LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.

Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

Cobra venom P-III class metalloproteinase atrase A induces inflammatory response and cell apoptosis in endothelial cells via its metalloproteinase domain.

Snake venom metalloproteinases (SVMPs), which are a critical component of viperid and crotalid venoms, play various important roles in the pathogenesis of snakebite envenomation. The SVMPs from elapid venoms are not well elucidated, as compared with those from viperid and crotalid venoms. Atrase A is a nonhemorrhagic P-III SVMP purified from Naja atra venom that possesses only weak fibrinogenolytic activity. In our prior study, we found that atrase A detached adherent cells from the substrate. In this work, we investigated further the effect and mechanism of atrase A on endothelial cells. Oxidative damage, inflammatory mediators, apoptosis, and activation of the NF-κB and MAPK signaling pathways were measured after HMEC-1 cells were exposed to atrase A. The results showed that HMEC-1 cells released inflammatory mediators, exihibited oxidative damage and apoptosis after exposure to atrase A. The Western blot analysis results revealed that atrase A increased Bax/Bcl-2 and caspase-3 levels and activated the NF-κB and MAPK signaling pathways in endothelial cells. The effects on endothelial cells were nearly completely abolished after atrase A was treated with ethylenediamine tetraacetic acid. These results showed that atrase A led to an inflammatory response, cellular injury and apoptosis in endothelial cells, and this effect was due to its metalloproteinase domain. The study contributes to a better understanding of the structures and functions of cobra venom P-III class metalloproteinases.

Independent factors associated with birth defects during the whole of pregnancy in Shenyang City, China: a case-control study.

Background: Birth defects, as a kind of diseases that seriously affect human life, have always attracted much attention. In the past, perinatal data have been studied for birth defects. This study analyzed the surveillance data of birth defects during the perinatal period and the whole of pregnancy, as well as the independent influencing factors, to help to minimize their risk of birth defects. Methods: A total of 23,649 fetuses delivered in the hospital from January 2017 to December 2020, were enrolled in this study. There were 485 cases of birth defects, including live births and stillbirths by detailed inclusion and exclusion criteria. Maternal and neonatal clinical data were collated to analyze the influencing factors associated with birth defects. Pregnancy complications and comorbidities were diagnosed according to the criteria of the Chinese Medical Association. Univariate and multivariate logistic regression models were used to investigate the association between independent variables and birth defect events. Results: The incidence of birth defects during the whole of pregnancy was 175.46/10,000, while the incidence of perinatal birth defects was 96.22/10,000. The birth defect group had significantly higher maternal age, gravidity, parity, rate of preterm birth, cesarean section (CS) rate, scarred uterus, stillborn, and male newborns compared to the control group. Multivariate logistic regression model analysis showed that preterm birth [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.01 to 2.86], CS (OR: 1.46, 95% CI: 1.08 to 1.98), scarred uterus (OR: 1.70, 95% CI: 1.01 to 2.85), and low birth weight (OR >4 compared to the other two classes) were significantly associated with birth defects during the whole of pregnancy (all P<0.05). The independent influencing factors associated with perinatal birth defects included CS (OR: 1.43, 95% CI: 1.05 to 1.93), gestational hypertension (OR: 1.70, 95%: 1.04 to 2.78), and low birth weight (OR >3.70 compared to the other two classes). Conclusions: The discovery and monitoring of known influencing factors associated with birth defects, such as, preterm birth, gestational hypertension, low birth weight, should be enhanced. For the controllable influencing factors, obstetrics providers should work with patients to minimize their risk of birth defects.

