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Iron Dextran is a widely used iron oxide compound to treat iron‐deficiency anemia patients in the clinic. Similar to other iron oxide compounds such as Ferumoxytol, it can also be used off‐label as an intravascular magnetic resonance imaging (MRI) contrast agent due to its strong iron‐induced T2 and T2* shortening effects. In this study, we seek to evaluate the feasibility of using Iron Dextran enhanced multi‐echo susceptibility weighted imaging (SWI) MRI at 7T to image arterial and venous blood vessels in the human brain. Phantom experiments were performed to measure the r2* relaxivity for Iron Dextran in blood, based on which the SWI sequence was optimized. Pre‐ and post‐infusion MR images were acquired in human subjects from which maps of arteries and veins were extracted. The post‐contrast SWI images showed enhanced susceptibility difference between blood and the surrounding tissue in both arteries and veins. Our results showed that the proposed Iron Dextran enhanced multi‐echo SWI approach allowed the visualization of blood vessels with diameters down to ~100 μm, including small blood vessels supplying and draining small brain structures such as the hippocampus. We conclude that Iron Dextran can be an alternative iron‐based MRI contrast agent for blood vessel imaging in the human brain. [ABSTRACT FROM AUTHOR]

Purpose: Acute gastroenteritis caused by Salmonella spp. among children post a great threat for global public health. The increasing rate of drug-resistant Salmonella spp. has also become a challenging problem worldwide. In this study, the prevalence, serotypes, and antimicrobial characteristics of Salmonella isolated from children in Guangzhou, China, were investigated to provide supporting information for clinical treatment and prevention. Methods: Clinical data of children featured with gastroenteritis symptoms from 2018 to 2023 in Guangdong Women and Children Hospital were collected. The difference and fluctuation of antimicrobial resistance between serotypes and years were retrospectively analyzed. Results: A total of 1304 Salmonella isolates were cultural-confirmed. The overall positive rate of Salmonella isolated from stool samples was 22.0% (1304/5924). Salmonella infections occur mainly from June to September and the majority of infected children aged under 4 years. Serogroup B was the most common serogroup among Salmonella isolates (74.6%, 973/1304). The predominant serotypes of Salmonella isolates were Typhimurium (63.1%, 823/1304). Higher drug resistance rate of Salmonella spp. to ceftriaxone was observed in 2023. The drug resistance rates of Salmonella isolates to sulfamethoxazole/trimethoprim and ampicillin are at high level during the past 6 years. Notably, higher multi-drug resistance (MDR) rate was demonstrated in Salmonella Typhimurium compared with other serotypes. Conclusion: Salmonella Typhimurium was the most common serotype isolated from children in Guangzhou, China, and it may mainly account for the high drug resistance rate in Salmonella spp. to most of the antimicrobial profiles. For controlling the high drug resistance rate of Salmonella spp. continuous surveillance of drug resistance and appropriate use of antibiotics based on clinical and laboratory results are of great significance. [ABSTRACT FROM AUTHOR]

Purpose: The inflow‐based vascular‐space‐occupancy (iVASO) MRI was originally developed in a single‐slice mode to measure arterial cerebral blood volume (CBVa). When vascular crushers are applied in iVASO, the signals can be sensitized predominantly to small pial arteries and arterioles. The purpose of this study is to perform a systematic optimization and evaluation of a 3D iVASO sequence on both 3 T and 7 T for the quantification of CBVa values in the human brain. Methods: Three sets of experiments were performed in three separate cohorts. (1) 3D iVASO MRI protocols were compared to single‐slice iVASO, and the reproducibility of whole‐brain 3D iVASO MRI was evaluated. (2) The effects from different vascular crushers in iVASO were assessed. (3) 3D iVASO MRI results were evaluated in arterial and venous blood vessels identified using ultrasmall‐superparamagnetic‐iron‐oxides–enhanced MRI to validate its arterial origin. Results: 3D iVASO scans showed signal‐to‐noise ratio (SNR) and CBVa measures consistent with single‐slice iVASO with reasonable intrasubject reproducibility. Among the iVASO scans performed with different vascular crushers, the whole‐brain 3D iVASO scan with a motion‐sensitized‐driven‐equilibrium preparation with two binomial refocusing pulses and an effective TE of 50 ms showed the best suppression of macrovascular signals, with a relatively low specific absorption rate. When no vascular crusher was applied, the CBVa maps from 3D iVASO scans showed large CBVa values in arterial vessels but well‐suppressed signals in venous vessels. Conclusion: A whole‐brain 3D iVASO MRI scan was optimized for CBVa measurement in the human brain. When only microvascular signals are desired, a motion‐sensitized‐driven‐equilibrium–based vascular crusher with binomial refocusing pulses can be applied in 3D iVASO. [ABSTRACT FROM AUTHOR]

