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Introduction: Poly (ADP‐ribose) polymerase (PARP) inhibitor has been widely used in ovarian cancer patients carrying BRCA mutations. However, resistance to PARP inhibitor is present in some patients, and no effective treatment is available for these patients. TH‐302 is a hypoxia‐activated prodrug, which releases the bis‐DNA alkylator bromo‐isophosphoramide mustard (Br‐IPM) under hypoxic condition. The present study aims to determine whether TH‐302 is effective in treating PARP inhibitor resistance. Methods: The in vitro cytotoxicity of TH‐302 was assessed by short‐term proliferation assay (50% inhibitory concentration, IC50) or long‐term clonogenic assay (90% inhibitory concentration, IC90) under various oxygen concentrations. In vivo efficacy of TH‐302 was assessed in PARP inhibitor resistance, partially responsive and sensitive patient‐derived xenograft (PDX) or cell line–derived xenograft (CDX) models. Antitumor activity via homologous recombination (HR) pathway for TH‐302 was evaluated using DLD1 BRCA2 knockout cell line and BRCA/RAD51D deleterious mutant PDX/CDX models. Breaks of double‐strand DNA and hypoxia fraction in tumors were determined by gamma histone 2AX (γH2AX) and pimonidazole immunohistochemistry in H460 CDX model following treatment. Results: Cytotoxicity was significantly enhanced under hypoxia in 12 human cancer cell lines including four ovarian cancer cell lines. The cytotoxicity was 70 times higher in human colon cancer cell line with BRCA2 knock out compared to wild type under hypoxia following TH‐302 treatment. γH2AX staining revealed that the cytotoxicity of TH‐302 was associated with DNA damage. In addition, administration of TH‐302 with olaparib led to better antitumor activities than either single drug/prodrug in olaparib‐resistant PDX models. Conclusion: TH‐302 exhibits hypoxia‐dependent cytotoxicity across a wide range of human cancer cell lines, and may be a drug candidate to treat ovarian cancer, bladder cancer, and pancreatic cancer with HR deficiencies with or without resistance to PARP inhibitor. TH‐302 may be effective in recurrent epithelial ovarian cancer (EOC) with homologous recombination deficiency (HRD) or in EOC patients resistant to PARP inhibitors. [ABSTRACT FROM AUTHOR]

The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR–aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is a systemic vasculitis accompanied by many systemic physiological and biochemical changes. Elucidating its molecular mechanisms is crucial for diagnosing and developing effective treatments. NLR Family CARD Domain Containing 4 (NLRC4) encodes the key components of inflammasomes that function as pattern recognition receptors. The purpose of this study was to investigate the potential of NLRC4 methylation as a biomarker for KD. Methods: In this study, pyrosequencing was utilized to analyze NLRC4 promoter methylation in blood samples from 44 children with initial complete KD and 51 matched healthy controls. Methylation at five CpG sites within the NLRC4 promoter region was evaluated. Results: Compared to controls, NLRC4 methylation significantly decreased in KD patients (CpG1: p = 2.93E-06; CpG2: p = 2.35E-05; CpG3: p = 6.46E-06; CpG4: p = 2.47E-06; CpG5: p = 1.26E-05; average methylation: p = 5.42E-06). These changes were significantly reversed after intravenous immunoglobulin (IVIG) treatment. ROC curve analysis demonstrated remarkable diagnostic capability of mean NLRC4 gene methylation for KD (areas under ROC curve = 0.844, sensitivity = 0.75, p = 9.61E-06, 95% confidence intervals were 0.762–0.926 for mean NLRC4 methylation). In addition, NLRC4 promoter methylation was shown to be significantly negatively correlated with the levels of central granulocyte percentage, age, mean haemoglobin quantity and mean erythrocyte volume. Besides, NLRC4 promoter methylation was positively correlated with lymphocyte percentage, lymphocyte absolute value. Conclusions: Our work revealed the role of peripheral NLRC4 hypomethylation in KD pathogenesis and IVIG treatment response, could potentially serve as a treatment monitoring biomarker, although its precise functions remain to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand‐foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose‐escalation strategy for elderly refractory mCRC patients. Patients and Methods: This open‐label, single‐arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28‐day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug‐related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression‐free survival (PFS). Results: A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7–4.9), and the median OS was 7.6 months (95% CI, 6.5–8.7). Treatment‐related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). Conclusion: Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose‐escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing. [ABSTRACT FROM AUTHOR]