FOXK1 regulates epithelial-mesenchymal transition and radiation sensitivity in nasopharyngeal carcinoma via the JAK/STAT3 signaling pathway.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck tumor in China. Forkhead box (FOX) proteins have 19 subfamilies, which can maintain cell metabolism, regulate cell cycle and cell growth, etc. FOXK1 is a member of the FOX family, and studies have found that FOXK1 is closely related to tumors. OBJECTIVE: This experiment aims to study the effects of FOXK1 interference on proliferation, apoptosis, invasion, epithelial-mesenchymal transition (EMT), and radiosensitivity, by regulating the Janus kinas/signal translator and activator of the transfer 3 (JAK/STAT3) pathway. METHODS: The expression of FOXK1 was detected via immunohistochemistry using clinical nasopharyngeal carcinoma tissues and adjacent tissues. The relationship between FOXK1 expression and tumor stage was subsequently evaluated. The colony formation rate was calculated through the colony formation experiment. Cell apoptosis and cell cycle distribution were detected using flow cytometry, while cell invasion was detected using the Transwell method. The number of cells in the nucleus of each group after 30 min, 4 h, and 24 h of radiotherapy with the 2 Gy dose was counted using immunofluorescence under γ-H2AX focal points of a laser confocal microscope. RESULTS: FOXK1 is clearly expressed in the patients' cancer tissues. The expression of FOXK1 was significantly correlated with the patient's sex. FOXK1 interference or Peficitinib can upregulate the apoptosis rate of 5-8 F and CNE-2 cells; increase the G2 phase of cells; and inhibit the invasion, migration, and EMT of cells. At the same time, FOXK1 interference can downregulate the protein expression of p-JAK1, p-JAK2, and p-STAT3 in cells. Interference from FOXK1 or Peficitinib alone can reduce the rate of cell colony formation under different radiation doses, and enhance the green fluorescence intensity of γ-H2AX in the nucleus after 4 and 24 h of the 2 Gy dose of radiotherapy. These results are optimal when FOXK1 interference and Peficitinib are used together. CONCLUSION: FOXK1 interference in NPC cells can regulate EMT through the JAK/STAT3 signal pathway, enhance the radiosensitivity of cells, and thus inhibit tumor cell progression.

The effect of maternal age and duration of labor on perinatal and neonatal outcomes: a retrospective cohort study.

Background: This study aimed to investigate the effect of maternal age and duration of labor on perinatal and neonatal outcomes. The results of this study are expected to provide a basis to aid maternal and child health care personnel to implement health education for late childbearing women. Methods: This was a retrospective observational study, wherein 9,241 parturients were included from 2016 to 2018. Parturients were divided into three groups based on age: <28 (n=2,911), 28-30 (n=3,631), and >30 (n=2,699) years. According to the total duration of labor, those who did not undergo cesarean section (CS) were subgrouped into <420 minutes (n=4,065) and ≥420 minutes (n=4,094) groups. A multivariate logistic regression model was used to investigate associations between age/total duration of labor group factors to different postpartum outcomes, including a switch to emergency CS, puerperal morbidity, abnormal fetal heart rate, and meconium-stained amniotic fluid (MSAF). Results: The rates of postpartum outcomes significantly differed in maternal age groups, including switch to emergency CS (9.07% vs. 13.03% vs. 11.23%; P<0.001), puerperal morbidity (6.32% vs. 6.46% vs. 5.00%; P=0.035), and abnormal fetal heart rate (25.34% vs. 28.21% vs. 25.67%; P=0.017). Of the comparisons between labor time groups, it was found that participants with longer labor time were also significantly higher in the use of episiotomy/forceps (46.61% vs. 69.77%; P<0.001), bleeding amount (381.35±108.02 vs. 389.60±146.40 mL; P=0.004), oxytocin use (25.03% vs. 39.56%; P<0.001), puerperal morbidity (1.98% vs. 6.86%; P<0.001), abnormal fetal heart rate (20.07% vs. 25.15%; P<0.001), and MSAF (26.53% vs. 31.91%; P<0.001). Multivariate logistic regression analysis showed that as age increased, the ORs of switching to emergency CS (1.58 and 1.87, both P<0.001) and having abnormal fetal heart rate (1.20 and 1.38; both P<0.01) also increased. Participants with longer labor time groups the ORs of puerperal morbidity (2.33; P<0.001) and MSAF (1.13; P=0.023) also increased. Conclusions: With the adjustment of covariates. Higher maternal age seems associated to the risk of switching to emergency CS and having abnormal fetal heart rate; longer total duration of labor seems associated to the risk of puerperal morbidity and MSAF.

Study the interactions between multiple flavonoids and bovine serum albumin by the developed equilibrium dialysis.

