Optimal vitamin D supplement dosage for improving insulin resistance in children and adolescents with overweight/obesity: a systematic review and network meta-analysis.

PURPOSE: We conducted a network meta-analysis which aims to evaluate the comparative efficacy of different supplementation dosages of vitamin D on cardiometabolic and bone-metabolic indicators as well as insulin resistance in children and adolescents with overweight/obesity. METHODS: Eligible studies published before December 10, 2022 were retrieved from PubMed, EMBASE, Cochrane Library, and Web of Science. Mean difference and 95% confidence interval (CI) were used to express pooled estimates. Network meta-analysis of multiple doses, including low (< 1000 IU/day, LDS), medium (1000-2000 IU/day, MDS), high (2000-4000 IU/day, HDS), and extremely high (> 4000 IU/day, EHDS) dosage strategy, was conducted using STATA/MP 14.0. RESULTS: Our network meta-analysis of 15 RCTs suggested that, compared with placebo and LDS, EHDS was increased 25-(OH)-D, with a pooled MD of 8.65 (95% CI 4.72-12.58) and 7.66 (95% CI 0.91-14.41), respectively. Meanwhile, EHDS also decreased ho meostasis model assessment-insulin resistance (HOMA-IR) (MD: - 0.74; 95% CI: - 1.45 to - 0.04) and C-reactive protein (CRP) (MD: - 18.99; 95% CI - 21.60 to - 16.38), and EHDS was also better than LDS (MD: - 18.47; 95% CI - 20.66 to - 16.28) and MDS (MD: - 19.69; 95% CI - 22.17 to - 17.21) in decreasing CRP. Ranking probability suggested that EHDS ranked best for increasing 25-(OH)-D, and decreasing HOMA-IR and CRP, with a probability of 86.1%, 83.1%, and 76.6%, respectively. CONCLUSIONS: The results of our network meta-analysis suggest that EHDS may be the best strategy for vitamin D supplementation to reduce inflammatory responses as well as improve insulin resistance in children and adolescents with overweight/obesity. PROSPERO REGISTRATION NUMBER: CRD42023387775.

A Novel 165 Kb Duplication Involving the α-Globin Gene Cluster Is Identified by Low-Pass Whole Genome Sequencing in a Chinese Thalassemia Intermedia Patient.

Copy number variations (CNVs) involving the α-globin gene cluster can lead to an imbalance in the proportion of α- and ß-globin chains and consequently cause clinical symptoms of ß-thalassemia. In our case, a 6-year-old boy, clinically diagnosed with ß thalassemia intermedia, was admitted for further genetic diagnosis with his family. Targeted sequencing and third generation sequencing (TGS) were used to detect the possible variants of the thalassemia genes. Low-pass whole genome sequencing (lpWGS) was conducted to specify the exact location of relevant CNVs across the genome, which was then validated by multiplex ligation-dependent probe amplification.The results revealed that the patient had a heterozygous ß0 mutation of Codon17 (A > T) and a full duplication of the α-globin gene cluster, inherited from his mother and father, respectively. Besides, a novel point mutation within the 5' untranslated region of ß-Globin (HBB: c. -175 (G > A) was only detected in the patient. This study suggests that lpWGS seems a powerful alternative to detect large CNVs related to thalassemia with second intention for more information of the breakpoints and a simultaneous genome-scale detection of other pathogenic CNVs.

An unusual tracheal foreign body in a middle-aged male with a 15-year history of coal use: a case report.

BACKGROUND: Long-term exposure to coal dust causes respiratory disease. In chest computer tomography (CT), pulmonary nodules, pulmonary interstitial fibrosis and emphysema manifest themselves. However, tracheal foreign bodies caused by coal dust are rarely reported. In this study, we report a special case of a tracheal coal foreign body, in which the patient has neither a history of coal work nor foreign body inhalation. CASE PRESENTATION: A 49-year-old man was diagnosed with chronic obstructive pulmonary disease (COPD) due to chronic cough and exertional dyspnoea. His symptoms gradually worsened despite treatment for COPD. Chest radiograph and CT images showed an irregular high-density nodule inserting fromthe trachea into the right thyroid at approximately the level of the 7th cervical vertebra. Fiberoptic bronchoscopy revealed that the tracheal lumen was mostly blocked. After the surgery, the energy spectrum CT quantitative analysis showed that the foreign body was likely that of a bituminous coal specimen. CONCLUSIONS: For cases in which a foreign body in the airway is highly suspected, early fiberoptic bronchoscopy and radiographic examinations should be performed as soon as possible to avoid misdiagnosis and ensure timely treatment.