Background and Objectives: ABO antigens are produced from H antigen by the activity of glycosyltransferase enzyme encoded by the ABO gene. Variants in the ABO gene can produce a weak ABO phenotype. In this study, we identify a novel ABO*BW allele and investigate the underlying mechanism leading to the Bweak phenotype. Materials and Methods: The ABO phenotype and genotype of the sample were determined using serological and direct DNA sequencing methods. We assessed the impact of the novel variant by three‐dimensional modelling to predict protein stability changes (ΔΔG), and carried out an in vitro expression assay. The total glycosyltransferase transfer capacity in the supernatant of transfected cells was also examined. Results: Serological analysis confirmed the Bweak phenotype in the subject, and gene sequencing identified a novel variant c.761C>T (p.A254V) on the ABO*B.01 allele, resulting in a BW‐var/O.01.02 genotype. In silico analysis suggested that the p.A254V variant on the B allele may reduce the stability of glycosyltransferase B (GTB), as indicated by the ΔΔG values. In vitro expression studies showed that the variant p.A254V impaired H to B antigen conversion, although it did not affect the expression of GTB. Conclusion: We identified a novel BW allele and demonstrated that the variant c.761C>T (p.A254V) can cause the Bweak phenotype by reducing the stability of GTB. [ABSTRACT FROM AUTHOR]

Medical knowledge graph can provide new auxiliary information for recommendation system because of its structural semantic knowledge characteristics. The combination of recommendation system and medical knowledge graph can not only effectively alleviate the problem of sparse data, but also enhance the accuracy and interpretability of recommendation results, thus realizing personalized recommendation of medical information. Aiming at the characteristics of strong professional barriers and various conceptual terms in the medical field, the medical knowledge graph structure is systematically sorted out. This paper summarizes the traditional recommendation algorithms and compares their advantages and disadvantages. It summarizes and introduces the recommendation systems based on path, embedding and fusion respectively, focusing on the research results of combining medical practice and their advantages and disadvantages. The existing problems and challenges in current research are analyzed, and the feasible future research direction is prospected. [ABSTRACT FROM AUTHOR]

Purpose: We investigated changes in plasma transfer RNA related fragments (tRF) in children with obstructive sleep apnea–hypopnea syndrome (OSAHS) and the potential value as a disease marker. Methods: Firstly, we randomly selected five plasma samples from the case group and the control group for high-throughput RNA sequencing. Secondly, we screened one tRF with different expression between the two groups, amplified it by quantitative reverse transcription-PCR (qRT-PCR) and sequenced the amplified product. After confirming that the qRT-PCR results were consistent with the sequencing results and the sequence of the amplified product contained the original sequence of the tRF, we performed qRT-PCR on all samples. Then we analyzed the diagnostic value of the tRF and its correlation with some clinical data. Results: A total of 50 OSAHS children and 38 control children were included in this study. There were significant differences in height, serum creatinine (SCR) and total cholesterol (TC) between the two groups. The plasma expression levels of tRF-21-U0EZY9X1B (tRF-21) were significantly different between the two groups. Receiver operating characteristic curve (ROC) showed that it had valuable diagnostic index, with area under the curve (AUC) of 0.773, 86.71% and 63.16% sensitivity and specificity. Conclusions: The expression levels of tRF-21 in the plasma of OSAHS children decreased significantly which were closely related to hemoglobin, mean corpuscular hemoglobin, triglyceride and creatine kinase-MB, may become novel biomarkers for the diagnosis of pediatric OSAHS. [ABSTRACT FROM AUTHOR]

