ABSTRACT
Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy-activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin-α1 and KPNB1/importin-ß1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor-deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient-derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients.
ABSTRACT
Objective. Ovarian cancer is the deadliest gynecologic malignancy worldwide. Ultrasound is the most useful non-invasive test for preoperative diagnosis of ovarian cancer. In this study, by leveraging multiple ultrasound images from the same patient to generate personalized, informative statistical radiomic features, we aimed to develop improved ultrasound image-based prognostic models for ovarian cancer.Approach. A total of 2057 ultrasound images from 514 ovarian cancer patients, including 355 patients with epithelial ovarian cancer, from two hospitals in China were collected for this study. The models were constructed using our recently developed Frequency Appearance in Multiple Univariate pre-Screening feature selection algorithm and Cox proportional hazards model.Main results. The models showed high predictive performance for overall survival (OS) and recurrence-free survival (RFS) in both epithelial and nonepithelial ovarian cancer, with concordance indices ranging from 0.773 to 0.794. Radiomic scores predicted 2 year OS and RFS risk groups with significant survival differences (log-rank test,P< 1.0 × 10-4for both validation cohorts). OS and RFS hazard ratios between low- and high-risk groups were 15.994 and 30.692 (internal cohort) and 19.339 and 19.760 (external cohort), respectively. The improved performance of these newly developed prognostic models was mainly attributed to the use of multiple preoperative ultrasound images from the same patient to generate statistical radiomic features, rather than simply using the largest tumor region of interest among them. The models also revealed that the roundness of tumor lesion shape was positively correlated with prognosis for ovarian cancer.Significance.The newly developed prognostic models based on statistical radiomic features from ultrasound images were highly predictive of the risk of cancer-related death and possible recurrence not only for patients with epithelial ovarian cancer but also for those with nonepithelial ovarian cancer. They thereby provide reliable, non-invasive markers for individualized prognosis evaluation and clinical decision-making for patients with ovarian cancer.
Subject(s)
Ovarian Neoplasms , Ultrasonography , Humans , Female , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/mortality , Prognosis , Middle Aged , Image Processing, Computer-Assisted/methods , Adult , Aged , RadiomicsABSTRACT
For optical interconnect applications, multi-wavelength comb sources require uniform comb spacings and high reliability at high operating temperature. Here, the high-temperature reliability measurements of a InAs quantum dot colliding pulse mode-locked (QD-CPML) laser with 100â GHz comb spacing are systematically investigated. Laser lifetime measurements are performed for over 1600 hours at 80 °C under constant stress current of 150â mA. The mean time to failure (MTTF) of the laser is approximately 38 years (336,203 hours), extracted from the threshold currents extrapolation method. The optical spectral revolutions are also monitored during the aging process, while the grids of comb laser are remarkably stable. The outstanding reliability and spectrum stability make this 100â GHz QD-CPML a promising candidate as a multi-wavelength laser source for datacom and optical I/O applications.
ABSTRACT
Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with each other to adapt to the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation, which is morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cell death and cuprotosis. Cancer metabolism plays opposite roles in ferroptosis. On the one hand, carbohydrate metabolism can produce NADPH to maintain GPX4 and FSP1 function, and amino acid metabolism can provide substrates for synthesizing GPX4; on the other hand, lipid metabolism might synthesize PUFAs to trigger ferroptosis. The mechanisms through which cancer metabolism affects ferroptosis have been investigated extensively for a long time; however, some mechanisms have not yet been elucidated. In this review, we summarize the interaction between cancer metabolism and ferroptosis. Importantly, we were most concerned with how these targets can be utilized in cancer therapy.