The therapeutic function of traditional Chinese medicine (TCM) is based on the combination effect of multiple active ingredients. However, the current pharmacological studies mainly focus on the protein binding of the single component from TCM, which is difficult to explain the overall therapeutic mechanism. Thus in this work the equilibrium dialysis method combined with high performance liquid chromatography (HPLC) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed to study the interactions between multi-components and protein. Firstly, the binding constants of seven different structural types of flavonoids with bovine serum albumin (BSA) were determined. The results showed that the binding affinity of flavones and flavonols with BSA was stronger than that of dihydroflavonoids, and the substitution of glycosides would reduce the binding affinity with BSA. The results of competitive displacement experiment showed that there existed competitive interactions among the four flavonoids (rutin, luteolin, hesperetin and kaempferol). The binding constants of flavonoids to BSA were significantly changed under the condition of multi-components coexistence. Especially, the binding constant of hesperetin to BSA increased from 9.46 × 104 L/mol to 1.49 × 106 L/mol under the coexistence of rutin. The results of fluorescence spectroscopy showed that the reason for competitive binding was that the four flavonoids were mainly bound to the IIA region of BSA. Finally, the method was successfully applied to study the binding of multiple components in Radix Scutellariae (RS) extract with BSA. Five flavonoids in RS extract were identified by UPLC-MS/MS, they had different degrees of binding to BSA, among which oroxylin A had the strongest binding degree. In conclusion, the equilibrium dialysis was reliable and sufficiently accurate for study of the interaction between multi-components or TCM extract and protein, which can provided a theoretical basis for the scientific explanation of the overall treatment mechanism of TCM.

Efficacy and safety of apatinib combined with whole-brain radiation therapy with a simultaneous integrated boost for brain metastases from non-small cell lung cancer: a multicenter retrospective study.

Background: Brain metastases (BMs) develop in 20-65% of non-small cell lung cancer (NSCLC) patients and are associated with a poor prognosis. Apatinib, a tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor 2, is safe and significantly prolongs the survival of chemotherapy-refractory gastric cancer patients. This retrospective study evaluated the safety and efficacy of apatinib combined with concurrent brain radiotherapy in NSCLC patients with BMs. Methods: This trial enrolled patients with non-recurrent BM from histologically-confirmed NSCLC without any limits regarding the BM size/quantity. Eligibility criteria were patients 18-75 years old with measurable BM from histologically-confirmed NSCLC (including both newly-diagnosed and previously treated NSCLC) and expected survival time greater than 3 months. Oral apatinib (500 or 250 mg/day) was started within 1 week prior to commencing whole brain radiotherapy with simultaneous integrated boost (WBRT-SIB) and continued until one week after radiotherapy completion. In addition to toxicities, analyzed outcomes included intracranial overall response rate (iORR), intracranial disease control rate (iDCR), intracranial progression free survival (iPFS), and overall survival (OS). Results: From July 2016 to January 2020, 16 patients were enrolled in this retrospective study. After 3 months of brain radiotherapy, the iORR was 75%, the iDCR was 100%, and the brain edema index (EI) was significantly reduced compared to that before brain radiation therapy (4.2 vs. 1.9; P=0.02). The median iPFS was 16.5 months [95% confidence interval (CI): 15.1-37.4 months]. The median OS was 26 months (95% CI: 17.0-54.0 months). Most of the patients tolerated apatinib well, but 7 patients had side effects, most commonly grade 1 or 2. Only 2 patients experienced grade 3 adverse events (hypertension and oral mucositis), and no grade 4 or 5 toxicities were observed. Conclusions: Apatinib combined with WBRT-SIB appears to be safe and effective in treating BMs in NSCLC patients.

Nanoemulsion for Improving the Oral Bioavailability of Hesperetin: Formulation Optimization and Absorption Mechanism.

This study aimed to prepare a nanoemulsion vehicle to improve the oral bioavailability of hesperetin. The pseudo-ternary phase diagrams and the RSM were used to optimize nanoemulsion parameters. Compared with hesperetin suspension, the AUC0-t and Cmax of nanoemulsion were increased by 5.67-fold and 2.64-fold, respectively. The proportion of lymphatic transport reached 87.72%, the cumulative absorption amount of jejunum, ileum, and duodenum increased by 1.1-fold, 1.92-fold, and 1.5-fold, respectively. The results implied that hesperetin nanoemulsion could effectively improve the bioavailability of hesperetin by increasing lymphatic transport and enhancing intestinal permeability. Therefore, nanoemulsion is a potential method to improve the bioavailability of hesperetin, which has strong practicability.

Effect of Surgical Mask on Setup Error in Head and Neck Radiotherapy.