Cotemplating synthesis of a rare borate Ni(en)3·Hen·[B9O13(OH)4]·H2O with a chiral polyanonic chain constructed from two different clusters.

Ni(en)3·Hen·[B9O13(OH)4]·H2O was prepared under the cotemplating effect of [Ni(en)3](2+) and Hen(+). It was the first example of a cotemplated borate with an unusual chiral polyanionic chain, which was constructed from [B5O8(OH)2] and [B4O7(OH)2] clusters.

A complementary strategy for enhancement of nanoparticle intracellular uptake.

PURPOSE: The complementary strategy by combining targeting ligand-mediated selectivity and CPP-mediated transmembrane function could be exploit synergies for enhancing cellular uptake of nanoparticles with negative charge. A heparin-based nanoparticles with negative charge was fabricated by complementary strategy, which was expected to attain efficient uptake and simultaneously exert great anticancer activity. METHODS: We synthesized heparin-based nanoparticles with targeting ligand folate and CPP ligand Tat to deliver paclitaxel (H-F-Tat-P NPs). The NPs were characterized by (1)H NMR, DLS and TEM, respectively. The effect of dual ligands on system behavior in aqueous solution was investigated. Moreover, its cellular internalization and anticancer activity were detected by flow cytometry, confocal microscopy and MTT. RESULTS: Folate played a key role in the formation of heparin-based NPs dependent on the balance of amphiphilic Tat and hydrophobic folate. Although H-F-Tat-P NPs primarily entered FR specific and non-specific cells by similar routes, there were no comparability due to cell-type specific variation. Unlike non-specific cells, the complementary ligands could help negative-charged NPs to enhance cellular uptake facilitating its endosome escape in specific cells thereby exhibiting great anticancer activity. CONCLUSIONS: The complementary strategy for negative-charged NPs was presented a promising delivery system for diverse anticancer agents enable simultaneously targeting and drug delivery.

[Uterine autologous transplantation in cynomolgus monkeys: a preliminary report of 6 case].

OBJECTIVE: To evaluate the surgical feasibility of uterine autologous transplantation in female cynomolgus monkeys and explore the effect of microsurgical technique. METHODS: From May 2011 to March 2014, 6 female cynomolgus monkeys, aged 7 to 12 years, were randomly divided into 2 surgical groups. In group A, gross surgeries were performed with naked eyes. In group B, uterine re-transplantation was performed under 10-time-magnifying microscopy. Anatomical data and operative durations were recorded and analyzed. Viable uterine tissue and vascular patency were observed on trans-abdominal ultrasonography and second-look laparotomy after 3 months. RESULTS: The average uterus retrieval time, average vascular anastomotic time, average perfusion time and average total operative time of group B were 88.7, 147.3 and 320.0 min versus 123.7, 180.7 and 393.7 min in group A. The average perfusion durations were 35.0 and 27.3 min. And there was no inter-group difference. A total of 12 successful vascular procedures (including 6 internal iliac arteries and 6 uterine-ovary veins) of vascular anastomosis were recorded in group B versus 4 cases (including 1 artery and 3 veins) in group A (vein, P > 0.05; artery, P < 0.05). In group A, there was only 1 successful operation but uterus turned necrotic after 4 weeks. In group B, the surgical success rate was 100%. However one animal died due to intestinal obstruction. And in another 2 animals, viable uterine tissue and vascular patency were observed on trans-abdominal ultrasonography and second-look laparotomy. Two survivors resumed cyclicity at days 17 and 50 respectively as a sign of re-established uterine function. CONCLUSION: This study has demonstrated the feasibility of uterus transplantation by vascular anastomosis in cynomolgus monkeys. And assistance of microsurgical technique can significantly improve the success rate of arterial anastomosis during uterus transplantation.

