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Exploring new strategies to manipulate the order parameter of magnetic materials by electrical means is of great importance not only for advancing our understanding of fundamental magnetism but also for unlocking potential applications. A well-established concept uses gate voltages to control magnetic properties by modulating the carrier population in a capacitor structure 1-5 . Here we show that, in Pt/Al/Fe/GaAs(001) multilayers, the application of an in-plane charge current in Pt leads to a shift in the ferromagnetic resonance field depending on the microwave frequency when the Fe film is sufficiently thin. The experimental observation is interpreted as a current-induced modification of the magnetocrystalline anisotropy ΔH A of Fe. We show that (1) ΔH A decreases with increasing Fe film thickness and is connected to the damping-like torque; and (2) ΔH A depends not only on the polarity of charge current but also on the magnetization direction, that is, ΔH A has an opposite sign when the magnetization direction is reversed. The symmetry of the modification is consistent with a current-induced spin 6-8 and/or orbit 9-13 accumulation, which, respectively, act on the spin and/or orbit component of the magnetization. In this study, as Pt is regarded as a typical spin current source 6,14 , the spin current can play a dominant part. The control of magnetism by a spin current results from the modified exchange splitting of the majority and minority spin bands, providing functionality that was previously unknown and could be useful in advanced spintronic devices., (© 2024. The Author(s).)

This paper proposes an advanced encryption standard (AES) cryptosystem based on memristive neural network. A memristive chaotic neural network is constructed by using the nonlinear characteristics of a memristor. A chaotic sequence, which is sensitive to initial values and has good random characteristics, is used as the initial key of AES grouping to realize "one-time-one-secret" dynamic encryption. In addition, the Rivest-Shamir-Adleman (RSA) algorithm is applied to encrypt the initial values of the parameters of the memristive neural network. The results show that the proposed algorithm has higher security, a larger key space and stronger robustness than conventional AES. The proposed algorithm can effectively resist initial key-fixed and exhaustive attacks. Furthermore, the impact of device variability on the memristive neural network is analyzed, and a circuit architecture is proposed., (© 2022. The Author(s).)

The gut microbiome is associated with diverse diseases 1-3 , but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 10 15 electronvolts) indicates the existence of the so-called PeVatrons-cosmic-ray factories that accelerate particles to PeV energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays 1 . The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref. 2 ). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane 3-6 , unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators.

Acute myeloid leukemia (AML) is a disease associated with epigenetic dysregulation. 11q23 translocations involving the H3K4 methyltransferase MLL1 (KMT2A) generate oncogenic fusion proteins with deregulated transcriptional potential. The polymerase-associated factor complex (PAFc) is an epigenetic co-activator complex that makes direct contact with MLL fusion proteins and is involved in AML, however, its functions are not well understood. Here, we explored the transcriptional targets regulated by the PAFc that facilitate leukemia by performing RNA-sequencing after conditional loss of the PAFc subunit Cdc73. We found Cdc73 promotes expression of an early hematopoietic progenitor gene program that prevents differentiation. Among the target genes, we confirmed the protein arginine methyltransferase Prmt5 is a direct target that is positively regulated by a transcriptional unit that includes the PAFc, MLL1, HOXA9 and STAT5 in leukemic cells. We observed reduced PRMT5-mediated H4R3me2s following excision of Cdc73 placing this histone modification downstream of the PAFc and revealing a novel mechanism between the PAFc and Prmt5. Knockdown or pharmacologic inhibition of Prmt5 causes a G1 arrest and reduced proliferation resulting in extended leukemic disease latency in vivo. Overall, we demonstrate the PAFc regulates Prmt5 to facilitate leukemic progression and is a potential therapeutic target for AMLs.