PURPOSE: With the widespread prevalence of Corona Virus Disease 2019 (COVID-19), cancer patients are suggested to wear a surgical mask during radiation treatment. In this study, cone beam CT (CBCT) was used to investigate the effect of surgical mask on setup errors in head and neck radiotherapy. METHODS: A total of 91 patients with head and neck tumors were selected. CBCT was performed to localize target volume after patient set up. The images obtained by CBCT before treatment were automatically registered with CT images and manually fine-tuned. The setup errors of patients in 6 directions of Vrt, Lng, Lat, Pitch, Roll and Rotation were recorded. The patients were divided into groups according to whether they wore the surgical mask, the type of immobilization mask used and the location of the isocenter. The setup errors of patients were calculated. A t-test was performed to detect whether it was statistically significant. RESULTS: In the 4 groups, the standard deviation in the directions of Lng and Pitch of the with surgical mask group were all higher than that in the without surgical mask group. In the head-neck-shoulder mask group, the mean in the Lng direction of the with surgical mask group was larger than that of the without surgical mask group. In the lateral isocenter group, the mean in the Lng and Pitch directions of the with surgical mask group were larger than that of the without surgical mask group. The t-test results showed that there was significant difference in the setup error between the 2 groups (p = 0.043 and p = 0.013, respectively) only in the Lng and Pitch directions of the head-neck-shoulder mask group. In addition, the setup error of 6 patients with immobilization open masks exhibited no distinguished difference from that of the patients with regular immobilization masks. CONCLUSION: In the head and neck radiotherapy patients, the setup error was affected by wearing surgical mask. It is recommended that the immobilization open mask should be used when the patient cannot finish the whole treatment with a surgical mask.

Trends of female and male breast cancer incidence at the global, regional, and national levels, 1990-2017.

PURPOSE: Breast cancer is a major public health concern worldwide and shows significant heterogeneity between male and female. Knowing the global incidence landscape in both sexes is critical for the breast cancer prevention and the reduction in disease burden. METHODS: We retrieved the incidence data of breast cancer in both sexes from the Global Burden of Disease 2017 database. Average annual percentage change was used to quantify the temporal trends of breast cancer incidence. RESULTS: Between 1990 and 2017, the number of newly diagnosed female breast cancer (FBC) cases increased from 870.2 thousand to 1937.6 thousand, with the age-standardized incidence rate (ASR) significantly increased from 39.2/100,000 to 45.9/100,000. A total of 166 countries experienced a significant increase in FBC-ASR. The most pronounced increase was mainly found in developing countries. The decrease was mostly detected in several developed countries, such as the USA and the UK. Male breast cancer (MBC) is a rare carcinoma and has no evident cluster across the world. Worldwide, the number of newly diagnosed MBC cases increased from 8.5 thousand in 1990 to 23.1 thousand in 2017, with the ASR significantly increased from 0.46/100,000 to 0.61/100,000. A total of 123 countries showed a significant increasing trend in MBC-ASR. CONCLUSIONS: Breast cancer incidence rates are increasing in most countries in both sexes, although the epidemiological features were not completely shared between FBC and MBC. More emphases should be placed on breast cancer primary prevention and the prevention strategies might need to be tailored for both FBC and MBC.

Friction Stir Welding of 5754 Aluminum Alloy with Cover Sheet.

Friction stir welding can realize high-strength aluminum alloy joints. In this study, friction stir welding with cover sheet (CFSW) is proposed to solve the thinning caused by the tool shoulder and reduce the heat-affected zone. The microstructures and mechanical properties of CFWS were also studied. After the cover sheet was added, a reinforcement was formed on the weld surface, which compensated the thinning caused by the friction of the tool shoulder. As the cover absorbed heat from the shoulder, the width of the heat-affected zone of the welded sheet became smaller than the diameter of the shoulder. Without milling the cover sheet, the tensile strength of the 5754 aluminum alloy joint reached 94% of that of the base metal. The fracture position was the heat-affected zone of the forward-side weld joint. After the cover sheet was added, the stress concentration shifted from the thinning area of traditional friction stir welding to the outside of the welding seam.

Bending Properties of Mg Alloy Tailored Arc-Heat-Treated Blanks.