Subject(s)
Ferroptosis , Neoplasms , Humans , Neoplasms/genetics , Apoptosis , Necrosis , Lipid Peroxidation , Amino Acids , Tumor MicroenvironmentABSTRACT
Motor proteins, encoded by Kinesin superfamily (KIF) genes, are critical for brain development and plasticity. Increasing studies reported KIF's roles in neurodevelopmental disorders. Here, a 6 years and 3 months-old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease-related family history. Whole exome sequencing identified a novel heterozygous in-frame deletion (c.265_267delTCA) in exon 3 of the KIF5C in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP-binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild-type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live-cell imaging of the cargo-trafficking assay revealed that mutant KIF5C lost the peroxisome-transporting ability. Drosophila models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the KIF5C gene in intracellular cargo-transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future.
ABSTRACT
The cytokine tumor necrosis factor (TNF) plays a crucial role in the proliferation and metastasis of colorectal cancer (CRC) cells, but the underlying mechanisms remain poorly understood. Here, we report that chondroitin polymerizing factor 2 (CHPF2) promotes CRC cell proliferation and metastasis mediated by TNF, independently of its enzymatic activity. CHPF2 is highly expressed in CRC, and its elevated expression is associated with poor prognosis of CRC patients. Mechanistically, upon TNF stimulation, CHPF2 is phosphorylated at the T588 residue by MEK, enabling CHPF2 to interact with both TAK1 and IKKα. This interaction enhances the binding of TAK1 and IKKα, leading to increased phosphorylation of the IKK complex and activation of NF-κB signaling. As a result, the expression of early growth factors (EGR1) is upregulated to promote CRC cell proliferation and metastasis. In contrast, introduction of a phospho-deficient T588A mutation in CHPF2 weakened the interaction between CHPF2 and TAK1, thus impairing NF-κB signaling. CHPF2 T588A mutation reduced the ability of CHPF2 to promote the proliferation and metastasis of CRC in vitro and in vivo. Furthermore, the NF-κB RELA subunit promotes CHPF2 expression, further amplifying TNF-induced NF-κB signaling activation. These findings identify a moonlighting function of CHPF2 in promoting tumor cell proliferation and metastasis and provide insights into the mechanism by which CHPF2 amplifies TNF-mediated NF-κB signaling activation. Our study provides a molecular basic for the development of therapeutic strategies for CRC treatment.
Subject(s)
Colorectal Neoplasms , NF-kappa B , Humans , NF-kappa B/metabolism , Phosphorylation , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Cell Line, Tumor , Tumor Necrosis Factor-alpha/metabolism , Cell Proliferation , Colorectal Neoplasms/pathology , Mitogen-Activated Protein Kinase Kinases/metabolismABSTRACT
Transcranial ultrasound imaging and therapy have gained significant attention due to their noninvasive nature, absence of ionizing radiation, and portability. However, the presence of the skull, which has a high acoustic impedance, presents a challenge for the penetration of ultrasound into intracranial tissue. This leads to a low transmission of ultrasound through the skull, hindering energy focusing and imaging quality. To address this challenge, we propose a novel approach that utilizes a flexible matching layer with gradual acoustic impedance to enhance ultrasound transmission through the skull. This matching layer is constructed using Poly(dimethylsiloxane) (PDMS)/tungsten powders as the structural component responsible for the gradual impedance, while agarose serves as the flexible matrix. Our simulation and experimental results demonstrate that the matching layer with an exponential gradual acoustic impedance significantly improves the ultrasound transmission coefficient across a wide frequency range compared to traditional quarter wavelength matching layers. Specifically, at 2 MHz, the maximum transmission coefficient reaches 49.5%, more than four times higher than that of the skull without a matching layer (only 11.7%). Additionally, the good flexibility of our matching layer ensures excellent adhesion to the curved surface of the skull, further enhancing its application potential in transcranial ultrasound imaging and therapy. The improved transmission performance allows for a lower ultrasound transmission power, effectively addressing overheating and safety issues.
