Multi-omics analysis of DNA replication-associated primase polymerase (PRIMPOL) in pan-cancer: A potential target for prognosis and immune response

Background: It is critical to understand the mechanisms of human cancers in order to develop the effective anti-cancer therapeutic strategies. Recent studies indicated that primase polymerase (PRIMPOL) is strongly associated with the development of human cancers. Nevertheless, a systematic pan-cancer analysis of PRIMPOL remains to be further clarified. Method: Comprehensive multi-omics bioinformatics algorithms, such as TIMER2.0, GEPIA2.0 and cBioPortal, were utilized to evaluate the biological roles of PRIMPOL in pan-cancer, including the expression profiles, genomic alterations, prognostic values and immune regulation. Results: PRIMPOL was upregulated in glioblastoma multiforme and kidney renal clear cell carcinoma. The brain lower grade glioma patients with enhanced PRIMPOL expression displayed poor prognostic values. We also demonstrated the PRIMPOL's immunomodulating effects on pan-cancer as well as its genomic changes and methylation levels. The aberrant expression of PRIMPOL was linked to various cancer-associated pathways, including DNA damage response, DNA repair, and angiogenesis, according to single-cell sequencing and function enrichment. Conclusions: This pan-cancer analysis offers a thorough review of the functional roles of PRIMPOL in human cancers, suggesting PRIMPOL as a potentially important biomarker for the progression and immunotherapy of various cancers.</p

Longitudinal prediction of infant MR images with multi-contrast perceptual adversarial learning

The infant brain undergoes a remarkable period of neural development that is crucial for the development of cognitive and behavioral capacities (Hasegawa et al., 2018). Longitudinal magnetic resonance imaging (MRI) is able to characterize the developmental trajectories and is critical in neuroimaging studies of early brain development. However, missing data at different time points is an unavoidable occurrence in longitudinal studies owing to participant attrition and scan failure. Compared to dropping incomplete data, data imputation is considered a better solution to address such missing data in order to preserve all available samples. In this paper, we adapt generative adversarial networks (GAN) to a new application: longitudinal image prediction of structural MRI in the first year of life. In contrast to existing medical image-to-image translation applications of GANs, where inputs and outputs share a very close anatomical structure, our task is more challenging as brain size, shape and tissue contrast vary significantly between the input data and the predicted data. Several improvements over existing GAN approaches are proposed to address these challenges in our task. To enhance the realism, crispness, and accuracy of the predicted images, we incorporate both a traditional voxel-wise reconstruction loss as well as a perceptual loss term into the adversarial learning scheme. As the differing contrast changes in T1w and T2w MR images in the first year of life, we incorporate multi-contrast images leading to our proposed 3D multi-contrast perceptual adversarial network (MPGAN). Extensive evaluations are performed to assess the qualityand fidelity of the predicted images, including qualitative and quantitative assessments of the image appearance, as well as quantitative assessment on two segmentation tasks. Our experimental results show that our MPGAN is an effective solution for longitudinal MR image data imputation in the infant brain. We further apply our predicted/imputed images to two practical tasks, a regression task and a classification task, in order to highlight the enhanced task-related performance following image imputation. The results show that the model performance in both tasks is improved by including the additional imputed data, demonstrating the usability of the predicted images generated from our approach

Acclimation of photosystem II to high temperature in two Wedelia species from different geographical origins: implications for biological invasions upon global warming

More intense, more frequent, and longer heat waves are expected in the future due to global warming, which could have dramatic ecological impacts. However, few studies have involved invasive species. The aims of this study were to examine the effect of extreme heating (40/35°C for 30d) on the growth and photosynthesis of an alien invasive species Wedelia trilobata and its indigenous congener (Wedelia chinensis) in South China, and to determine the development of this invasive species and its potential adaptive mechanism. In comparison with W. chinensis, W. trilobata suffered less inhibition of the relative growth rate (RGR) and biomass production due to high temperature, which was consistent with the changes of photosystem II (PSII) activity and net photosynthetic rate (Pn). High temperature caused a partial inhibition of PSII, but the adverse effect was more severe in W. chinensis. Measurement of the minimum fluorescence (Fo) versus temperature curves showed that W. trilobata had a higher inflexion temperature of Fo (Ti), indicating greater thermostability of the photosynthetic apparatus. Moreover, comparisons of absorbed light energy partitioning revealed that W. trilobata increased xanthophyll-dependent thermal dissipation (ΦNPQ) under high temperature, while retaining the higher fraction of absorbed light allocated to photochemistry (ΦPSII) relative to W. chinensis. The results suggest that the invasive W. trilobata has a high thermostability of its photosynthetic apparatus and an effective regulating mechanism in energy partitioning of PSII complexes to minimize potential damage and to retain greater capability for carbon assimilation. These factors confer greater heat stress tolerance compared with the native species. Therefore, the invasive W. trilobata may become more aggressive with the increasingly extreme heat climates