MRPL33 gene encodes a large mitoribosomal subunit protein, which may be involved in mitochondrial translation. Although two splice variants of MRPL33 have been described, its splicing regulation remains elusive. Here we observed that inclusion of alternative exon 3 was greatly promoted in a panel of human cancer cells. Depletion of the exon 3-containing long isoform of MRPL33 (MRPL33-L) led to impaired proliferation and increased apoptosis in cancer cell lines and in a xenograft model. MRPL33-L knockdown could also induce mitochondrial dysfunction including increased accumulation of reactive oxygen species, decreased ATP production and 16 S rRNA levels. We further showed that alternative splicing of MRPL33-L pre-mRNA is regulated by hnRNPK and that knocking down hnRNPK could phenocopy MRPL33-L depletion. More importantly, overexpression of MRPL33-L could increase tumorigenic potential of hnRNPK-depleted cancer cells, likely indicating that hnRNPK mediates tumorigenesis through splicing regulation of MRPL33 pre-mRNA. Finally, we found that inclusion of MRPL33 exon 3 was promoted in human colorectal cancer tissues and this was correlated with hnRNPK levels. In summary, our findings underscore the biological significance of MRPL33-L and hnRNPK in the tumor formation and identifies hnRNPK as a critical splicing regulator of MRPL33 pre-mRNA in cancer cells.

Current anti-epidermal growth factor receptor (EGFR) therapy for oral cancer does not provide satisfactory efficacy due to drug resistance or reduced EGFR level. As an alternative candidate target for therapy, here we identified an oncogene, ROS1, as an important driver for oral squamous cell carcinoma (OSCC) metastasis. Among tumors from 188 oral cancer patients, upregulated ROS1 expression strongly correlated with metastasis to lung and lymph nodes. Mechanistic studies uncover that the activated ROS1 results from highly expressed ROS1 gene instead of gene rearrangement, a phenomenon distinct from other cancers. Our data further reveal a novel mechanism that reduced histone methyltransferase EZH2 leads to a lower trimethylation of histone H3 lysine 27 suppressive modification, relaxes chromatin, and promotes the accessibility of the transcription factor STAT1 to the enhancer and the intron regions of ROS1 target genes, CXCL1 and GLI1, for upregulating their expressions. Down-regulation of ROS1 in highly invasive OSCC cells, nevertheless, reduces cell proliferation and inhibits metastasis to lung in the tail-vein injection and the oral cavity xenograft models. Our findings highlight ROS1 as a candidate biomarker and therapeutic target for OSCC. Finally, we demonstrate that co-targeting of ROS1 and EGFR could potentially offer an effective oral cancer therapy.

The attachment of cell-surface carbohydrates to proteins mediated by the amino acids serine or threonine (O-glycan) is involved in tumor metastasis; the roles of O-glycans vary depending on their structure, but the detailed mechanisms by which O-glycans trigger signaling to control tumor metastasis are largely unknown. In this study, we found that the reduced expression of core 3 synthase correlated with metastasis to lymph nodes and distant organs, resulting in poor prognosis for colorectal cancer (CRC) patients. Mechanically, we revealed that mucin-type core 3 O-glycan was synthesized at the membrane-tethered MUC1 N terminus because of core 3 synthase expression in colon cancer cells. This further inhibited the translocation of MUC1-C to the nucleus, initiated p53 gene transcription that was dependent on the inhibition of MUC1-C nucleus translocation, activated p53-mediated miR-200c expression and resulted in mesenchymal-epithelial transition (MET). Inhibition of MUC1 via small interfering RNA (siRNA) in re-expressed core 3 synthase colon cancer cells further inhibited MUC1-C nucleus translocation, increased p53 and miR-200c expression, and enhanced MET. However, inhibition of p53 via siRNA or miR-200c via miR-200c inhibitor in re-expressed core 3 synthase colon cancer cells promoted the epithelial-mesenchymal transition (EMT) in a reversible manner. Core 3 synthase mRNA levels and the p53 mRNA levels or miR-200c levels in the colon cancerous samples were positively correlated. Our findings suggest a novel mechanism linking mucin-type core 3 O-glycan to the EMT-MET plasticity of CRC cells via MUC1/p53/miR-200c-dependent signaling cascade and shed light on therapeutic strategies to treat this malignancy.