Subject(s)
Acoustics , Skull , Electric Impedance , Ultrasonography , Skull/diagnostic imaging , Computer SimulationABSTRACT
Despite the remarkable clinical success of immunotherapy and molecular targeted therapy in patients with advanced tumors, chemotherapy remains the most commonly used treatment for most tumor patients. Chemotherapy drugs effectively inhibit tumor cell proliferation and survival through their remarkable mechanisms. However, tumor cells often develop severe intrinsic and acquired chemoresistance under chemotherapy stress, limiting the effectiveness of chemotherapy and leading to treatment failure. Growing evidence suggests that alterations in lipid metabolism may be implicated in the development of chemoresistance in tumors. Therefore, in this review, we provide a comprehensive overview of fatty acid metabolism and its impact on chemoresistance mechanisms. Additionally, we discuss the potential of targeting fatty acid metabolism as a therapeutic strategy to overcome drug resistance.
Subject(s)
Fatty Acids , Neoplasms , Humans , Drug Resistance, Neoplasm , Neoplasms/drug therapy , Cell Proliferation , ImmunotherapyABSTRACT
OBJECTIVE: To investigate the role of MRI in the diagnosis and classification of fetal microtia. METHODS: Ninety-five fetuses with suspected microtia based on ultrasound and MRI performed within 1 week were enrolled in this study. The diagnosis based on MRI was compared with postnatal diagnosis. Among the microtia cases suspected on the basis of MRI, mild and severe cases were further classified. In addition, external auditory canal (EAC) atresia was evaluated by MRI in 29 fetuses with a gestational age > 28 weeks, and the accuracy of MRI in the diagnosis and classification of microtia was determined. RESULTS: Of 95 fetuses, 83 were considered to have microtia on the basis of MRI, 81 were confirmed to have microtia, and 14 were found to be normal according to postnatal diagnosis. Among 190 external ears in 95 fetuses, 40 ears were suspected to have mild microtia, and 52 ears were suspected to have severe microtia on the basis of MRI. According to the postnatal diagnosis, mild and severe microtia were confirmed in 43 and 49 ears, respectively. Among the 29 fetuses with a gestational age > 28 weeks, 23 ears were suspected to have EAC atresia according to MRI and 21 ears were ultimately confirmed to have EAC atresia. The accuracy of MRI in diagnosing microtia and EAC atresia was 93.68% and 93.10%, respectively. CONCLUSION: MRI shows good performance in diagnosing fetal microtia and has the potential to evaluate its severity on the basis of classification and EAC status. CLINICAL RELEVANCE STATEMENT: This study was aimed at investigating the role of MRI in the diagnosis and classification of fetal microtia. MRI shows good performance and can help evaluate microtia severity and EAC atresia, thus allowing for better clinical management. KEY POINTS: ⢠MRI is a useful adjunct to prenatal ultrasound. ⢠MRI has a higher accuracy rate than ultrasound in diagnosing fetal microtia. ⢠The accurate classification of fetal microtia and the diagnosis of external auditory canal atresia through MRI may help guide clinical management.
Subject(s)
Congenital Microtia , Pregnancy , Female , Humans , Infant , Congenital Microtia/diagnostic imaging , Ear, External/diagnostic imaging , Ear, External/abnormalities , Prenatal Diagnosis , Fetus/abnormalities , Magnetic Resonance Imaging , Ultrasonography, Prenatal , Retrospective StudiesABSTRACT
Ovarian cancer is a kind of malignant tumour which locates in the pelvic cavity without typical clinical symptoms in the early stages. Most patients are diagnosed in the late stage while about 60 % of them have suffered from the cancer cells spreading in the abdominal cavity. The high recurrence rate and mortality seriously damage the reproductive needs and health of women. Although recent advances in therapeutic regimes and other adjuvant therapies improved the overall survival of ovarian cancer, overcoming metastasis has still been a challenge and is necessary for achieving cure of ovarian cancer. To present potential targets and new strategies for curbing the occurrence of ovarian metastasis and the treatment of ovarian cancer after metastasis, the first section of this paper explained the metastatic mechanisms of ovarian cancer comprehensively. Nanomedicine, not limited to drug delivery, offers opportunities for metastatic ovarian cancer therapy. The second section of this paper emphasized the advantages of various administration routes of nanodrugs in metastatic ovarian cancer therapy. Furthermore, the third section of this paper focused on advances in nanotechnology-integrated strategies for targeting metastatic ovarian cancer based on the metastatic mechanisms of ovarian cancer. Finally, the challenges and prospects of nanotherapeutics for ovarian cancer metastasis therapy were evaluated. In general, the greatest emphasis on using nanotechnology-based strategies provides avenues for improving metastatic ovarian cancer outcomes in the future.