Fertility-Sparing Surgery and Adjuvant Chemotherapy with Trastuzumab Result in Complete Remission in a Young Woman with Rare Primary Mucinous Ovarian Cancer due to ERBB2 Co-amplification with CDK12 and Chromosome 11q13.3 Amplicon: A Case Report and Literature Review.

Primary mucinous ovarian carcinoma (PMOC) is a rare tumor, accounting for approximately 3% of all epithelial ovarian cancers (EOCs), with clinical risk factors and biologic features distinct from that of EOC. The prognosis for women with recurrent and high-grade PMOC remains poor, likely related to a poor response to conventional chemotherapy for EOC. A 27-year-old Chinese woman sought medical attention in January 2021 for abdominal distention from a large pelvic mass. After extensive investigations and workup, she was diagnosed with PMOC of the right ovary. Following multidisciplinary team (MDT) discussions, the patient underwent fertility-sparing surgery (FSS) (abdominal left adnexectomy, right partial oophorectomy, pelvic lymph node dissection, para-aortic lymph node dissection, omentectomy) as she yearned to preserve her fertility and the contralateral ovary appeared normal. Deep genetic analyses revealed ERBB2 co-amplification with CDK12 and chromosome 11q13.3 amplicon. Treatment with fertility-sparing surgery and adjuvant chemotherapy with trastuzumab results in complete remission. This novel strategy utilizing precise diagnostics and characterization of the histo-type of rare tumors allowed personalized targeting with optimum drug response for women who yearn fertility preservation and remission from the disease, especially when there is very limited clinical experience on management of such rare ovarian tumors.

Co(II)-doped hybrid Zn(II) tetraborate complexes, [ZnxCo(1-x)(1,3-dap)B4O7] (1,3-dap = 1,3-diaminopropane): BET analysis and N2/H2O/D2O adsorption studies.

A series of mono/bimetallic isostructural hybrid tetraborates of the general formula [ZnxCo(1-x)(1,3-dap)B4O7] has been prepared using a solvothermal method. Their adsorption/desorption curves for H2O and D2O demonstrate that these materials have a stronger affinity for H2O than for D2O and enrich the D2O content of D2O/H2O mixtures.

Development and validation of health-oriented personal evaluation for the community-dwelling older person based on the International Classification of Functioning, Disability and Health.

BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) offers a standardized international terminology to operationalize function management across multiple domains, but the summary score of the ICF qualifier scale provides limited information on the comparison of personal abilities and functioning difficulties. OBJECTIVES: To enhance the interpretative power of the ICF-based Health-oriented Personal Evaluation for the community-dwelling older person (iHOPE-OP) scale through the implementation of the item response theory (IRT) modelling. METHODS: This cross-sectional, multi-centre study administrated 161 ICF categories (58 on body functions, 15 on body structures, 60 on activities or participation and 28 on environmental factors) to evaluate the functional level of 338 older citizens (female = 158, male = 180) residing in community or supportive living facilities. The validation process encompassed assessing the IRT model fitness and evaluating the psychometric properties of the IRT-derived iHOPE-OP scale. RESULTS: The age of participants ranged from 60 to 94.57, with the mean age of 70. The analysis of non-parametric and parametric models revealed that the three-parameter logistic IRT model, with a dichotomous scoring principle, exhibited the best fit. The 53-item iHOPE-OP scale demonstrated high reliability (Cronbach's α = 0.9729, Guttman's lambda-2 = 0.9749, Molenaar-Sijtsma Statistic = 0.9803, latent class reliability coefficient = 0.9882). There was a good validity between person abilities and the Barthel Index (p < .001, r = .83), as well as instrumental activities of daily living (p < .001, r = .84). CONCLUSIONS: IRT methods generate the reliable and valid iHOPE-OP scale with the most discriminable and minimal items to represent the older person's functional performance at a comprehensive level. The use of the Wright map can aid in presby-functioning management by visualizing item difficulties and person abilities. IMPLICATIONS FOR PRACTICE: Considering the intricate and heterogeneous health status of older persons, a single functional assessment tool might not fulfil the need to fully understand the multifaceted health status. For use in conjunction with the IRT and ICF framework, the reliable and valid iHOPE-OP scale was developed and can be applied to capture presby-functioning. The Wright map depicts the distribution of item difficulties and person abilities on the same scale that facilitates person-centred goal setting and tailors intervention.