Purpose: We investigated changes in plasma transfer RNA related fragments (tRF) in children with obstructive sleep apnea–hypopnea syndrome (OSAHS) and the potential value as a disease marker. Methods: Firstly, we randomly selected five plasma samples from the case group and the control group for high-throughput RNA sequencing. Secondly, we screened one tRF with different expression between the two groups, amplified it by quantitative reverse transcription-PCR (qRT-PCR) and sequenced the amplified product. After confirming that the qRT-PCR results were consistent with the sequencing results and the sequence of the amplified product contained the original sequence of the tRF, we performed qRT-PCR on all samples. Then we analyzed the diagnostic value of the tRF and its correlation with some clinical data. Results: A total of 50 OSAHS children and 38 control children were included in this study. There were significant differences in height, serum creatinine (SCR) and total cholesterol (TC) between the two groups. The plasma expression levels of tRF-21-U0EZY9X1B (tRF-21) were significantly different between the two groups. Receiver operating characteristic curve (ROC) showed that it had valuable diagnostic index, with area under the curve (AUC) of 0.773, 86.71% and 63.16% sensitivity and specificity. Conclusions: The expression levels of tRF-21 in the plasma of OSAHS children decreased significantly which were closely related to hemoglobin, mean corpuscular hemoglobin, triglyceride and creatine kinase-MB, may become novel biomarkers for the diagnosis of pediatric OSAHS. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is typically characterized by chronic intermittent hypoxia (CIH), associated with cognitive dysfunction in children. Calcium-sensing receptor (CaSR) mediates the apoptosis of hippocampal neurons in various diseases. However, the effect of CaSR on OSAHS remains elusive. In the present study, we investigated the role of CaSR in CIH-induced memory dysfunction and underlying mechanisms on regulation of PKC-ERK1/2 signaling pathway in vivo and in vitro. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to cognitive dysfunction. CIH accelerated apoptosis of hippocampal neurons and resulted in the synaptic plasticity deficit via downregulated synaptophysin (Syn) protein level. The mice were intraperitoneally injected with CaSR inhibitor (NPS2143) 30 min before CIH exposure and the results demonstrated CaSR inhibitor alleviated the apoptosis and synaptic plasticity deficit in the hippocampus of CIH mice. We established intermittent hypoxia PC12 cell model and found that the activation of CaSR accelerated CIH-induced PC12 apoptosis and synaptic plasticity deficit by upregulated p-ERK1/2 and PKC. Overall, our findings revealed that CaSR held a critical function on CIH-induced cognitive dysfunction in mice by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity via augmenting CaSR-PKC-ERK1/2 pathway; otherwise, inhibition of CaSR alleviated CIH-induced cognitive dysfunction. [ABSTRACT FROM AUTHOR]

We present an experimental study on the double K-shell ionization of argon in single collisions with the Xe54+ ion at 197 MeV/u. The X-ray spectra of multi-ionized argon are measured at the observation angles of 90° and 145° with respect to the projectile beam. The target K X-ray satellite and hypersatellite lines are analyzed with a fitting model and the cross-section ratio of double to single K-shell ionization is derived. The experimental results are compared to the relativistic time-dependent, two-center calculations, and a reasonable agreement is reached. [ABSTRACT FROM AUTHOR]

Background and Objectives: The chimaerism phenomenon constitutes a significant mechanism underlying ABO phenotype discrepancies; however, its detection has technical challenges. In the current study, we explored different techniques to establish the chimaeric status of ABO blood types. Materials and Methods: Fifteen individuals with possible chimaeric ABO blood type, as suggested by standard tube or column agglutination method and RBC adsorption‐elution test, were enrolled in the study. The red blood cells from 11 investigated subjects showed mix‐field agglutination with anti‐A or anti‐B in blood typing; weak A or B antigens on the other four individuals' RBCs were detected by adsorption‐elution tests. The genetic study was conducted with PCR‐SSP genotype, DNA sequencing of the ABO gene, STR analysis and ddPCR. Results: The genetic chimaeric status was confirmed in four (27%) individuals by SSP test alone. The ABO gene sequencing identified an additional ABO allele and enabled chimaerism detection in 10 (67%) subjects. The STR analyses established the chimaerism status in 13 (87%) individuals. In the two cases where neither of the tests mentioned above had positive findings, the ddPCR was adopted, and microchimaerism, with an extremely low degree of chimaerism (0.77% and 0.12%), was revealed. The ddPCR revealed the unequal haplotypes (29.5% B vs. 70.5% O) in one subject and distinguished this B/O‐O/O chimaera from certain B subgroups (B/O genotype without any mutation) like B3. Conclusion: The ABO blood type chimaerism can be genetically established by comprehensive molecular methods, including PCR‐SSP/DNA sequencing, STR and ddPCR, which is particularly sensitive for the detection of microchimaerism. [ABSTRACT FROM AUTHOR]