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDH high sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDH low . Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDH high sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDH high sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.

Circular RNAs (circRNAs) represent a class of non-coding RNAs that are widely expressed in mammals. However, it is largely unknown about the function of human circRNAs and the roles of circRNAs in human oral squamous cell carcinomas (OSCC). Here we performed a comprehensive study of circRNAs in human OSCC using circRNA and mRNA microarrays, and identified many circRNAs that are differentially expressed between OSCC tissue and paired non-cancerous matched tissue. We further found a circRNA termed circRNA_100290 that served as a critical regulator in OSCC development. We discovered that circRNA_100290 was upregulated and co-expressed with CDK6 in OSCC tissue. Knockdown of circRNA_100290 decreased expression of CDK6 and inhibited proliferation of OSCC cell lines in vitro and in vivo. Via luciferase reporter assays, circRNA_100290 was observed to directly bind to miR-29 family members. Further EGFP/RFP reporter assays showed that CDK6 was the direct target of miR-29b. Taken together, we conclude that circRNA_100290 may function as a competing endogenous RNA to regulate CDK6 expression through sponging up miR-29b family members. Taken together, it indicates that circRNAs may exert regulatory functions in OSCC and may be a potential target for OSCC therapy.

Management of curable sexually-transmitted infections (STI) such as Chlamydia can be revolutionized by highly sensitive nucleic acid testing that is deployable at the point-of-care (POC). Here we report the development of a mobile nucleic acid amplification testing (mobiNAAT) platform utilizing a mobile phone and droplet magnetofluidics to deliver NAAT in a portable and accessible format. By using magnetic particles as a mobile substrate for nucleic acid capture and transport, fluid handling is reduced to particle translocation on a simple magnetofluidic cartridge assembled with reagents for nucleic acid purification and amplification. A mobile phone user interface operating in tandem with a portable Bluetooth-enabled cartridge-processing unit facilitates process integration. We tested 30 potentially Chlamydia trachomatis (CT)-infected patients in a hospital emergency department and confirmed that mobiNAAT showed 100% concordance with laboratory-based NAAT. Concurrent evaluation by a nontechnical study coordinator who received brief training via an embedded mobile app module demonstrated ease of use and reproducibility of the platform. This work demonstrates the potential of mobile nucleic acid testing in bridging the diagnostic gap between centralized laboratories and hospital emergency departments.

Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II-IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14-3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48-1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II-IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.

In insects, there is a considerable diversity in leg distribution on the body, including number, segmental arrangement, morphological identity and consequent function, but the genetic basis for these differences is not well understood. Here by positional cloning, we showed that a ~355 kb region, including Bombyx mori Ultrabithorax (BmUbx) and abdominal-A (Bmabd-A), was responsible for the silkworm mutant Kh-extra-crescents-like (E Kh -l) that displayed additional thoracic limb-like legs on the first abdominal segment (A1) and occasionally on the second abdominal segment (A2). We found that BmUbx gene was downregulated at both messenger RNA level and protein level in E Kh -l embryo, while its expression domain in the E Kh -l embryo was almost the same as that in the wild type. Whereas Bmabd-A was upregulated at both levels and was ectopically overexpressed on the supernumerary leg-bearing segments in E Kh -l. Compared with the previously reported E cs -l mutant in which increased expression of both BmUbx and Bmabd-A gave rise to ectopic proleg-like appendages on the same segments, we propose that overexpressed Bmabd-A gene is capable to promote the outgrowth of extra leg appendages on A1 and A2 segments, whereas BmUbx gene is required to specify accurate morphologies of the ectopic legs in a dosage-dependent manner in silkworm. These results provide insights into how these hox genes regulate the leg morphologic diversity on the same segments.