Synthesis of composite materials combining magnetic metal-organic frameworks and conjugated organic frameworks for selective extraction of carbendazim and thiabendazole residues from Chinese herbal medicine samples.

A magnetic metal-organic framework MIL-68(Al) and a covalent organic framework were used as magnetic solid-phase extraction (MSPE) adsorbents in combination with high-performance liquid chromatography ultraviolet detection (HPLC-UV) to detect carbendazim (CBZ) and thiabendazole (TBZ). The main parameters affecting the extraction in the MSPE process were studied and optimized. Fe3O4@MIL-68(Al) coated with 1,3,5-tris(4-aminophenyl)benzene and terephthaldehyde (Fe3O4@MIL-68(Al)@TAPB-PDA-COF) was analyzed and verified. The material was proven to be suitable for adsorbing CBZ and TBZ. Various adsorption models were used to study its adsorption mechanism. The adsorption results were in good agreement with the pseudo-second-order kinetic model and Langmuir isotherm model. The maximum adsorption capacities of Fe3O4@MIL-68(Al)@TAPB-PDA-COF over CBZ and TBZ were 54.24 and 67.87 mg g-1, respectively, and the equilibrium adsorption time was 200 min. Fe3O4@MIL-68(Al)@TAPB-PDA-COF with excellent recyclability showed higher adsorption capacity and selectivity. A method based on Fe3O4@MIL-68(Al)@TAPB-PDA-COF combined with HPLC-UV was established under the optimal extraction conditions and used to separate and detect trace imidazole drugs in Chinese herbal samples, achieving a low limit of detection (0.65-1.30 µg L-1) with excellent linear correlation (r > 0.999). The recovery rate and relative standard deviation were 86.05-99.78 % and 0.15-4.90 %, respectively. Therefore, the Fe3O4@MIL-68@TAPB-PDA-COF can be regarded as an effective adsorbent for the pretreatment of CBZ and TBZ drugs in Chinese herbal samples.

Malignant Struma Ovarii (Papillary Carcinoma) with Hyperthyroidism: A Case Report and Literature Review.

Malignant struma ovarii (MSO) is an extremely rare monodermal ovarian teratoma. Preoperative diagnosis and intraoperative freezing diagnosis are exceedingly difficult due to the rarity of the disease and its clinically noncharacteristic manifestations with less than 200 reports in the current literature. In this paper, a case of MSO (papillary carcinoma) with hyperthyroidism was discussed in terms of its epidemiology, clinicopathology, molecular features, treatment, and prognosis.

Application of spectral CT in diagnosis, classification and prognostic monitoring of gastrointestinal cancers: progress, limitations and prospects.

Gastrointestinal (GI) cancer is the leading cause of cancer-related deaths worldwide. Computed tomography (CT) is an important auxiliary tool for the diagnosis, evaluation, and prognosis prediction of gastrointestinal tumors. Spectral CT is another major CT revolution after spiral CT and multidetector CT. Compared to traditional CT which only provides single-parameter anatomical diagnostic mode imaging, spectral CT can achieve multi-parameter imaging and provide a wealth of image information to optimize disease diagnosis. In recent years, with the rapid development and application of spectral CT, more and more studies on the application of spectral CT in the characterization of GI tumors have been published. For this review, we obtained a substantial volume of literature, focusing on spectral CT imaging of gastrointestinal cancers, including esophageal, stomach, colorectal, liver, and pancreatic cancers. We found that spectral CT can not only accurately stage gastrointestinal tumors before operation but also distinguish benign and malignant GI tumors with improved image quality, and effectively evaluate the therapeutic response and prognosis of the lesions. In addition, this paper also discusses the limitations and prospects of using spectral CT in GI cancer diagnosis and treatment.

Differentiating between pulmonary adenocarcinoma and squamous cell carcinoma by spectral CT volumetric quantitative analysis: a comparative study with conventional spectral analysis.