Video question answering (Video-QA) is a subject undergoing intense study in Artificial Intelligence, which is one of the tasks which can evaluate such AI abilities. In this paper, we propose a Modality Attention Fusion framework with Hybrid Multi-head Self-attention (MAF-HMS). MAF-HMS focuses on the task of answering multiple-choice questions regarding a video-subtitle-QA representation by fusion of attention and self-attention between each modality. We use BERT to extract text features, and use Faster R-CNN to ex-tract visual features to provide a useful input representation for our model to answer questions. In addition, we have constructed a Modality Attention Fusion (MAF) framework for the attention fusion matrix from different modalities (video, subtitles, QA), and use a Hybrid Multi-headed Self-attention (HMS) to further determine the correct answer. Experiments on three separate scene datasets show our overall model outperforms the baseline methods by a large margin. Finally, we conducted extensive ablation studies to verify the various components of the network and demonstrate the effectiveness and advantages of our method over existing methods through question type and required modality experimental results. [ABSTRACT FROM AUTHOR]

Social media allows users to express opinions in multiple modalities such as text, pictures, and short-videos. Multi-modal sentiment detection can more effectively predict the emotional tendencies expressed by users. Therefore, multi-modal sentiment detection has received extensive attention in recent years. Current works consider utterances from videos as independent modal, ignoring the effective interaction among diffence modalities of a video. To tackle these challenges, we propose transformer-based interactive multi-modal attention network to investigate multi-modal paired attention between multiple modalities and utterances for video sentiment detection. Specifically, we first take a series of utterances as input and use three separate transformer encoders to capture the utterances-level features of each modality. Subsequently, we introduced multimodal paired attention mechanisms to learn the cross-modality information between multiple modalities and utterances. Finally, we inject the cross-modality information into the multi-headed self-attention layer for making final emotion and sentiment classification. Our solutions outperform baseline models on three multi-modal datasets. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea–hypopnea syndrome (OSAHS), typically characterized by chronic intermittent hypoxia (CIH), is associated with neurocognitive dysfunction in children. Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been demonstrated to protect against oxidative stress in various diseases. However, the effect of SFN on OSAHS remains elusive. In this research, we investigated the neuroprotective role of SFN in CIH-induced cognitive dysfunction and underlying mechanisms of regulation of Nrf2 signaling pathway and autophagy. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to neurocognitive dysfunction, manifested as increased working memory errors (WMEs), reference memory errors (RMEs) and total memory errors (TEs) in the 8-arm radial maze test. The mice were intraperitoneally injected with SFN (0.5 mg/kg) 30 min before CIH exposure everyday. SFN treatment ameliorated neurocognitive dysfunction in CIH mice, which demonstrates less RME, WME, and TE. Also, SFN effectively alleviated apoptosis of hippocampal neurons following CIH by decreased TUNEL-positive cells, downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2. SFN protects hippocampal tissue from CIH-induced oxidative stress as evidenced by elevated superoxide dismutase (SOD) activities and reduced malondialdehyde (MDA). In addition, we found that SFN enhanced Nrf2 nuclear translocation to hold an antioxidative function on CIH-induced neuronal apoptosis in hippocampus. Meanwhile, SFN promoted autophagy activation, as shown by increased Beclin1, ATG5, and LC3II/LC3I. Overall, our findings indicated that SFN reduced the apoptosis of hippocampal neurons through antioxidant effect of Nrf2 and autophagy in CIH-induced brain damage, which highlights the potential of SFN as a novel therapy for OSAHS-related neurocognitive dysfunction. [ABSTRACT FROM AUTHOR]