Tailored heat-treated blank is a special kind of sheet, and the plastic forming ability can be improved. In this work, the poor room-temperature plasticity of a tailored magnesium alloy blank was address through arc heat treatment. The formability of the material was enhanced through local modification with arc pretreatment. The plasticity of the tailored arc-heat-treated blank was verified through the V-bending test. The microstructure and mechanical properties of the blank were tested, and the mechanisms underlying its improved deformability were analyzed. The bendability of the blank first increased and then decreased as heat input increased. The maximum V-bending ability of the arc-heat-treated blank increased by 88% relative to that of the untreated blank. Although springback decreased under increasing heat input, the local strength and elastic modulus of the alloy blank were equivalent to those of the base metal. This result indicated that the springback resistance of the material did not improve. The back of the blank treated under the optimal parameters comprised heat-affected zones with good plasticity. Recrystallization and grain growth occurred in the heat-affected zones. The blank exhibited reduced hardness and improved malleability. When the heat input was further increased, however, a semi-melting zone formed on the lower surface of the blank. The formation of this zone resulted in the precipitation of intermetallic compounds from the crystal phase and increased the hardness of the blank. It also decreased the plasticity and malleability of the blank.

Paper-Based Versatile Surface-Enhanced Raman Spectroscopy Chip with Smartphone-Based Raman Analyzer for Point-of-Care Application.

With the advanced development of miniaturized Raman spectroscopy, surface-enhanced Raman spectroscopy (SERS) has extended its applications into the field of point-of-care testing (POCT) and demonstrated its great significance by virtue of its noninvasive property and capability of fingerprint identification. In the SERS-based analysis and/or sensing system, the preparation of a low-cost, high-performance SERS substrate is critically important. In this manuscript, vacuum filtration is utilized to fabricate the silver nanoparticles (AgNPs)-embedded nylon filter membrane (ANFM) as flexible paper-based SERS chips. By characterizing the typical analytes with a miniaturized smartphone-based Raman analyzer, the proposed SERS chips have successfully demonstrated good sensitivity, repeatability, and stability. The lowest concentration as detected can approach 1 pmol for rhodamine 6G (RH6G) and 10 pmol for both crystal violet (CV) and malachite green (MG), respectively. With the help of the microporous structure of the membrane, the ANFM-based SERS chips can implement the separation of small molecules from a complex mixture and can achieve "purified" SERS signals of targeted molecules. Besides, with the function of antifriction resistance and flexibility, the ANFM can serve as SERS papers to preconcentrate the contaminates by multiple swapping and further enhance the SERS signals for point-of-care analysis. Therefore, we demonstrate multifunctions of the flexible ANFM-based SERS chips, which provide a promising solution for the POCT analysis with the SERS technique on account of their flexibility and low fabrication cost.

Paper-based SERS analysis with smartphones as Raman spectral analyzers.

SERS (Surface Enhanced Raman Spectroscopy) can realize fingerprint recognition of molecular samples with high detection accuracy and sensitivity. However, rapid and convenient measurement of the Raman spectra of analytes for a point-of-care test (POCT) has put forward a high demand for portable Raman spectrometers, as well as reliable SERS substrates. Hereby, we first utilize a smartphone as a miniaturized Raman spectral analyzer, which has the revolutionary advantages of a friendly human-machine interface, fast measurement time, and good sensitivity. Meanwhile, a paper-based SERS chip was prepared based on commonly used filter paper and silver nanoparticles (AgNP), which was successfully used to detect low concentrations of typical SERS analyte model molecules including rhodamine 6G and crystal violet. The current method of smartphone-based SERS spectroscopy as a POCT device will greatly promote the application of Raman technology in a variety of scenarios, such as safety inspections, pesticide residue detection, water pollution monitoring, and so on. Coupled with paper-based SERS chips with advantages of facile preparation, low cost and good reliability, the current work proves to have a great potential for industrial production and for meeting the vast marketing demand of Raman based POCT technology.

Bilayer Tubular Micromotors for Simultaneous Environmental Monitoring and Remediation.