Retroviral vectors including lentiviral vectors are commonly used tools to stably express transgenes or RNA molecules in mammalian cells. Their utilities are roughly divided into two categories, stable overexpression of transgenes and RNA molecules, which requires maximal transduction efficiency, or functional selection with retrovirus (RV)-based libraries, which takes advantage of retroviral superinfection resistance. However, the dynamic features of RV-mediated transduction are not well characterized. Here, we engineered two murine stem cell virus-based retroviral vectors expressing dual fluorescence proteins and antibiotic markers, and analyzed virion production efficiency and virion stability, dynamic infectivity and superinfection resistance in different cell types, and strategies to improve transduction efficiency. We found that the highest virion production occurred between 60 and 72 h after transfection. The stability of the collected virion supernatant decreased by >60% after 3 days in storage. We found that RV infectivity varied drastically in the tested human cancer lines, while low transduction efficiency was partially overcome with increased virus titer, prolonged infection duration and/or repeated infections. Furthermore, we demonstrated that RV receptors PIT1 and PIT2 were lowly expressed in the analyzed cells, and that PIT1 and/or PIT2 overexpression significantly improved transduction efficiency in certain cell lines. Thus, our findings provide resourceful information for the optimal conditions of retroviral-mediated gene delivery.

The recombinant sTRAIL has been in clinical trial for various human malignancies. However, the half-life time of sTRAIL is very short, which might be an important factor influencing its clinical efficacy for cancer therapy. We previously reported the recombinant adeno-associated virus (AAV)-encoding sTRAIL 95-281 -mediated sTRAIL expression in vivo up to 8 months and suppressed tumor growth markedly in mouse xenografts. In the present study, we further evaluated the clinical potency for cancer gene therapy and the safety in mouse and non-human primates. The mouse models with HCT-116, NCI-H460 and BEL-7402 cancers were injected intraperitoneally with a single dose of 1.0 × 10 11 , 1.0 × 10 10 and 1.0 × 10 9  vg of rAAV2-sTRAIL 95-281 virus, respectively. The cynomolgus monkeys were injected (i.m.) with a single dose of rAAV2-sTRAIL 95-281 of 1 × 10 11 , 3 × 10 11 and 1 × 10 12  vg, corresponding to 6-, 20- and 60-fold of intended use dosage for humans, respectively. The efficacy, pharmacology and toxicity of rAAV-sTRAIL in the animals were analyzed accordingly. The tumor inhibitory rates reached 44-76%, 48-52% and 55-74% in the three tumor models, respectively, and they had no influence on mouse spontaneous activity. Administration (s.c.) of a single dose of rAAV2-sTRAIL 95-281 virus of 1.0 × 10 9 or 1.0 × 10 10  vg in mice with implanted tumor led to mainly distribution in the spleen, liver, implanted tumor, blood, injected site of muscle and bone marrow. Two weeks later, there was no rAAV2-sTRAIL 95-281 detected in blood and bone marrow, and it significantly decreased in other tissues and organs and then gradually cleared away in 4-12 weeks after administration. There was no rAAV2-sTRAIL accumulation in the animal's body and no influence on the body weights. Administration (i.v.) did not cause animal death, and no dose-related abnormal clinical symptoms were found in the mice. There were no abnormal tissue and organ found in all animals. Long-term toxicity test in cynomolgus monkeys did not cause rAAV2-sTRAIL 95-281 -related toxic and side effects, except that anti-AAV and anti-sTRAIL antibodies were generated. In conclusion, these data demonstrated that administration of rAAV2-sTRAIL 95-281 in mice and in cynomolgus monkeys is safe without obvious toxic and side effects to the animals, and throw light on pharmacokinetics and safety in human clinical trials for cancer gene therapy.