Treating red blood cells (RBCs) with dithiothreitol (DTT) is a wildly-recommended to overcome the interference of the daratumumab (DARA) with blood compatibility testing. Nevertheless, DTT can be hard to obtain in the clinical laboratory, while its use in routine practice may be time-consuming. In the following study, we explored the feasibility of using a commercial 2-mercaptoethanol (2-ME) working solution or the time-saving Polybrene method to mitigate DARA interference. Antibody screening and cross-matching were performed using 2-ME or DTT-based indirect antiglobulin tests (IATs) and Polybrene method (with human IgG anti-E same IATs titer as DARA as positive control) on 37 samples. Most clinically important blood group antigens on RBCs were detected after treatment with 2-ME or DTT. Treating RBCs with 2-ME eliminates the DARA interference with the antibody screening or cross-matching; yet, K antigen is denatured during treatment. DARA does not interfere with antibody screening and cross-matching via Polybrene method, while 2+ agglutinations of anti-E antibody with the same titer (IATs method) as DARA could be observed in the positive controls via this method. 2-ME-based IATs or Polybrene method could replace DTT-based IATs to mitigate DARA interference. [ABSTRACT FROM AUTHOR]

Background: Here we report a case of para-Bombay phenotype due to a novel mutation FUT1 c.361G>A p.(Ala121Thr) and a nonfunctional allele FUT1*01N.13(c.881_882delTT) which showed a discrepancy in the routine ABO blood group typing. Materials and Methods: The ABO phenotype and the Lewis blood group were typed with serological methods. The ABH antigens in saliva were determined by a hemagglutination inhibition test. The CDS region of ABO, FUT1and FUT2 were amplified with polymerase chain reaction and then directly sequenced. The novel mutation was confirmed by cloning and sequencing. Three-dimensional (3-D) structural analysis of the mutant and wild-type Fut1 were performed by the Chimera software. Results: A, B and H antigens were not detected on the surface of red blood cells (RBCs) by the serological technique, and the B and H blood group substances were detected in the saliva, while the Lewis phenotype was Le(a–b+). Sequencing and cloning analysis showed the presence of a novel FUT1 mutation c.361G>A and a nonfunctional allele FUT1*01N.13(c.881_882delTT). The ABO genotype was ABO*B.01/ABO*O.01.01. The in silico analysis showed that the mutation p.(Ala121Thr) of FUT1did not change the 3-D structure of the whole enzyme but caused a certain amplitude of turnover in the loop region where Ala121 was located. Conclusions: A novel FUT1 allele (FUT1*c.361G>A) was identified in a Chinese individual with para-Bombay B phenotype. The FUT1c.361G>A mutation may significantly downregulate the expression of H antigens on RBCs by damaging the enzyme conformation. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a breathing disorder associated with cognitive impairment. However, the mechanisms leading to cognitive deficits in OSAHS remain uncertain. In this study, a mouse model of chronic intermittent hypoxia (CIH) exposures were applied for simulating the deoxygenation-reoxygenation events occurring in OSAHS. The conventional adenosine A1 receptor gene (A1R) knockout mice and the A1R agonist CCPA- or antagonist DPCPX-administrated mice were utilized to determine the precise function of A1R signaling in the process of OSAHS-relevant cognitive impairment. We demonstrated that CIH induced morphological changes and apoptosis in hippocampal neurons. Further, CIH blunted hippocampal long-term potentiation (LTP) and resulted in learning/memory impairment. Disruption of adenosine A1R exacerbated morphological, cellular, and functional damage induced by CIH. In contrast, activation of adenosine A1R signaling reduced morphological changes and apoptosis of hippocampal neurons, promoted LTP, and enhanced learning and memory. A1Rs may up-regulate protein kinase C (PKC) and its subtype PKC-ζ through the activation of Gα(i) improve spatial learning and memory disorder induced by CIH in mice. Taken together, A1R signaling plays a neuroprotective role in CIH-induced cognitive dysfunction and pathological changes in the hippocampus. [ABSTRACT FROM AUTHOR]