Aims: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. Materials and Methods: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. Results: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large‐for‐gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32‐times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49‐, 1.24‐, and 1.23‐times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U‐shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut‐off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37‐times increased risks of LGA and PTB, respectively. Conclusions: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large‐scale studies are required to confirm these findings. [ABSTRACT FROM AUTHOR]

The data explosion driven by advancements in genomic research, such as high-throughput sequencing techniques, is constantly challenging conventional methods used in genomics. In parallel with the urgent demand for robust algorithms, deep learning has succeeded in various fields such as vision, speech, and text processing. Yet genomics entails unique challenges to deep learning, since we expect a superhuman intelligence that explores beyond our knowledge to interpret the genome from deep learning. A powerful deep learning model should rely on the insightful utilization of task-specific knowledge. In this paper, we briefly discuss the strengths of different deep learning models from a genomic perspective so as to fit each particular task with proper deep learning-based architecture, and we remark on practical considerations of developing deep learning architectures for genomics. We also provide a concise review of deep learning applications in various aspects of genomic research and point out current challenges and potential research directions for future genomics applications. We believe the collaborative use of ever-growing diverse data and the fast iteration of deep learning models will continue to contribute to the future of genomics. [ABSTRACT FROM AUTHOR]

Purpose: A new regularizer is proposed for the magnitude least‐squares optimization algorithm, to ensure robust parallel transmit RF shimming and small‐tip‐angle multispoke pulse designs for ultrahigh‐field MRI. Methods: A finite‐difference regularization term is activated as an additional regularizer in the iterative magnitude‐least‐squares based pulse design algorithm when an unwanted flip angle null distribution is detected. Both simulated and experimental B1+ maps from different transmit arrays and different human subjects at 7 T were used to evaluate the proposed algorithm. The algorithm was further demonstrated in experiment with dynamic multislice RF shimming for a single‐shot gradient‐echo EPI for human functional MRI at 7 T. Results: The proposed finite‐difference regularizer effectively prevented excitation null to be formed for RF shimming and small‐tip‐angle multispoke pulses, and improved the latter with a monotonic trade‐off relationship between flip angle error and RF power. The proposed algorithm was demonstrated to be effective with several head‐array geometries by simulation and with a commercial head array with 12 healthy human subjects by experiment. During a functional MRI scan at 7 T with dynamic RF shimming, the proposed algorithm ensured high image SNR throughout the human brain, compared with near‐complete local signal loss by the conventional magnitude‐least‐squares algorithm. Conclusion: Using finite‐difference regularization to avoid unwanted solutions, the robustness of RF shimming and small‐tip‐angle multispoke pulse design algorithms are improved, with better flip angle homogeneity and a monotonic trade‐off relationship between flip angle error and RF power. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20–47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. Objectives: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. Methods: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex. Results: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. Conclusions: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies. [ABSTRACT FROM AUTHOR]

In this study, the feasibility of using ultrasonic differential attenuation coefficient intercept (Δα0) imaging to evaluate thermal lesions induced by microwave ablation (MWA) was explored using an in vivo porcine model. The attenuation coefficient intercept (Δα0 is estimated by subtracting an initial value of Δα0 images. Receiver operating characteristic (ROC) curves and the area under ROC curve (AUC) were employed to statistically assess the predictability of ultrasonic imaging. Ultrasonic Δα0 values were approximately 0.13 dB/cm and 0.16 dB/cm in a normal liver and kidney, respectively, increasing to 2.9 dB/cm and 2.55 dB/cm in ablated regions after MWA. The CNR values of the ultrasonic Δα0 images (0.9 dB and 0.6 dB in the liver and kidney, respectively) were significantly higher (p < 0.05) than the values of B-mode images (0.6 dB and 0.3 dB). The AUC value of the ultrasonic Δα0 image was higher than the B-mode image value, 0.95 compared with 0.88. This in vivo study suggests that ultrasonic Δα0 imaging has the potential to evaluate thermal lesions with high accuracy and better image contrast for monitoring MWA. [ABSTRACT FROM AUTHOR]