Subject(s)
Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Nanotechnology , Nanomedicine , Drug Delivery SystemsABSTRACT
Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.
Subject(s)
Colorectal Neoplasms , Tumor Suppressor Protein p53 , Humans , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Oxaliplatin/pharmacology , Oxaliplatin/therapeutic use , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
The aim of this work was to investigate the effects of dielectric barrier discharge-air cold plasma (DBD-ACP, 15-35 kV, 2-12 min) on the quality of foxtail millets. The L and b* values were evaluated by a digital colorimeter representing that the color of millets was significantly changed at 25 kV for 4-12 min or at 35 kV for 2-12 min. The results were consistent with the change of total yellow pigment in millets, indicating that DBD-ACP damaged the carotenoids if the treatment condition was too high. The activity of lipoxygenase and lipase, involving the oxidation and hydrolysis of lipids of millet, decreased significantly induced by DBD-ACP. For example, the lipoxygenase and lipase activity of Mizhi millet was decreased from 44.0 to 18.7 U g-1min-1, 56.0-15.1 U/(mg pro) (p<0.05) after being exposed to 25 kV for 2-12 min, respectively. Changes of color, lipoxygenase and lipase activity, and malondialdehyde content of millets were determined during accelerated storage (40 ± 2°C and 75% Relative Humidity) for 15 days after being treated by DBD-ACP under 15 and 25 kV for 4 min. Results showed that millets treated by DBD-ACP at 15 kV kept a better color with lower malondialdehyde content, and lower lipoxygenase and lipase activity compared to control. This work implied that DBD-ACP is an underlying approach for the storage of foxtail millets.
ABSTRACT
OBJECTIVE: The aim was to assess the expression levels of SLC7A11 and GPX4 in relation to platinum resistance and prognosis in patients with epithelial ovarian cancer (EOC). DESIGN: A retrospective cohort study. SETTING: Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. POPULATION OR SAMPLE: We included 192 eligible patients from hospital between January 2002 and December 2018. METHODS: We retrospectively analysed the medical records of patients with EOC. Surgical specimens of EOC were stained for SLC7A11 and GPX4. Survival analysis was performed using the Kaplan-Meier and Cox regression methods. MAIN OUTCOME MEASURES: Clinical end points include platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: Patients with high co-expression levels of SLC7A11 and GPX4 had a 60-fold higher risk of platinum resistance compared with those with low co-expression (risk ratio, 60.46; 95% confidence interval [CI] 22.76-160.58; p < 0.001). Moreover, high co-expression level of SLC7A11 and GPX4 was an independent prognostic factor for poor OS (p < 0.001, hazard ratio [HR] 4.44, 95% CI, 2.77-7.14) and poor PFS (p < 0.001, HR = 5.73, 95% CI, 3.86-8.73). For in vitro experiments, SLC7A11 and GPX4 expression were both upregulated in platinum-resistant cells compared with their parental ovarian cancer cells, and siRNA-induced SLC7A11 and GPX4 inhibition decreased platinum resistance. CONCLUSIONS: High expression levels of SLC7A11 and GPX4 are associated with platinum resistance in EOC patients. High co-expression of SLC7A11 and GPX4 may be a significant independent prognostic factor and a potential therapeutic target for platinum resistance in EOC patients.