Epigenetic regulators are attractive targets for the development of new cancer therapies. Among them, the ATP-dependent chromatin remodeling complexes control the chromatin architecture and have important roles in gene regulation. They are often found to be mutated and de-regulated in cancers, but how they influence the cancer gene expression program during cancer initiation and progression is not fully understood. Here we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC). Ino80, the SWI/SNF ATPase in the complex, is highly expressed in NSCLC cells compared with normal lung epithelia cells. Further, its expression, as well as that of another subunit Ino80B, negatively correlates with disease prognosis in lung cancer patients. Functionally, INO80 silencing inhibits NSCLC cell proliferation and anchorage-independent growth in vitro and tumor formation in mouse xenografts. It occupies enhancer regions near lung cancer-associated genes, and its occupancy correlates with increased genome accessibility and enhanced expression of downstream genes. Together, our study defines a critical role of INO80 in promoting oncogenic transcription and NSCLC tumorigenesis, and reveals a potential treatment strategy for inhibiting the cancer transcription network by targeting the INO80 chromatin remodeling complex.

Accumulative evidence demonstrated that mesenchymal stem cell (MSC) engraftment could protect tissue injury from ischemia/reperfusion (I/R). Hepatocyte growth factor (HGF) has important roles in the cell and tissue repairment and regeneration. Here we investigated the enhanced effects of HGF-modified MSCs on I/R-induced acute lung injury. Rat bone marrow-derived MSCs were successfully transfected to express HGF. HGF modification did not affect the characteristics of MSCs, and increased MSC viability, and inhibit the proinflammatory phenotype of MSCs in the inflammatory condition. In the rat model of I/R-induced lung injury, MSC-HGF engraftment attenuated lung wet-to-dry weight ratio, enhanced PaO 2 level and improved lung pathological injury, compared with MSC treatment. Moreover, the decreased acitivity of malondialdehyde, myeloperoxidase and tumor necrosis factor-α and increased superoxide dismutase content and interleukin-10 level were also observed in the MSC-HGF treatment, compared with the MSC group. Importantly, we found that HGF contributed to the survival of engrafted MSCs in the lung tissue through upregulation of Bcl-2 level and reduction of Caspase 3 activation. Thus our data show for the first time a clear beneficial effect of HGF gene modification on the survival of MSCs and enhanced improvement for I/R-induced lung injury.

In this paper, we demonstrate the temperature of lightning channel utilizing the theory of lightning spectra and the model of local thermodynamic equilibrium (LTE). The impulse current generator platform (ICGS) was used to simulate the lightning discharge channel, and the spectral energy of infrared spectroscopy (930 nm) and the visible spectroscopy (648.2 nm) of the simulated lightning has been calculated. Results indicate that the peaks of luminous intensity of both infrared and visible spectra increase with the lightning current intensity in range of 5-50 kA. Based on the results, the temperature of the lightning channel is derived to be 6140.8-10424 K. Moreover, the temperature of the channel is approximately exponential to the lightning current intensity, which shows good agreement with that of the natural lightning cases.

Inflammation has been shown to play a pivotal role in the pathogenesis and development of hypertensive vascular injury. Neopterin is a novel marker of immune activation produced mainly by activated macrophages. Few data are available to show the association between neopterin and vascular function in hypertension. The present study was designed to investigate the relationship between neopterin levels related to arterial stiffness and endothelial function in patients with hypertension, and their changes after blood pressure-lowering treatment. Twenty-four hypertensive patients and 30 age- and gender-matched healthy volunteers were recruited. Plasma neopterin levels were higher in hypertensive patients compared with their counterparts (log-neopterin: 0.77±0.18 versus 0.61±0.16, P=0.003). Increased neopterin levels were correlated with increased brachial-ankle pulse wave velocity (baPWV; control: r=0.659, P<0.001; hypertension: r=0.487, P=0.021), and inversely associated with impaired brachial flow-mediated dilation (FMD; control: r=-0.735, P<0.001; hypertension: r=-0.557, P=0.005). Fifteen hypertensives received 3 months of standard antihypertensive treatment. Three months later, their plasma neopterin levels decreased (log-neopterin: 0.63±0.17 versus 0.50±0.19, P=0.001), whereas arterial elasticity (baPWV: 1764±101 versus 1685±96 cm s(-1), P=0.272) and endothelial function (FMD: 5.92±1.43% versus 7.73±1.31%, P<0.05) were improved. The decline in neopterin levels was linearly correlated with baPWV decrease (r=0.800, P<0.001), FMD improvement (r=0.670, P=0.006) and blood pressure reduction (r=0.548, P=0.042). Our present study demonstrated for the first time that neopterin is closely correlated with vascular dysfunctions, and measurement of plasma neopterin levels might be used as a surrogate biomarker for the clinical evaluation of vascular damage and risk stratification of future atherosclerotic cardiovascular disease in patients with hypertension.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