The feasibility of ultrasonic Nakagami imaging to evaluate thermal lesions by high-intensity focused ultrasound and microwave ablation was explored in ex vivo and in vivo liver models. Dynamic changes of the ultrasonic Nakagami parameter in thermal lesions were calculated, and ultrasonic B-mode and Nakagami images were reconstructed simultaneously. The contrast-to-noise ratio (CNR) between thermal lesions and normal tissue was used to estimate the contrast resolution of the monitoring images. After thermal ablation, a bright hyper-echoic region appeared in the ultrasonic B-mode and Nakagami images, identifying the thermal lesion. During thermal ablation, mean values of Nakagami parameter showed an increasing trend from 0.72 to 1.01 for the ex vivo model and 0.54 to 0.72 for the in vivo model. After thermal ablation, mean CNR values of the ultrasonic Nakagami images were 1.29 dB (ex vivo) and 0.80 dB (in vivo), significantly higher ( ${p} <0.05$ ) than those for B-mode images. Thermal lesion size, assessed using ultrasonic Nakagami images, shows a good correlation to those obtained from the gross-pathology images (for the ex vivo model: length, ${r}$ = 0.96; width, ${r}$ = 0.90; for the in vivo model: length, ${r}$ = 0.95; width, ${r}$ = 0.85). This preliminary study suggests that ultrasonic Nakagami parameter may have a potential use in evaluating the formation of thermal lesions with better image contrast. Moreover, ultrasonic Nakagami imaging combined with B-mode imaging may be utilized as an alternative modality in developing monitoring systems for image-guided thermal ablation treatments. [ABSTRACT FROM AUTHOR]

Background: miR-155 acts as a ubiquitous oncogene in major classes of human cancers and is a potential target for therapeutic intervention. However, the role of miR-155 in multiple myeloma is poorly understood. Methods: To explore the role of miR-155 in multiple myeloma, we assessed the influence of tiny seed-targeting anti-miR-155 (t-anti-miR-155) on multiple myeloma cell line (RPMI-8266) viability and apoptosis in vitro. Results: t-anti-miR-155 significantly inhibited multiple myeloma cell proliferation, migration, and colony formation. Additionally, t-anti-miR-155 significantly increased CD19 positive cell numbers, which are novel biomarkers for multiple myeloma and suppressor of cytokine signaling 1(SOCS1) was shown to be a target gene for miR-155 in multiple myeloma. Finally, the miR-155 signaling pathway was investigated by KEGG assay. Conclusion: miR-155 in RPMI-8266 cells is a critical oncomiR in multiple myeloma and seed-targeting t-anti-miR-155 might be a novel strategy for miR-155-based therapeutics. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence has linked dyslipidemia during pregnancy to the risk of delivering infants born either large for gestational age (LGA) or small for gestational age (SGA). However, the effects of the vitamin D status on these relationships require further investigation. This study investigated whether the relationship between lipid profiles and the risk of LGA or SGA was influenced by vitamin D levels during the second trimester., Methods: Maternal lipid profile levels, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and vitamin D levels, were measured in a cohort of 6,499 pregnant women during the second trimester. Multivariate regression models and subgroup analyses were employed to evaluate the potential associations between maternal lipid profiles, vitamin D levels, and the risk of LGA or SGA., Results: The prevalence of SGA infants was 9.8% (n=635), whereas that of LGA infants was 6.9% (n=447). Maternal TG levels were found to be positively associated with the risk of LGA (odds ratio [OR] = 1.41, 95% confidence interval [CI]:1.17-1.70), whereas a negative association was observed between maternal TG, TC, LDL-C levels, and risk of SGA. Additionally, mothers with higher HDL-C levels were less likely to give birth to an LGA infant (OR=0.58, 95% CI:0.39-0.85). Importantly, associations between TG, TC, LDL-c, and SGA as well as between TG and LGA were primarily observed among pregnant women with insufficient vitamin D levels. As for HDL-C, the risk of LGA was lower in mothers with sufficient vitamin D (OR = 0.42, 95% CI:0.18-0.98) compared to those with insufficient vitamin D (OR = 0.65, 95% CI:0.42-0.99)., Conclusion: Vitamin D status during the second trimester exerts a modifying effect on the association between lipid profiles and the risk of LGA and SGA infants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Lai, Liu, Chen, Zhang, Wu, Luo and Gu.)