Simultaneous testing of multiple genetic variants for association is widely recognized as a valuable complementary approach to single-marker tests. As such, principal component regression (PCR) has been found to have competitive power. We focus on exploring a robust test for an unknown genetic mode of all SNPs, an unknown Hardy-Weinberg equilibrium (HWE) in a population, and a large number of all SNPs. First, we propose a new global test by means of the use of codominant codes for all markers and PCR. The new global test is built on an empirical Bayes-type score statistic for testing marginal associations with each single marker. The new global test gains power by robustly exploiting the Hardy-Weinberg equilibrium in the control population and effectively using linkage disequilibrium among test markers. The new global test reduces to PCR when the genotype for each marker is coded as the number of minor alleles. This connection lends insight into the power of the new global test relative to PCR and some other popular multimarker test methods. Second, we propose a robust test method based on the new global test and the ordinary PCR test built on a prospective score statistic for testing marginal associations with each single marker when the genotype for each marker is coded as the number of minor alleles by taking the minimum p value of these two tests. Finally, through extensive simulation studies and analysis of the association between pancreatic cancer and some genes of interest, we show that the proposed robust test method has desirable power and can often identify association signals that may be missed by existing methods. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the third most prevalent cancer in China but few large-scale studies were conducted to understand CRC patients. The current study is aimed to gain a real-world perspectives of CRC patients in China.Methods: Using electronic medical records of sampled patients between 2011 and 2016 from 12 hospitals in China, a retrospective cohort study was conducted to describe demographics and disease prognosis of CRC patients, and examine treatment sequences among metastatic CRC (mCRC) patients. Descriptive, comparative and survival analyses were conducted.Results: Among mCRC patients (3878/8136, 48%), the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most widely-used first-line treatment (42%). Fluorouracil, leucovorin, irinotecan (FOLFIRI) and other irinotecan-based regimens dominated the second-line (40%). There was no a dominated regimen for the third-line. The proportion of patients receiving chemotherapy with targeted biologics increased from less than 20% for the first- and second- lines to 34% for the third-line (p < 0.001). The most common sequence from first- to second-line was from FOLFOX and other oxaliplatin-based regimens to FOLFIRI and other irinotecan-based regimens (286/1200, 24%).Conclusions: Our findings reflected a lack of consensus on the choice of third-line therapy and limited available options in China. It is evident o continue promoting early CRC diagnosis and to increase the accessibility of treatment options for mCRC patients. As the only nationwide large-scale study among CRC and mCRC patients before more biologics became available in China, our results can also be used as the baseline to assess treatment pattern changes before and after more third-line treatment were approved and covered into the National Health Insurance Plan in China between 2017 and 2018. [ABSTRACT FROM AUTHOR]

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A two-dimensional position-sensitive microchannel plate detector, with a Ø100 mm sensitive area and equipped with four integrated amplifiers, is realized with a new anode scheme. The anode is constructed by two independent one-dimensional resistive anodes, each consisting of an array of parallel copper strips connected by resistors in series on a printed circuit board (PCB). The arrays are perpendicularly aligned to realize two-dimensional position resolution, with the intervals between the adjacent strips on the PCB nearer to the microchannel plate cut out to allow electrons passing through. The detector is tested with an 55Fe x-ray source, and a position resolution of 0.38 mm is achieved. [ABSTRACT FROM AUTHOR]

Background: The amino acid substitutions caused by ABO gene mutations are usually predicted to impact glycosyltransferase's function or its biosynthesis. Here we report an ABO exonic missense mutation that affects B-antigen expression by decreasing the mRNA level of the ABO gene rather than the amino acid change.Study Design and Methods: Serologic studies including plasma total GTB transfer capacity were performed. The exon sequences of the ABO gene were analyzed by Sanger sequencing. B310 cDNA with c.28G>A (p.G10R) mutation was expressed in HeLa cells and total GTB transfer capacity in cell supernatant was measured. Flow cytometry was performed on these HeLa cells after transfection, and agglutination of Hela-Bweak cells was also examined. The mRNA of the ABO gene was analyzed by direct sequencing and real-time reverse transcriptase-polymerase chain reaction. A minigene construct was prepared to evaluate the potential of splicing.Results: While plasma total GTB transfer capacity was undetectable in this B3 -like individual, the relative percentage of antigen-expressing cells and mean fluorescence index of the Bweak red blood cells (RBCs) were 19 and 14% of normal B RBCs, respectively. There was no significant difference of total GTB transfer capacity in cell supernatant and B-antigen expression on cell surfaces between HeLa cells transfected with B310 cDNA and B cDNA. The mRNA expression level of B310 in peripheral whole blood was significantly reduced. The amount of splicing is significantly lower in c.28G>A construct compared to that in wild-type construct after transfection in K562 cells.Conclusion: ABO c.28G>A mutation may cause B3 -like subgroup by affecting RNA splicing of the ABO gene. [ABSTRACT FROM AUTHOR]