Consecutive Slides on Axial View Is More Effective Than Transversal Diameter to Differentiate Mechanisms of Single Subcortical Infarctions in the Lenticulostriate Artery Territory

Objective: Lipohyalinosis or atherosclerosis might be responsible for single subcortical infarctions (SSIs); however, ways of differentiating between the two clinically remain uncertain. We aimed to investigate whether consecutive slides on axial view or transversal diameter is more effective to differentiate mechanisms by comparing their relationships with white matter hyperintensities (WMHs).Methods: All the participants from the Standard Medical Management in Secondary Prevention of Ischemic stroke in China (SMART) cohort who had SSIs in the lenticulostriate artery territory were included and categorized according to consecutive slides on axial view (≥4 consecutive slices or not) and transversal diameter (≥15 mm or not). The associations between the severity of WMHs and the different categories were analyzed.Results: Among the 3,821 patients of the SMART study, 281 had diffusion-weighted image-proven SSIs in the lenticulostriate artery territory. When classified by consecutive slides on axial view, SSIs on ≥4 slices were significantly associated with the severity of the WMHs, both in deep WMH (DWMH) (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.11–0.97; p = 0.04) and periventricular hyperintensity (PVH) (OR, 0.37; 95% CI, 0.17–0.78; p = 0.01). No such association was found on the basis of the transversal diameter (p &gt; 0.1).Conclusion: Consecutive slides on axial view (≥4 consecutive slices) might be more effective than transversal diameter to identify the atherosclerotic mechanisms of SSIs in the lenticulostriate artery territory.Clinical Trial Registration:http://www.clinicaltrials.gov. Unique identifier: NCT0066484

Amide proton transfer-weighted imaging of pediatric brainstem glioma and its predicted value for H3 K27 alteration

BACKGROUND: Non-invasive determination of H3 K27 alteration of pediatric brainstem glioma (pedBSG) remains a clinical challenge. PURPOSE: To predict H3 K27-altered pedBSG using amide proton transfer-weighted (APTw) imaging. MATERIAL AND METHODS: This retrospective study included patients with pedBSG who underwent APTw imaging and had the H3 K27 alteration status determined by immunohistochemical staining. The presence or absence of foci of markedly increased APTw signal in the lesion was visually assessed. Quantitative APTw histogram parameters within the entire solid portion of tumors were extracted and compared between H3 K27-altered and wild-type groups using Student's t-test. The ability of APTw for differential diagnosis was evaluated using logistic regression. RESULTS: Sixty pedBSG patients included 48 patients with H3 K27-altered tumor (aged 2-48 years) and 12 patients with wild-type tumor (aged 3-53 years). Visual assessment showed that the foci of markedly increased APTw signal intensity were more common in the H3 K27-altered group than in wild-type group (60% vs. 16%, P = 0.007). Histogram parameters of APTw signal intensity in the H3 K27-altered group were significantly higher than those in the wild-type group (median, 2.74% vs. 2.22%, P = 0.02). The maximum (area under the receiver operating characteristic curve [AUC] = 0.72, P = 0.01) showed the highest diagnostic performance among histogram analysis. A combination of age, median and maximum APTw signal intensity could predict H3 K27 alteration with a sensitivity of 81%, specificity of 75% and AUC of 0.80. CONCLUSION: APTw imaging may serve as an imaging biomarker for H3 K27 alteration of pedBSGs

Cluster-randomized, crossover trial of head positioning in acute stroke

The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. METHODS In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). RESULTS The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P\u3c0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P = 0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P = 0.83). There were no significant betweengroup differences in the rates of serious adverse events, including pneumonia. CONCLUSIONS Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours

