. Here we use detrended fluctuation analysis in order to study the properties of fixational eye movements at different time scales. Results show different scaling behavior between horizontal and vertical movements. When the small ballistic movements, i.e., microsaccades, are removed, the scaling exponents in both planes become similar. Our findings suggest that microsaccades enhance the persistence at short time scales mostly in the horizontal component and much less in the vertical component. This difference may be due to the need for continuously moving the eyes in the horizontal plane, in order to match the stereoscopic image for different viewing distances.