The ABO phenotypes were determined by manual tube method and adsorption-elution test according to the standard methods.1 Monoclonal anti-A, anti-B, anti-H, anti-A SB 1 sb lectin ( I Dolichos biflorus) i , and ABO red blood cell kit (SHPBC, Shanghai, China) were used for blood group typing. ABO gene mutation c.815 816insG in an African individual forms a novel Ael allele The ABO system is the most important blood system in transfusion and transplantation medicine, and over 300 ABO subgroup alleles have been reported worldwide. [Extracted from the article]

Background: The prognostic value of epidermal growth factor receptor (EGFR) mutations in resected non-small cell lung cancer (NSCLC) remains controversial. We performed a systematic review with meta-analysis to assess its role. Methods: Studies were identified via an electronic search on PubMed, Embase and Cochrane Library databases. Pooled hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis. Results: There were 16 evaluated studies (n = 3337) in the meta-analysis. The combined HR evaluating EGFR mutations on disease free survival was 0.96 (95% CI [0.79–1.16] P = 0.65). The combined HR evaluating EGFR mutations on overall survival was 0.86 (95% CI [0.72–1.04] P = 0.12). The subgroup analysis based on univariate and multivariate analyses in DFS and OS showed no statistically significant difference. There was also no statistically significant difference in DFS and OS of stage I NSCLC patients. Conclusion: The systematic review with meta-analysis showed that EGFR mutations were not a prognostic factor in patients with surgically resected non-small cell lung cancer. Well designed prospective study is needed to confirm the result. [ABSTRACT FROM AUTHOR]

Background Identifying genetic variants of the ABO gene may reveal new biologic mechanisms underlying variant phenotypes of the ABO blood group. We report the molecular genetic analysis of 322 apparently unrelated ABO subgroup individuals in an estimated 2.1 million donors. Study Design and Methods We performed phenotype investigations by serology studies, analyzed the DNA sequence of the ABO gene by direct sequencing or sequencing after cloning, and evaluated promoter activity by reporter assays. Results In 62 rare ABO alleles, we identified 29 novel ABO subgroup alleles in 43 apparently unrelated subgroup individuals and their four available pedigrees. Of these alleles, one was a deletion-mutation allele, four were hybrid alleles, and 24 were point-mutation alleles. Most of the point mutations were detected in Exons 6 to 7, while several others were also detected in Exons 1 to 5 or splicing regions. One ABO promoter mutation, −35 to −18 del, was found and verified to reduce promoter activity, as determined by dual luciferase assays. Two mutations, 7 G> T and 52 C> T, carrying the premature terminal codons E3 X and R18 X in the 5′-region, were found to be associated with the very weak ABO subgroups ' Ael' and ' Bel.' Conclusion Twenty-nine ABO subgroup alleles were newly linked to different kinds of ABO variations. We provide the first evidence that promoter abnormality is involved in the formation of weak ABO phenotypes. We also described the first naturally occurring ABO alleles with premature terminal codons in the 5′-region that led to Ael and Bel phenotypes. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the pharmacokinetics of the prodrug, TH-302, and its active metabolite, bromo-IPM (Br-IPM), in nonclinical species. Methods: TH-302 was administered in single oral, intraperitoneal and intravenous bolus doses to mice, rats, dogs and monkeys as well as in acute and chronic safety studies in rats and dogs as a 30-min intravenous infusion given once a week for 3 weeks. Assessments were made using liquid chromatography-tandem mass spectrometry. Results: TH-302 was extensively distributed with high systemic clearance exceeding hepatic plasma flow in all species studied, resulting in half-lives ranging between 8 min (mice) and over 4 h (rats). In rats, TH-302 exhibited linear kinetics following intravenous administration and good oral bioavailability. In acute and chronic safety studies, there was no accumulation of TH-302 following once weekly dosing for 3 weeks in the rat and dog. Br-IPM plasma concentrations were a small fraction of the TH-302 plasma concentrations with significantly smaller percentages present in dogs than in rats. Allometric scaling predicted that the systemic clearance and steady-state volume of distribution in humans would be 38.8 l/h/m and 34.3 l/m, respectively, resulting in a terminal elimination half-life of about 36 min. These values were similar to those observed in patients with solid tumors (27.1 l/h/m, 23.5 l/m and 47 min). Conclusions: TH-302 exhibited good safety, efficacy and pharmacokinetic properties in nonclinical species, translating into favorable properties in humans. [ABSTRACT FROM AUTHOR]