Carrier-induced nature of ferromagnetism in a ferromagnetic semiconductor, (Ga,Mn)As, offers a great opportunity to observe novel spin-related phenomena as well as to demonstrate new functionalities of spintronic devices. Here, we report on low-temperature angle-resolved photoemission studies of the valence band in this model compound. By a direct determination of the distance of the split-off band to the Fermi energy EF we conclude that EF is located within the heavy/light hole band. However, the bands are strongly perturbed by disorder and disorder-induced carrier correlations that lead to the Coulomb gap at EF, which we resolve experimentally in a series of samples, and show that its depth and width enlarge when the Curie temperature decreases. Furthermore, we have detected surprising linear magnetic dichroism in photoemission spectra of the split-off band. By a quantitative theoretical analysis we demonstrate that it arises from the Dresselhaus-type spin-orbit term in zinc-blende crystals. The spectroscopic access to the magnitude of such asymmetric part of spin-orbit coupling is worthwhile, as they account for spin-orbit torque in spintronic devices of ferromagnets without inversion symmetry.

Background: Previous studies concerning the association between body mass index (BMI) and mortality in prostate cancer yielded mixed results. We investigated the association by performing a meta-analysis of all available studies., Methods: Relevant studies were identified by searching PubMed and EMBASE to August 2015. We calculated the summary hazard ratio (HR) and 95% confidence interval (CI) using random-effects models. We estimated combined HRs associated with defined increments of BMI, using random-effects meta-analysis and dose-response meta-regression models., Results: Thirty-seven cohort studies and one case-control study involving 27 38 000 patients of prostate cancer were selected for meta-analysis. The summary results indicated higher prediagnosis BMI but not postdiagnosis BMI was associated with increased risk of death from prostate cancer. An increment of every 5 kg/m(2) in prediagnosis BMI was associated with a 15% higher prostate cancer-specific mortality (HR=1.15, 95% CI: 1.07-1.23, P<0.01). Prediagnosis or postdiagnosis BMI showed no effect on all-cause mortality in prostate cancer patients., Conclusions: In conclusion, higher prediagnosis BMI is associated with a higher risk of death from prostate cancer. Considering the significant heterogeneity among included studies, these findings require confirmation in future studies.

Nude mice are important in vivo model for characterization of cell malignancy behavior; however, many cancer cells fail to form tumors in it. Understanding this defective mechanism may provide novel insights into tumorigenesis and how tumor cells escape innate immunity. Whole-genome sequencing was conducted on two gastric cancer (GC) cells, BGC823 and AGS, which do and do not form tumors in nude mice, to identify their genomic differences relevant to natural killer (NK) cells. We found that the tumorigenic capacity of human GC cell lines was dependent on the recruitment and activation of NK cells in xenograft tumors. We used whole-genome sequence (WGS) on GC cell lines to identify potential genes controlling susceptibility to NK-mediated killing. The tumorigenic cell line BGC823 expressed high levels of HLA-I because of copy gain and was resistant to NK cell killing. In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression. In human GC specimens, decreased HLA-I expression and increased NK cells surrounding tumor cells were correlated with decreased metastasis potential and better prognosis of patients. Our results provide a mechanistic basis for GC cells to escape NK lysis and a promising prospect of NK immunotherapy for GC cells.