Objective: Although the incidence of bloodstream infection (BSI) during pregnancy is relatively low, it can lead to unfavorable outcomes. The aim of our study was to analyze the clinical and microbiological characteristics of maternal bacteremia and to assess maternal and fetal outcomes., Methods: Our study was a retrospective study conducted in a tertiary women and children's hospital in Guangzhou, China, from 2013 to 2022. Data were extracted from medical records and the laboratory information system. The participants were divided into groups, and the difference between the groups was analyzed., Results: The incidence of maternal BSI during the 10 years study period was 10.2 cases/10,000 maternities, with a peak found from 2014 to 2016. Escherichia coli (48%) was the predominant causative pathogen, followed by Streptococcus agalactiae (13%). Gestational diabetes mellitus (GDM) (15%) was the most common underlying condition among maternal BSI episodes. Urinary tract (13%) and genital tract (28%) were the predominant source of BSI. About 14% of neonates were infected, and BSI was the most common type of infection. E. coli was the predominant pathogen in mother-neonate pairs with concurrent BSI. Premature rupture of membranes (PROM, OR:4.68) and preterm birth (OR:3.98) were the risk factors predicting neonatal infection. More than 85% of the E. coli were resistant to ampicillin (AMP) and 50% of the E. coli were extended-spectrum β-lactamase (ESBL)-producing bacteria., Conclusion: Maternal BSI is a rare event, but continuous monitoring on the aspects of pathogen composition, antimicrobial resistance characteristics, and risk factors for adverse outcomes remains necessary to further reduce poor outcomes and mitigate bacterial resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Wu, Li, Deng, Lai, Gu and Luo.)

The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment. SIGNIFICANCE STATEMENT This study provides new evidence for differential neuronal activation in the superficial versus deep layers of the entorhinal cortex associated with encoding and retrieval memory processes, respectively, in cognitively normal adults. The study further shows that this dissociation can be observed in both the medial and the lateral entorhinal cortex. The study was achieved by using a novel functional MRI method allowing us to measure robust functional MRI signals in both the medial and lateral entorhinal cortex that was not possible in previous studies. The methodology established here in healthy human subjects lays a solid foundation for subsequent studies investigating layer-specific and region-specific changes in the entorhinal cortex associated with memory impairment in various conditions such as Alzheimer's disease., (Copyright © 2023 the authors.)