The X-ray spectra of Nb surface induced by Ar q+ ( q = 16,17) ions with the energy range from 10 to 20 keV/q were studied by the optical spectrum technology. The experimental results indicate that the multi-electron excitation occurred as a highly charged Ar16+ ion was neutralized below the metal surface. The K shell electron of Ar16+ was excited and then de-excited cascadly to emit K X-ray. The intensity of the X-ray emitted from K shell of the hollow Ar atom decreased with the increase of projectile kinetic energy. The intensity of the X-ray emitted from L shell of the target atom Nb increased with the increase of projectile kinetic energy. The X-ray yield of Ar17+ is three magnitude orders larger than that of Ar16+. [ABSTRACT FROM AUTHOR]

In fMRI experiments on object representation in visual cortex, we designed two types of stimuli: one is the gray face image and its line drawing, and the other is the illusion and its corresponding completed illusion. Both of them have the same global features with different minute details so that the results of fMRl experiments can be compared with each other. The first kind of visual stimuli was used in a block design fMRI experiment, and the second was used in an event-related fMRI experiment. Comparing and analyzing interesting visual cortex activity patterns and blood oxygenation level dependent (BOLD)- fMRI signal, we obtained results to show some invariance of global features of visual images. A plausible explanation about the invariant mechanism is related with the cooperation of synchronized response to the global features of the visual image with a feedback of shape perception from higher cortex to cortex V1, namely the integration of global features and embodiment of sparse representation and distributed population code. [ABSTRACT FROM AUTHOR]

ABO subgroup is an important reason to cause ABO blood grouping discrepancy. Genomic analysis of I ABO i gene was performed and a mutation c.618C>G (p.Tyr206Ter) in I A i allele was found. According to the direct sequencing and cloning results, there was a heterozygote of I ABO*O.01.02 i and a novel I A i allele on the I ABO*A1.01 i with a mutation c.618C>G (Fig. [Extracted from the article]

Multiple electron transfer processes are studied for Ar q++Ne ( q=8, 9, 11, 12) collisions by using multi-parameter coincidence techniques. Various electron transfer processes are identified experimentally and the related cross-sections are measured. The dependence of transfer ionization cross-sections on the recoil charge states is compared with the results from the modified molecular classical overbarrier model. It is found that the modified model described the experimental results reasonably. [ABSTRACT FROM AUTHOR]

The coincidence experimental setup for studying multiple electron processes at low energies established at the Institute of Modern Physics was presented. The setup includes time-of-flight spectrometer, position sensitive detector, and multi-parameter data acquisition system. Presented were a TOF spectrum for Ar12+ on Ar collisions, a position spectrum obtained in O2+ + He collisions, and a two-dimension spectrum for Ar8+ + Ar collisions at 104 keV. The experimental results were analyzed in detail and 12 subprocesses were identified from the two-dimension spectrum. [ABSTRACT FROM AUTHOR]

Looks at some of the methods which are used to isolate clones which bind melanoma cells, while highlighting single-chain Fv fusion phage library. Origin of the phage library; Findings of studies conducted.

The K X-ray relative transition probabilities Kb/Ka of some elements for atomic numbers 23≤Z≤33 induced by 3 MeV protons were measured. The experimental results are compared with the relativistic Hartree-Fock (RHF) calculations. Good agreements have been obtained considering the experimental error. [ABSTRACT FROM AUTHOR]