Background: Unlike the conventional spectral analyses of spectral computed tomography (CT) that cannot fully represent the whole lesion, the volumetric quantitative analysis reveals the information of the whole lesion and is of more accurate. So this study sought to evaluate the value of volumetric quantitative analysis in the differential diagnosis of pulmonary adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). Methods: Fifty-seven patients with lung cancer confirmed by pathology, including 35 ADC and 22 SQCC patients, were retrospectively analyzed. Calcium concentration and effective-Z (Eff-Z) in plain scan (PS), iodine concentration, and water concentration in the arterial phase (AP) were measured. The Student t-test or rank-sum test was used to determine the statistically significant parameters. Receiver operating characteristic (ROC) curve was used, and the corresponding area under the curve (AUC), sensitivity and specificity was calculated to evaluate the diagnostic efficacy in differential diagnosis of ADC and SQCC. Results: In the volumetric quantitative analysis of spectral CT, the concentration of calcium [(6.97±2.83) mg/cm3], Eff-Z (7.90±0.14), and iodine [1.42 (0.84) mg/cm3] was significantly higher in ADC than SQCC [(5.14±2.39) mg/cm3, (7.80±0.10), 1.16 (0.65) mg/cm3, t=2.513, 2.860, Z=-2.246, P=0.015, 0.006, 0.025], but the concentration of water was significantly lower in ADC [995.00 (38.70) mg/cm3] than SQCC [1,007.00 (14.38) mg/cm3, Z=-2.082, P=0.037]. Moreover, whether it's ADC or SQCC, the concentrations of calcium [(8.51±4.28) mg/cm3, (5.96±2.50) mg/cm3], Eff-Z (7.97±0.20, 7.86±0.13), and water [1,007.00 (14.38) mg/cm3, 1,029.28 (10.49) mg/cm3] were lower in the volumetric spectral analysis than the conventional spectral analysis, while the concentration of iodine [1.33 (0.80) mg/cm3, 0.94 (0.63) mg/cm3] was significantly higher in the volumetric spectral analysis than the conventional spectral analysis. The ROC curve analysis showed that the areas under the curves (AUC) (0.76, 0.76, 0.75, 0.71), sensitivity (66.7%, 66.7%, 66.7%, 85.2%), and specificity (92.3%, 84.6%, 86.9%, 69.2%) of the volumetric spectral analysis parameters for the differential diagnosis of ADC and SQCC were higher than those of the conventional spectral analysis [(0.65, 0.66, 0.73, 0.63), (44.4%, 48.1%, 59.3%, 66.7%), (69.2%, 69.2%, 84.6%, 53.8%)] parameters. Conclusions: The volumetric quantitative analysis has a promising advantage in the observation range of whole lesions, it may be invaluable in the differential diagnosis of ADC and SQCC, and is worthy of clinical recommendation.

Clinical Impact of 11q13.3 Amplification on Immune Cell Infiltration and Prognosis in Breast Cancer.

Introduction: Amplification of the 11q13.3 locus has been observed in various tumors. This study sought to determine the correlation of gene amplification at the 11q13.3 locus with the immune status and survival of breast cancer. Methods: Amplification of the 11q13.3 locus was characterized by analyzing a publicly available database from the cBioPortal platform (TCGA). The correlation of amplified genes with immune cell infiltration in breast cancer was further analyzed using the TIMER2.0 platform. Immunohistochemical staining was used to determine the expression levels of Cyclin D1 (CCND1), Fas-associated death domain (FADD) and P53 in 156 clinical breast cancer samples. Results: This study revealed that amplification of the 11q13.3 amplicon in breast cancer is likely more frequently detected in luminal B breast cancer. Moreover, high expression or amplification of CCND1, fibroblast growth factor 3 (FGF3), fibroblast growth factor 4 (FGF4), fibroblast growth factor 19 (FGF19) and FADD was inversely correlated with the abundance of CD4+ T cells and dendritic cell infiltration in breast cancer (P < 0.05). Data analysis also demonstrated that high expression of CCND1, FGF4 and FADD mRNA levels was closely correlated with shorter recurrence-free survival (RFS) in patients with breast cancer (P < 0.05). The results of immunohistochemical staining from clinical samples further confirmed that high expression of CCND1 and FADD was frequently detected in luminal B and high-grade breast cancer with shorter metastasis-free survival times (P < 0.05). Conclusion: This study demonstrated that coamplification of genes located on the 11q13.3 amplicon is frequently detected in luminal B subtype breast cancer and is closely associated with worse survival in patients with breast cancer. Moreover, coamplification of the CCND1-FGF locus might decrease antitumor immune activity in breast cancer, indicating that coamplification of the 11q13.3 amplicon is likely to be a key determinant of therapeutic resistance and accelerate the aggressive evolution of breast cancer.