Subject(s)
Carcinoma, Ovarian Epithelial , Drug Resistance, Neoplasm , Ovarian Neoplasms , Phospholipid Hydroperoxide Glutathione Peroxidase , Female , Humans , Amino Acid Transport System y+ , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/genetics , Drug Resistance, Neoplasm/genetics , Neoplasms, Glandular and Epithelial , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Platinum/metabolism , Platinum/therapeutic use , Prognosis , Retrospective Studies , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolismABSTRACT
Since COVID-19 emerged in 2019, significant levels of suffering and disruption have been caused on a global scale. Although vaccines have become widely used, the virus has shown its potential for evading immunities or acquiring other novel characteristics. Whether current drug treatments are still effective for people infected with Omicron remains unclear. Due to the long development cycles and high expense requirements of de novo drug development, many researchers have turned to consider drug repositioning in the search to find effective treatments for COVID-19. Here, we review such drug repositioning and combination efforts towards providing better handling. For potential drugs under consideration, aspects of both structure and function require attention, with specific categories of sequence, expression, structure, and interaction, the key parameters for investigation. For different data types, we show the corresponding differing drug repositioning methods that have been exploited. As incorporating drug combinations can increase therapeutic efficacy and reduce toxicity, we also review computational strategies to reveal drug combination potential. Taken together, we found that graph theory and neural network were the most used strategy with high potential towards drug repositioning for COVID-19. Integrating different levels of data may further improve the success rate of drug repositioning.
ABSTRACT
As a result of antibiotic overuse, bacterial antibiotic resistance has become a severe threat to worldwide public health. The development of more effective antimicrobial therapies and alternative antibiotic strategies is urgently required. The role played by bacterial membrane vesicles (BMVs) in antibiotic resistance has become a current focus of research. BMVs are nanoparticles derived from the membrane components of Gram-negative and Gram-positive bacteria and contain diverse components originating from the cell envelope and cytoplasm. Antibiotic stress stimulates the secretion of BMVs. BMVs promote and mediate antibiotic resistance by multiple mechanisms. BMVs have been investigated as conceptually new antibiotics and drug-delivery vehicles. In this article, we outline the research related to BMVs and antibiotic resistance as a reference for the intentional use of BMVs to combat antibiotic resistance.
Subject(s)
Anti-Infective Agents , Bacteria , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cell Membrane , Drug Resistance, Bacterial , Drug Resistance, Multiple, BacterialABSTRACT
AIMS: To explore the synovial expression of mucin 1 (MUC1) and its role in rheumatoid arthritis (RA), as well as the possible downstream mechanisms. METHODS: Patients with qualified synovium samples were recruited from a RA cohort. Synovium from patients diagnosed as non-inflammatory orthopaedic arthropathies was obtained as control. The expression and localization of MUC1 in synovium and fibroblast-like synoviocytes were assessed by immunohistochemistry and immunofluorescence. Small interfering RNA and MUC1 inhibitor GO-203 were adopted for inhibition of MUC1. Lysophosphatidic acid (LPA) was used as an activator of Rho-associated pathway. Expression of inflammatory cytokines, cell migration, and invasion were evaluated using quantitative real-time polymerase chain reaction (PCR) and Transwell chamber assay. RESULTS: A total of 63 RA patients and ten controls were included. Expression of MUC1 was observed in both the synovial lining and sublining layer. The percentage of MUC1+ cells in the lining layer of synovium was significantly higher in RA than that in control, and positively correlated to joint destruction scores of RA. Meanwhile, MUC1+ cells in the sublining layer were positively correlated to the Krenn subscore of inflammatory infiltration. Knockdown of MUC1, rather than GO-203 treatment, ameliorated the expression of proinflammatory cytokines, cell migration, and invasion of rheumatoid synoviocytes. Knockdown of MUC1 decreased expression of RhoA, Cdc42, and Rac1. Treatment with LPA compromised the inhibition of migration and invasion, but not inflammation, of synoviocytes by MUC1 knockdown. CONCLUSION: Upregulated MUC1 promotes the aggression of rheumatoid synoviocytes via Rho guanosine triphosphatases (GTPases), thereby facilitating synovitis and joint destruction during the pathological process of RA.Cite this article: Bone Joint Res 2022;11(9):639-651.