Sustained activation of nuclear factor-κB (NF-κB) in cancer cells has been shown to promote inflammation, expansion of cancer stem cell (CSC) population, and tumor development. In contrast, recent studies reveal that CSCs exhibit increased inflammation due to constitutive NF-κB activation; however, the underlying molecular mechanism remains unclear. In the present study, the analysis of microarray data revealed upregulation of NF-κB-regulated pro-inflammatory genes and downregulation of copper metabolism MURR1 domain-containing 1 (COMMD1) during the enrichment for stemness in SAS head and neck squamous-cell carcinoma (HNSCC) cells. The 3'-UTR of COMMD1 mRNA contains microRNA (miR)-205 target site. Parallel studies with HNSCC and NSCLC cells indicated that miR-205 is upregulated upon NF-κB activation and suppresses COMMD1 expression in stemness-enriched cancer cells. COMMD1 negatively regulates the inflammatory responses induced by TLR agonists, IL-1β, and TNF-α by targeting RelA for degradation. The shRNA-mediated downregulation of COMMD1 in cancer cells enhanced inflammatory response, generating favorable conditions for macrophage recruitment. In addition, genes associated with stemness were also upregulated in these cells, which exhibited increased potential for anchorage-independent growth. Furthermore, COMMD1 downregulation promoted in vivo tumorigenesis and tumor growth, and tumors derived from COMMD1-knockdown cells displayed elevated level of NF-κB activation, increased expression of inflammatory- and stemness-associated genes, and contain expanded population of tumor-associated leukocytes and stemness-enriched cancer cells. These results suggest that COMMD1 downregulation by miR-205 promotes tumor development by modulating a positive feedback loop that amplifies inflammatory- and stemness-associated properties of cancer cells.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common problem with unclear etiology. Some diet and lifestyle factors were thought to correlate with CP/CPPS, but studies comprehensively investigate this correlation are rarely available. The current study was conducted to determine the potential lifestyle-related risk factors of CP/CPPS and its pain severity in Chinese population., Methods: Participants were recruited from seven hospitals in Shanghai from July 2012 to August 2013. Demographics, medical history, diet and lifestyle information, and CP/CPPS symptoms were obtained from each participant using a questionnaire. Univariate and multivariate logistic regression analyses were used to identify potential lifestyle-related risk factors for CP/CPPS and its pain severity., Results: A total of 784 men with CP/CPPS and 785 controls were enrolled in this study. Multivariate regression model indicated that age, nightshift work, stress, smoking status, alcohol consumption, less water intake, imbalanced diet, frequent sexual activity, delaying ejaculation and holding urine were identified as potential risk factors for CP/CPPS, whereas sedentary lifestyle, caffeinated drinks and less water intake were associated with severe pain in CP/CPPS patients., Conclusions: Several diet and lifestyle factors associated with CP/CPPS and pain severity were determined in this study. These modifiable conditions are potential targets for treatment of CP/CPPS. However, further studies are necessary to determine their role in the pathogenesis of CP/CPPS.

Phase transitions have been a research focus in many-body physics over past decades. Cold ions, under strong Coulomb repulsion, provide a repealing paradigm of exploring phase transitions in stable confinement by electromagnetic field. We demonstrate various conformations of up to sixteen laser-cooled (40)Ca(+) ion crystals in a home-built surface-electrode trap, where besides the usually mentioned structural phase transition from the linear to the zigzag, two additional phase transitions to more complicated two-dimensional configurations are identified. The experimental observation agrees well with the numerical simulation. Heating due to micromotion of the ions is analysed by comparison of the numerical simulation with the experimental observation. Our investigation implies very rich and complicated many-body behaviour in the trapped-ion systems and provides effective mechanism for further exploring quantum phase transitions and quantum information processing with ultracold trapped ions.