Value of multiphase contrast-enhanced CT with three-dimensional reconstruction in detecting depth of infiltration, lymph node metastasis, and extramural vascular invasion of gastric cancer.

BACKGROUND: Multiphase contrast-enhanced computed tomography (CECT) can reveal the location, morphology, size, and enhancement pattern of gastric cancer (GC), whereas the three-dimensional reconstruction (3DR) technique can better display the relationships of the lesions with surrounding structures, the feeding vessels, and lymph node metastasis. Here, we investigated the value of multi-phase CECT with 3DR in detecting depth of infiltration, lymph node metastasis, and extramural vascular invasion (EMVI) of GC. METHODS: The clinical and imaging data of 132 GC patients admitted to the Chongqing Hospital of Traditional Chinese Medicine and the Third Affiliated Hospital of Chongqing Medical University during the period from January 2012 to October 2019 were collected. All patients received plain and multiphase contrast-enhanced CT scans. The agreement between the results of preoperative CT evaluation and the surgical/pathological findings was compared. RESULTS: (I) CT findings of GC of 3 differentiation levels: on the multiphase CECT, the peak enhancement percentage was highest in the portal venous phase. The CT values significantly differed among the arterial, portal venous, and equilibrium phases (P<0.05); the differences in the arterial, portal venous, and equilibrium phases were statistically significant among the well-, moderately, and poorly differentiated groups (all P<0.05); finally, the difference in the equilibrium phase was statistically significant between the well- and moderately differentiated groups (P<0.05). (II) Preoperative CT and postoperative pathology had good consistency in T staging (Kappa =0.667). (III) The Kappa values between the preoperative CT-diagnosed lymph node metastasis and postoperative pathologically showing an increasing consistency with the increase of CT enhancement differences. (IV) Preoperative CT and postoperative pathology had good consistency in N staging (Kappa =0.779). (V) Preoperative CT in displaying arterial supply to the stomach. The rate of positive EMVI was 32.6% (43/132) on preoperative CT. The positive EMVI diagnosed by preoperative CT was correlated with tumor size, growth pattern, tissue differentiation degree, T stage, and N stage (all P<0.05). CONCLUSIONS: Multiphase CECT combined with 3DR has high diagnostic performance in detecting the depth of infiltration, lymph node metastasis, and EMVI of GC.

Enhanced targeting of 3D pancreatic cancer spheroids by aptamer-conjugated polymeric micelles with deep tumor penetration.

Pancreatic cancer is a high degree malignant tumor which makes its diagnosis and treatment highly critical. The effect of conventional chemotherapy for pancreatic cancer is quite poor due to the low accumulation of the chemotherapeutic drugs at the tumor site. Therefore, enhancing the targeting efficiency and accumulation of the drug carrier at tumor site with subsequent release of drug within the effective time period is one of the key factors for successful targeted chemotherapy of pancreatic cancer. Our previous studies have demonstrated that aptamer can be a valid targeting moiety to guide the chemotherapeutic drug doxorubicin (DOX) to accumulate at the tumor tissue. Herein, the present study aims to further investigate the targeting efficiency as well as therapeutic efficacy of the drug delivery system comprised of aptamer-modified polymeric nano drug carrier encapsulated with DOX (DOX@PCL-b-PEO-Aptamer micelles). The in vitro cytotoxicity studies and laser confocal microscopy indicated that DOX@PCL-b-PEO-Aptamer micelles exhibited enhanced targeting and cytotoxic efficacy towards human pancreatic cancer cells (Panc-1 cells) as compared to free DOX and DOX-loaded PCL-b-PEO-NH2 micelles (DOX@PCL-b-PEO-NH2 micelles). Furthermore, the aptamer-decorated drug delivery system exhibited better tumor penetration into the three-dimensional (3D) spheroid of Panc-1 cells with successful release of DOX as compared to the drug delivery system without aptamer modification. Overall, this study suggests that the aptamer-modified polymeric micelles could be effectively employed for the targeted delivery of anticancer drug to treat pancreatic cancer in near future.