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Importance: It remains unknown whether neurodevelopmental impairments are directly associated with the structural development of the brain in offspring with fetal growth restriction (FGR) and mothers with preeclampsia (PE) or gestational hypertension (GH). Objectives: To assess whether fetal corpus callosum (CC) development differed among pregnancies with PE or GH with FGR, pregnancies with PE or GH without FGR, and normotensive pregnancies, particularly the severity of maternal disease and FGR, and to identify the association between adverse perinatal outcomes and structural development of the CC in fetuses with FGR in pregnancies with PE or GH. Design, Setting, and Participants: This retrospective matched case-control study was conducted between January 1, 2014, and January 31, 2021, at Women's Hospital, Zhejiang University School of Medicine in Hangzhou, China. The participant group included cases of singleton pregnancies with PE or GH with FGR; the control groups included cases with PG or GH without FGR and cases with paired normotensive pregnancy. Exposures: Maternal PE or GH and FGR. Main Outcomes and Measures: The length, thickness, total area, subdivision areas, and apparent diffusion coefficient (ADC) values of fetal CC were measured on magnetic resonance imaging (MRI) and analyzed. The association between adverse perinatal outcomes and structural development of CC was further investigated. Results: A total of 56 pregnant individuals with singleton pregnancies and PE or GH and fetuses with FGR were enrolled (maternal median [IQR] age, 29.0 [26.0-34.0] years; mean [SD] gestational age at MRI, 33.6 [2.5] weeks). Significant patterns of decreased median (IQR) fetal CC length (0.4284 [0.4079-0.4470] mm vs 0.4614 [0.4461-0.4944] mm, P < .001, vs 0.4591 [0.4310-0.4927] mm, P < .001) and mean (SD) CC total area (1.0779 [0.1931] mm2 vs 1.1896 [0.1803] mm2, P = .001, vs 1.1438 [0.1935] mm2, P = .02), adjusted for the cephalic index, was observed in cases of PE or GH with FGR compared with cases without FGR and cases with normotensive pregnancy. The splenium region of fetal CC also exhibited the distinct alterations in macrostructural development (with FGR: 0.3149 [0.0697] mm2 vs without FGR: 0.3727 [0.0698] mm2, P < .001, vs normotensive pregnancies: 0.3565 [0.0763] mm2, P < .001) and microstructural development (median [IQR] ADC values: 1.47 [1.38-1.57] × 10-3 mm2/s vs 1.57 [1.53-1.63] × 10-3 mm2/s, P = .009, vs 1.63 [1.50-1.70] × 10-3 mm2/s, P < .001) in all groups. Furthermore, significant associations were found between structural abnormality of the splenium region and adverse perinatal outcomes in the PE or GH with FGR group (mean [SD] ADC value: 1.40 [0.07] × 10-3 mm2/s; P = .04). Conclusions and Relevance: Results of this study suggest that, in fetuses with FGR in pregnancies with PE or GH, decreased structural development of the CC, predominantly the splenium region, may be significantly associated with a higher risk of adverse perinatal outcomes and may be regarded as an MRI-based biomarker for better prenatal counseling and early management decisions.