There are two main aspects of environmental governance including monitoring and remediation, both of which are essential for environmental protection. Self-propelled micro/nanomotors (MNM) have shown promising potential for achieving on-demand tasks in environmental field, including environmental sensing and pollutant removal or degradation. However, most of the current MNM used in environmental protection can hardly accomplish the two major tasks of both monitoring and pollutant degradation. Hereby, we present a bubble-propelled mesoporous silica-coated titania (TiO2@mSiO2) bilayer tubular micromotor with platinum (Pt) and magnetic Fe3O4 nanoparticles modified on their inner walls. The outer mesoporous silica (mSiO2) layer can effectively adsorb and collect the pollutants, and the adsorption capacity of the TiO2@mSiO2 tube is about 3 times higher than that of the TiO2 tube due to the presence of mSiO2 shell. By magnetic manipulation, the micromotors can be recovered to release the collected pollutant for precise analysis of the composition of the pollutants, such us pollutant molecule identification by surface-enhanced Raman scattering. The active motion and photocatalytic TiO2 inner layer of the micromotors can greatly enhance the degradation rate of the model pollutant rhodamine 6G (R6G). Our results show that within 30 min, up to 98% of R6G can be degraded by the motors. The successful demonstration of the TiO2@mSiO2 bilayer tubular motors for simultaneous environmental monitoring and pollutant degradation paves the way for future development of active and intelligent micro/nanorobots for advanced environmental governance.

Photocatalytically Powered Matchlike Nanomotor for Light-Guided Active SERS Sensing.

Surface enhanced Raman spectroscopy (SERS) is a powerful optical sensing technique that can detect analytes of extremely low concentrations. However, the presence of enough SERS probes in the detection area and a close contact between analytes and SERS probes are critical for efficient acquisition of a SERS signal. Presented here is a light-powered micro/nanomotor (MNM) that can serve as an active SERS probe. The matchlike AgNW@SiO2 core-shell structure of the nanomotors work as SERS probes based on the shell-isolated enhanced Raman mechanism. The AgCl tail serves as photocatalytic nanoengine, providing a self-propulsion force by light-induced self-diffusiophoresis. The phototactic behavior was utilized to achieve enrichment of the nanomotor-based SERS probes for on-demand biochemical sensing. The results demonstrate the possibility of using photocatalytic nanomotors as active SERS probes for remote, light-controlled, and smart biochemical sensing on the micro/nanoscale.

Disassembly of Hydrophobic Photosensitizer by Biodegradable Zeolitic Imidazolate Framework-8 for Photodynamic Cancer Therapy.

Photodynamic therapy (PDT), an alternative to conventional cancer therapeutics, has gained increasing attention for its noninvasive advantage and simultaneous fluorescence imaging property. PDT is a tripartite process that functions in the simultaneous presence of a photosensitizer (PS), light, and available oxygen molecules. However, many highly efficient PSs are hydrophobic and highly tend to self-aggregate in aqueous solution, leading to quick quenching of the PDT effect. Here we construct zeolitic imidazolate framework-8 (ZIF-8) containing water-insoluble photosensitizer zinc(II) phthalocyanine (ZnPc), a typical hydrophobic PS, by one-step coprecipitation process, named as ZnPc@ZIF-8. The micropores of ZIF-8 act as molecular cages to separate and maintain hydrophobic ZnPc in the monomeric state and protect it against self-aggregation, which enables the encapsulated ZnPc to generate cytotoxic singlet oxygen (1O2) under light irradiation (650 nm) in aqueous condition. The formed nanosystem of ZnPc@ZIF-8 can be endocytosed by cancer cells and exhibits red fluorescent emission with excellent photodynamic activity for cancer treatment in vitro. In addition, ZnPc@ZIF-8 is acid-sensitive and would completely degrade after PDT, which can be monitored by the self-quenching of fluorescence emission of ZnPc. This work paves a facile way for resolving the problem of solubility and bioavailability of hydrophobic PS by utilizing metal-organic frameworks as nanocarriers.

BLCAP arrests G1/S checkpoint and induces apoptosis through downregulation of pRb1 in HeLa cells.

BLCAP (bladder cancer-associated protein) gene exhibited tumor suppressor function in different tumors and is regarded as a candidate tumor suppressor gene; however, the mechanism by which BLCAP exerts its function remains elusive. This study investigated the functional association between BLCAP and proliferation or apoptosis in cervical cancer cells, to identify the functional motifs of BLCAP. The BLCAP-shRNA expression vector based on pRNA-U6.1/Hygro plasmid was used to specifically inhibit BLCAP activity in HeLa cells. The optimal shRNA plasmid was selected to knock down BLCAP expression and the biological effects were investigated. The effects on cell cycle and apoptosis were detected by flow cytometric or Annexin V-FITC staining analysis. The gene expression profiles of HeLa cells transfected with blcap-wt and BLCAP-shRNA were analyzed using human signal pathway gene Oligochips. The levels of protein expression and interaction of BLCAP with Rb1 proteins were determined by western blotting and Co-IP assays. The site-specific mutagenesis assay was used to identify amino acid residues important for BLCAP. Significantly differentially expressed genes were found by gene Oligo chips analysis. These genes were all correlated with proliferation, cell cycle and apoptosis. The results of western blotting and Co-IP assays confirmed that overexpression of BLCAP could interact with Rb1 and inhibit Rb1 phosphorylation. Further investigation revealed that SAXX mutation in the key regions of BLCAP suppressed the function of BLCAP and significantly increased the level of phosphorylated Rb1 protein. Here our findings suggested that the functional association of BLCAP and Rb1 might play important roles in proliferation and apoptosis of HeLa cells. It suggested that BLCAP could be a novel therapeutic target for cervical cancer.