Background: Ovarian cancer (OC) is the most lethal malignancy among gynecological cancers worldwide. It is urgent to identify effective biomarkers for the prognosis and diagnosis of OC., Methods: We analyzed 4 OC Gene Expression Omnibus (GEO) data sets to detect differentially expressed genes (DEGs). To explore potential correlations between the gene sets and clinical features, we conducted weighted gene co-expression network analysis (WGCNA). Hub genes were identified from the key modules by univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses and risk scores were calculated based on the expressions of the hub genes. Univariate and multivariate Cox regression analyses were conducted to determine the values of the diagnoses for OC patients. We also determined the predictive value of the long non-coding RNA (lncRNA) score in response to immunotherapy and chemotherapeutic drugs., Results: DEGs were analyzed between the OC and normal ovarian tissues and prognostic modules were identified by a WGCNA. Nine hub genes chose from the prognostic modules were determined the prognostic values in OC. The risk scores were calculated based on the expression of hub genes, and patients with high-risk scores had poor survival. Univariate and multivariate Cox regression analyses showed that the risk score was an independent prognostic factor for OC. Additionally, the levels of hub genes were also found to be related to immune cell infiltration in OC microenvironments. An immunotherapy cohort showed that high-risk scores enhanced the response to anti-programmed death-ligand 1 (PD-L1) immunotherapy and was remarkably correlated with the inflamed immune phenotype, and had significant therapeutic advantages and clinical benefits. Further, patients with high-risk scores were more sensitive to midostaurin., Conclusions: We identified the risk score including protein phosphatase, Mg2+/Mn2+ dependent 1K (PPM1K), protein phosphatase 1 catalytic subunit alpha (PPP1CA), exostosin glycosyltransferase 1 (EXT1), RAB GTPase activating protein 1 like (RABGAP1L), mitotic arrest deficient 2 like 1 (MAD2L1), xeroderma pigmentosum complementation group C (XPC), Egl-9 family hypoxia inducible factor 3 (EGLN3), cyclin D1 binding protein 1 (CCNDBP1), and zinc finger protein 25 (ZNF25), and validated their prognostic and predicted values for OC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3752/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Evidence suggests a potential relationship between gestational weight gain (GWG) and adverse birth outcomes. However, the role of maternal genetic polymorphisms remains unclear. This study was conducted to investigate whether the relationship of GWG with risk of adverse birth outcomes was modified by methylenetetrahydrofolate reductase ( MTHFR ) polymorphisms. A total of 2,967 Chinese pregnant women were included and divided into insufficient, sufficient, and excessive groups based on the Institute of Medicine (IOM) criteria. Polymorphisms of C677T and A1298C in gene MTHFR were genotyped. Multivariable logistic regression models were introduced after controlling major confounders. Excessive GWG was found to increase the odds ratio (OR) for macrosomia [OR = 3.47, 95% confidence interval (CI): 1.86-6.48] and large-for-gestational age (LGA, OR = 3.25, 95% CI: 2.23-4.74), and decreased the OR for small-for-gestational age (SGA, OR = 0.60, 95% CI: 0.45-0.79). Pregnant women with insufficient GWG had a higher frequency of SGA (OR = 1.68, 95% CI: 1.32-2.13) and a lower rate of LGA (OR = 0.51, 95% CI: 0.27-0.96). Interestingly, significant associations of GWG categories in relation to low birth weight (LBW), macrosomia, and SGA were only suggested among pregnant women with MTHFR A1298C AA genotype. Among pregnant women with insufficient GWG group, an increased risk of 3.96 (95% CI: 1.57-10.01) for LBW was observed among subjects with the A1298C AA genotype, compared to the AC+CC genotype group. GWG categories are closely related to LBW, macrosomia, SGA and LGA, and the associations were modified by the polymorphism of MTHFR A1298C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Luo, Ruan, Gu, Lu, Lian and Mu.)

Purpose: Cervical cancer is the fourth most common cancer in women worldwide and is the main cause of cancer-related deaths in women. Cisplatin (DDP) is one of the major chemotherapeutic drugs for cervical cancer patients. But, drug resistance limits the effectiveness of cancer therapy. Nucleolin (NCL) is a nucleocytoplasmic multifunctional protein involved in the development of cancer. It has been reported that NCL may be a potential target for modulation of drug resistance. However, the precise molecular mechanisms are poorly understood., Materials and Methods: Human cervical cancer Hela cells and their cisplatin-resistant cell line Hela/DDP were used in this study. The protein level of NCL in cervical cancer cells was measured by western blot analysis. Hela cells and Hela/DDP cells were transfected with NCL overexpression plasmid or NCL siRNA separately. MTT and EdU assay were performed to evaluate the cell viability and sensitivity to cisplatin. The drug efflux function of MDR1 protein was assessed by intracellular rhodamine-123 accumulation assay.The promoter activity of MDR1 was assessed by using a dual-luciferase reporter assay., Results: We found that the protein level of NCL was elevated in Hela/DDP cells. Overexpression of NCL increased cervical cancer cell proliferation and attenuated the sensitivity to cisplatin. Overexpression of NCL increased Multidrug resistance (MDR1) gene expression and drug efflux. Our results demonstrated that NCL was highly related with cisplatin resistance in cervical cancer. NCL played an important role in MDR1 gene transcription through regulation of the transcription factor YB1., Conclusion: Our findings revealed the novel role of NCL in cisplatin-resistant cervical cancer and NCL may be a potential therapeutic target for chemoresistance., Competing Interests: The authors report no conflicts of interest in this work., (Copyright © 2021 Jing Ke et al.)