Subject(s)
Hypertension, Pregnancy-Induced , Pre-Eclampsia , Adult , Case-Control Studies , Corpus Callosum/diagnostic imaging , Female , Fetal Growth Retardation , Humans , Pregnancy , Retrospective StudiesABSTRACT
Presently, the biggest hurdle to cancer therapy is the inevitable emergence of drug resistance. Since conventional therapeutic schedules fall short of the expectations in curbing drug resistance, the development of novel drug resistance management strategies is critical. Extensive research over the last decade has revealed that the process of ferroptosis is correlated with cancer resistance; moreover, it has been demonstrated that ferroptosis inducers reverse drug resistance. To elucidate the development and promote the clinical transformation of ferroptosis strategies in cancer therapy, we first analyzed the roles of key ferroptosis-regulating molecules in the progression of drug resistance in-depth and then reviewed the design of ferroptosis-inducing strategies based on nanotechnology for overcoming drug resistance, including glutathione depletion, reactive oxygen species generation, iron donation, lipid peroxidation aggregation, and multiple-drug resistance-associated tumor cell destruction. Finally, the prospects and challenges of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance were evaluated. This review aimed to provide a comprehensive understanding for researchers to develop ferroptosis-inducing nanoplatforms that can overcome drug resistance.
Subject(s)
Ferroptosis , Neoplasms , Drug Resistance, Neoplasm , Glutathione/therapeutic use , Humans , Iron , Nanotechnology , Neoplasms/pathology , Reactive Oxygen SpeciesABSTRACT
BACKGROUND: Isolated sulfite oxidase deficiency (ISOD) is a rare type of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. Germline mutation in SUOX gene causes ISOD. Till date, only 32 mutations of SUOX gene have been identified and reported to be associated with ISOD. METHODS: Here, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, hyperlactatemia, severe metabolic acidosis, hyperglycemia, and hyperkalemia. RESULTS: Whole exome sequencing identified a novel homozygous transition (c.1227G > A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. This variant causes partial loss of the dimerization domain of sulfite oxidase. Hence, it is a loss-of-function variant. Proband's father and mother is carrying this novel variant in a heterozygous state. This variant was not found in 200 ethnically matched normal healthy control individuals. CONCLUSIONS: Our study not only expanded the mutational spectrum of SUOX gene associated with ISOD, but also strongly suggested the significance of whole exome sequencing for identifying candidate genes and novel disease-causing variants.
Subject(s)
Infant, Newborn, Diseases , Sulfite Oxidase , Amino Acid Metabolism, Inborn Errors , Female , Humans , Infant, Newborn , Mutation , Oxidoreductases Acting on Sulfur Group Donors/genetics , Pedigree , Seizures , Sulfite Oxidase/deficiency , Sulfite Oxidase/genetics , Sulfite Oxidase/metabolism , Exome SequencingABSTRACT
Ultrasound targeted microbubble destruction (UTMD) was introduced as a promising method to improve anti-tumor therapeutic efficacy, while minimizing side effects to healthy tissues. Nevertheless, the acoustical phenomenon behind the UTMD as well as the exact mechanisms of autophagy action involved in the increased anti-cancer response are still not fully understood. Therefore, we examined the drug resistance-reversing effects of low-intensity focused ultrasound with microbubble (LIFU+MB) in paclitaxel (PTX)-resistant ovarian cancer cells. Cell viability was evaluated using CCK8 (Cell Counting Kit-8), apoptosis was detected by flow cytometry, quantitative real-time PCR and Western blot were used to detect the expressions of mRNA and protein, and autophagy was observed by transmission electron microscopy (TEM). We revealed that the level of autophagy was increased (p < 0.05) in PTX-resistant ovarian cancer cells. Treatment of LIFU+MB combined with PTX can notably inhibit proliferation as well as increase apoptosis (p < 0.01) in drug-resistant cells. We proposed that LIFU+MB might affect the sensitivity of ovarian cancer cells to PTX by modulating autophagy. To verify the hypothesis, we analyzed the autophagy level of drug-resistant cells after the treatment of LIFU+MB and found that autophagy was significantly inhibited. Altogether, our findings demonstrated that LIFU+MB could reverse PTX resistance in ovarian cancer via inhibiting autophagy, which provides a novel strategy to improve chemosensitivity in ovarian cancer.