A risk evaluation model of cervical cancer based on etiology and human leukocyte antigen allele susceptibility.

BACKGROUND: There are no reliable risk factors to accurately predict progression to cervical cancer in patients with chronic cervicitis infected with human papillomavirus (HPV). The aim of this study was to create a validated predictive model based on the risk factors for cervical cancer. A model to estimate the risk of cervical cancer may help select patients for intervention therapy in order to reduce the occurrence of cervical cancer after HPV infection. METHODS: This retrospective analysis included 68 patients with cervical cancer and 202 healthy female controls. HPV infection and human leukocyte antigen (HLA) class II alleles in HLA-DRB1, 3-7, and 9 were detected. Other information was collected, including level of education and age at first parturition. Multiple regression analysis and an artificial neural network (ANN) were performed to identify the independent risk factors for cervical cancer, and based on these, an evaluation model for the prediction of the incidence of cervical cancer was formed. RESULTS: This model showed HPV to be a pivotal player in cervical cancer that increased the risk by 7.6-fold. The presence of the HLA-DRB1*13-2 and HLA-DRB1*3(17) alleles was associated with an increased risk of developing cervical cancer. Conversely, the HLA-DRB1*09012 and HLA-DRB1*1201 alleles were found to be associated with a reduced cervical cancer risk. In addition, other factors, such as age at first parturition and education level, had significant effects on cervical cancer risk. The model was applied to conduct a risk assessment of women in the mountain area of Wufeng County, Hubei Province in China. The sensitivity and specificity of our model both exceeded 95%. CONCLUSIONS: This model, based on etiology and HLA allele susceptibility, can estimate the risk of cervical cancer in chronic cervicitis patients after HPV infection. It combines genetic and environmental factors and significantly enhances the accuracy of risk evaluation for cervical cancer. This model could be used to select patients for intervention therapy and to guide patient classification management.

Dosimetric comparison of intensity-modulated radiotherapy plans, with or without anterior myocardial territory and left ventricle as organs at risk, in early-stage left-sided breast cancer patients.

PURPOSE: We evaluated heart sparing using an intensity-modulated radiotherapy (IMRT) plan with the left ventricle (LV) and/or the anterior myocardial territory (AMT) as additional organs at risk (OARs). METHODS AND MATERIALS: A total of 10 patients with left-sided breast cancer were selected for dosimetric planning. Both lungs, the right breast, heart, LV, and AMT were defined as OARs. We generated one tangential field plan and four IMRT plans for each patient. We examined the dose-volume histogram parameters of the planning target volume and OARs. RESULTS: Compared with the tangential field plan, the mean dose to the heart in the IMRT plans did not show significant differences; however, the dose to the AMT and LV decreased by 18.7-45.4% and 10.8-37.4%, respectively. The maximal dose to the heart decreased by 18.6-35.3%, to the AMT by 22.0-45.1%, and to the LV by 23.5-45.0%, And the relative volumes of the heart (V≥12), AMT (V>11) and LV (V>10) decreased significantly with different levels, respectively. The volume of the heart, AMT, LV, both lungs, and right breast receiving≥5 Gy showed a significant increase. Compared with the IMRT (H) plan, the mean dose to the heart, AMT, and LV decreased by 17.5-21.5%, 25.2-29.8%, and 22.8-29.8% and the maximal dose by 13.6-20.6%, 23.1-29.6%, and 17.3-29.1%, respectively. The IMRT plans for both lungs and the right breast showed no significant differences. CONCLUSIONS: The IMRT plans with the addition of the AMT and/or LV as OARs considerably increased heart sparing. We recommend including the LV as an additional OAR in such plans.