Radio pulsations from a neutron star within the gamma-ray binary LS I +61° 303

LS I +61° 303 is one of the rare gamma-ray binaries that emit most of their luminosity in photons with energies beyond 100 MeV (ref. ). It is well characterized—the ~26.5 day orbital period is clearly detected at many wavelengths—and other aspects of its multifrequency behaviour make it the most interesting example of its class. The morphology of high-resolution radio images changes with orbital phase, displaying a cometary tail pointing away from the high-mass star component and LS I +61° 303 also shows superorbital variability. A couple of energetic (~10 erg s), short, magnetar-like bursts have been plausibly ascribed to it. Although the phenomenology of LS I +61° 303 has been the subject of theoretical scrutiny for decades, there has been a lack of certainty regarding the nature of the compact object in the binary that has hampered our understanding of the source. Here, using observations with the Five-hundred-meter Aperture Spherical radio Telescope, we report the existence of transient radio pulsations from the direction of LS I +61° 303 with a period P = 269.15508 ± 0.00016 ms at a significance of >20σ. These pulsations strongly argue for the existence of a rotating neutron star within LS I +61° 303.This work made use of the data from FAST. FAST is a Chinese national mega-science facility, operated by National Astronomical Observatories, Chinese Academy of Sciences. We acknowledge the use of the ATNF Pulsar Catalogue. S.-S.W. and B.-J.W. thank Z. Pan for discussions on the FAST data analysis. S.-S.W. thanks Z.-X. Wang, S.-N. Zhang and K. Lee for many valuable discussions. J.L., D.F.T. and A.P. acknowledge discussions with the international team on ‘Understanding and unifying the gamma rays emitting scenarios in high mass and low mass X-ray binaries’ of the ISSI (International Space Science Institute), Beijing. We acknowledge support from National Key R&D programme of China grant numbers 2017YFA0402602 and 2021YFA0718500, National SKA Program of China grant numbers 2020SKA0120100 and 2020SKA0120201, National Natural Science Foundation of China grant numbers U2038103, 11733009, U2031205, U1938109 and 11873032, the Youth Innovation Promotion Association of the CAS (grant id 2018075), the Chinese Academy of Sciences Presidential Fellowship Initiative 2021VMA0001, National Foreign Experts Program of Ministry of Science and Technology of the People’s Republic of China grant number G2021200001L and the International Visiting Professorship programme of the University of Science and Technology of China grant number 2021BVR05. S.-S.W. acknowledges financial support from the Jiangsu Qing Lan Project. D.F.T. also acknowledges grants PID2021-124581OB-I00, PGC2018-095512-B-I00 and Spanish programme Unidad de Excelencia ‘María de Maeztu’ grant number CEX2020-001058-M. A.P. acknowledges financial support from the Italian Space Agency (ASI) and National Institute for Astrophysics (INAF) under grant agreement numbers ASI-INAF I/037/12/0 and ASI-INAF n.2017-14-H.0, from INAF ’Sostegno alla ricerca scientifica main streams dell’INAF’, Presidential Decree 43/2018 and from PHAROS COST Action number 16214

Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness.

BACKGROUND: KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. METHODS: We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. RESULTS: KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. CONCLUSIONS: Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it may represent a novel target for biomarker development and a novel therapeutic target for breast cancer

Incorporation of a TGF-β2-inhibiting oligodeoxynucleotide molecular adjuvant into a tumor cell lysate vaccine to enhance antiglioma immunity in mice

IntroductionTransforming growth factor β2 (TGF-β2), also known as glioma-derived T-cell suppressor factor, is associated with the impairment of tumor immune surveillance. Therefore, blocking TGF-β2 signaling probably be a feasible strategy to develop a novel type of adjuvant for glioma vaccines to enhance antitumor immunity.MethodsA TGF-β2 inhibitory oligodeoxynucleotide, TIO3, was designed with sequences complementary to the 3' untranslated region of TGF-β2 mRNA. The expression of TGF-β2 and MHC-I was detected by qPCR, western and flow cytometry in vitro. All the percentage and activation of immune cells were detected by flow cytometry. Subsequently, TIO3 was formulated with Glioma cell lysate (TCL) and investigated for its antitumor effects in GL261 murine glioma prophylactic and therapeutic models.ResultsTIO3 could efficiently downregulate the expression of TGF-β2 while increase the MHC-I's expression in GL261 and U251 glioma cells in vitro. Meanwhile, TIO3 was detected in mice CD4+ T, CD8+ T, B and Ly6G+ cells from lymph nodes after 24 hours incubation. Moreover, TCL+TIO3 vaccination significantly prolonged the survival of primary glioma-bearing mice and protected these mice from glioma re-challenge in vivo. Mechanistically, TCL+TIO3 formulation strongly evoke the antitumor immune responses. 1) TCL+TIO3 significantly increased the composition of CD4+ and CD8+ T cells from draining lymph nodes while promoted their IFN-γ production and reduced the expression of TGF-β2 and PD1. 2) TCL+TIO3 activated the NK cells with the elevation of CD69 or NKG2D expression and PD1 reduction. 3) TCL+TIO3 increased the glioma-specific lysis CTLs from spleen. 4) TCL+TIO3 downregulated PD-L1 expression in glioma tissues and in Ly6G+ cells among glioma-infiltrating immune cells.ConclusionTIO3 is a promising adjuvant for enhancing TCL-based vaccines to produce a more vigorous and long-lasting antitumor response by interfering with TGF-β2 expression