Brain hothubs and dark functional networks: correlation analysis between amplitude and connectivity for Broca's aphasia.

Source localization and functional brain network modeling are methods of identifying critical regions during cognitive tasks. The first activity estimates the relative differences of the signal amplitudes in regions of interest (ROI) and the second activity measures the statistical dependence among signal fluctuations. We hypothesized that the source amplitude-functional connectivity relationship decouples or reverses in persons having brain impairments. Five Broca's aphasics with five matched cognitively healthy controls underwent overt picture-naming magnetoencephalography scans. The gamma-band (30-45 Hz) phase-locking values were calculated as connections among the ROIs. We calculated the partial correlation coefficients between the amplitudes and network measures and detected four node types, including hothubs with high amplitude and high connectivity, coldhubs with high connectivity but lower amplitude, non-hub hotspots, and non-hub coldspots. The results indicate that the high-amplitude regions are not necessarily highly connected hubs. Furthermore, the Broca aphasics utilized different hothub sets for the naming task. Both groups had dark functional networks composed of coldhubs. Thus, source amplitude-functional connectivity relationships could help reveal functional reorganizations in patients. The amplitude-connectivity combination provides a new perspective for pathological studies of the brain's dark functional networks.

cRGD-functionalized nanoparticles for combination therapy of anti-endothelium dependent vessels and anti-vasculogenic mimicry to inhibit the proliferation of ovarian cancer.

Accumulating evidence has disclosed effective anti-angiogenic strategies should simultaneously inhibit endothelium-dependent vessels (EDV) and tumor cell-mediated vasculogenic mimicry (VM). The αvß3 integrin-targeting peptide cRGD has the ability to inhibit EDV and we have found cRGD can also suppress the formation of VM in ovarian cancer cells. Herein, a cRGD-based combination strategy was developed to suppress the proliferation of tumor cells by anti-EDV and anti-VM. We firstly engineered two cRGD functionalized nanoparticles (cRGD-NPs1 and cRGD-NPs2) by self-assembly using heparin conjugated with cRGD and folate. In vitro experiments demonstrated cRGD-NPs2 exhibited more significant cytotoxicity and higher intracellular uptake ability than cRGD-NPs1. Also, cRGD-NPs2 could efficiently discourage EDV, VM and proliferation in HUVECs and SKOV3 (VM+) cells. In vivo studies showed cRGD-NPs2 could specifically accumulate in ovarian cancer tissues and exerted a superior anti-tumor effect in SKOV3 xenografts. The mechanisms responsible for creating anti-EDV and anti-VM action of cRGD-NPs2 related to combined effects of cRGD, heparin and folate. The results demonstrated cRGD-NPs2 represented a versatile anti-angiogenic medicine via their combined inhibitory effect. STATEMENT OF SIGNIFICANCE: Accumulating documents indicate tumor cell-mediated vasculogenic mimicry (VM) is positively correlated with poor prognosis, occurrence of distant metastasis and low survival rate in cancer patients, suggesting VM is a potential therapeutic target for cancer treatment. Thus, effective anti-angiogenic strategies should simultaneously inhibit VM as well as endothelium-dependent vessels (EDV). Integrin αvß3 is a crucial inducer involved in the formation of both EDV and VM. In this study, we engineered αvß3 integrin-targeting peptide cRGD functionalized nanoparticles (cRGD-NPs) by self-assembly using heparin conjugated with cRGD and folate. The prepared cRGD-NPs represent a promising anti-angiogenic medicine in that they are able to inhibit endothelial sprouting angiogenesis and tumor cell-mediated VM. This work may provide useful information with which to construct effective anti-angiogenic nanomedicines.