Cognitive impairment amongst Parkinson's disease (PD) patients is highly prevalent and associated with an increased risk of dementia. There is growing evidence that altered cerebrovascular functions contribute to cognitive impairment. Few studies have compared cerebrovascular changes in PD patients with normal and impaired cognition and those with mild-cognitive-impairment (MCI) without movement disorder. Here, we investigated arteriolar-cerebral-blood-volume (CBVa), an index reflecting the homeostasis of the most actively regulated segment in the microvasculature, using advanced MRI in various brain regions in PD and MCI patients and matched controls. Our goal is to find brain regions with altered CBVa that are specific to PD with normal and impaired cognition, and MCI-without-movement-disorder, respectively. In PD patients with normal cognition (n=10), CBVa was significantly decreased in the substantia nigra, caudate and putamen when compared to controls. In PD patients with impaired cognition (n=6), CBVa showed a decreasing trend in the substantia nigra, caudate and putamen, but was significantly increased in the presupplementary motor area and intracalcarine gyrus compared to controls. In MCI-patients-without-movement-disorder (n=18), CBVa was significantly increased in the caudate, putamen, hippocampus and lingual gyrus compared to controls. These findings provide important information for efforts towards developing biomarkers for the evaluation of potential risk of PD dementia (PDD) in PD patients. The current study is limited in sample size and therefore is exploratory in nature. The data from this pilot study will serve as the basis for power analysis for subsequent studies to further investigate and validate the current findings., (© 2020 The Authors. Published by Grapho Publications, LLC.)

Purpose: Imatinib, the breakpoint cluster region protein (BCR)/Abelson murine leukemia viral oncogene homolog (ABL) inhibitor, is widely used to treat chronic myeloid leukemia (CML). However, imatinib resistance develops in many patients. Therefore, new drugs with improved therapeutic effects are urgently needed. Berberine (BBR) is a potent BCR-ABL inhibitor for imatinib-sensitive and -resistant CML., Experimental Design: Protein structure analysis and virtual screening were used to identify BBR targets in CML. Molecular docking analysis, surface plasmon resonance imaging, nuclear magnetic resonance assays, and thermoshift assays were performed to confirm the BBR target. The change in BCR-ABL protein expression after BBR treatment was assessed by Western blotting. The effects of BBR were assessed in vitro in cell lines, in vivo in mice, and in human CML bone marrow cells as a potential strategy to overcome imatinib resistance., Results: We discovered that BBR bound to the protein tyrosine kinase domain of BCR-ABL. BBR inhibited the activity of BCR-ABL and BCR-ABL with the T315I mutation, and it also degraded these proteins via the autophagic lysosome pathway by recruiting E3 ubiquitin-protein ligase LRSAM1. BBR inhibited the cell viability and colony formation of CML cells and prolonged survival in CML mouse models with imatinib sensitivity and resistance., Conclusions: The results show that BBR directly binds to and degrades BCR-ABL and BCR-ABL T315I via the autophagic lysosome pathway by recruiting LRSAM1. The use of BBR is a new strategy to improve the treatment of patients with CML with imatinib sensitivity or resistance. See related commentary by Elf, p. 3899 ., (©2020 American Association for Cancer Research.)

BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr-Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model. Ablation of RalA by either siRNA or miR-181a, a RalA targeting microRNA, attenuated the malignant phenotypes in K562 cells. RBC8, a selective Ral inhibitor, enhanced the inhibitory effects of IM in K562, KCL22 and BaF3-P210 cells. Interestingly, the phospho-specific protein microarray assay revealed that multiple phosphorylation signal proteins were decreased by RalA inhibition, including SAPK, JNK, SRC, VEGFR2, P38 MAPK, c-Kit, JunB, and Keratin18. Among them, P38 MAPK and SAPK/JNK are Ras downstream signaling kinases. Taken together, RalA GTPase might be an important oncogene activating the Ras-related signaling pathway in CML.