Hematopoietic cell transplantation (HCT) has become a standard treatment for many adult and pediatric conditions. Emerging evidence suggests that perturbations in the microbiota diversity increase recipients' susceptibilities to gut-mediated conditions such as diarrhea, infection and acute GvHD. Probiotics preserve the microbiota and may minimize the risk of developing a gut-mediated condition; however, their safety has not been evaluated in the setting of HCT. We evaluated the safety and feasibility of the probiotic, Lactobacillus plantarum (LBP), in children and adolescents undergoing allogeneic HCT. Participants received once-daily supplementation with LBP beginning on day -8 or -7 and continued until day +14. Outcomes were compliance with daily administration and incidence of LBP bacteremia. Administration of LBP was feasible with 97% (30/31, 95% confidence interval (CI) 83-100%) of children receiving at least 50% of the probiotic dose (median 97%; range 50-100%). We did not observe any case of LBP bacteremia (0% (0/30) with 95% CI 0-12%). There were not any unexpected adverse events related to LBP. Our study provides preliminary evidence that administration of LBP is safe and feasible in children and adolescents undergoing HCT. Future steps include the conduct of an approved randomized, controlled trial through Children's Oncology Group.

Cytosolic Ca(2+), closely related to endoplasmic reticulum (ER) Ca(2+), plays a critical role in regulating cell proliferation and tumorigenesis. However, the role of ER lumen proteins in regulating cytosolic Ca(2+) level remains poorly understood. Here, we find that the Cab45S, localizes in the ER lumen, inhibits sarco/ER Ca(2+)-ATPase 2b (SERCA2b) activity through its first EF-hand domain directly binding to the intra-lumenal loop 4 of SERCA2b, and reduces ER Ca(2+). STIM1 activation, induced by the Cab45S-dependent drop in ER Ca(2+), together with the upregulation of the plasma membrane Ca(2+) channel TRPC1 ultimately increases extracellular Ca(2+) influx. Furthermore, increased cytosolic Ca(2+) level elicits Ca(2+)-NFAT signaling and promotes cell proliferation. Consistently, in cervical carcinoma patients, Cab45S is upregulated. Thus, our data reveal that the ability of Cab45S to inhibit SERCA2b activity is crucial for its role as a modulator of cell proliferation and tumor growth.

The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout non-obese diabetic mice shares clinical and histological features with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Secondary axonal loss is prominent in the progressive phase of this neuropathy. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulates neurite outgrowth and myelination. The anti-inflammatory and immunomodulatory effects of NT-3 raised considerations of potential efficacy in the SAPP model that could be applicable to CIDP. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 25-week-old SAPP mice. Measurable NT-3 levels were found in the serum at 7-week postgene delivery. The outcome measures included functional, electrophysiological and histological assessments. At week 32, NT-3-treated mice showed increased hind limb grip strength that correlated with improved compound muscle action potential amplitude. Myelinated fiber density was 1.9 times higher in the NT-3-treated group compared with controls and the number of demyelinated axons was significantly lower. The remyelinated nerve fiber population was significantly increased. These improved histopathological parameters from scAAV1.tMCK.NT-3 treatment occurred in the setting of reduced sciatic nerve inflammation. Collectively, these findings suggest a translational application to CIDP.

Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD(+)) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD(+) promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD(+)-dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD(+) does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors.

We demonstrate a ytterbium (Yb) and an erbium (Er)-doped fiber laser Q-switched by a solution processed, optically uniform, few-layer tungsten disulfide saturable absorber (WS2-SA). Nonlinear optical absorption of the WS2-SA in the sub-bandgap region, attributed to the edge-induced states, is characterized by 3.1% and 4.9% modulation depths with 1.38 and 3.83 MW/cm(2) saturation intensities at 1030 and 1558 nm, respectively. By integrating the optically uniform WS2-SA in the Yb- and Er-doped laser cavities, we obtain self-starting Q-switched pulses with microsecond duration and kilohertz repetition rates at 1030 and 1558 nm. Our work demonstrates broadband sub-bandgap saturable absorption of a single, solution processed WS2-SA, providing new potential efficacy for WS2 in ultrafast photonic applications.

Epstein-Barr virus (EBV) causes human lymphoid malignancies, and the EBV product latent membrane protein 1 (LMP1) has been identified as an oncogene in epithelial carcinomas such as nasopharyngeal carcinoma (NPC). EBV can epigenetically reprogram lymphocyte-specific processes and induce cell immortalization. However, the interplay between LMP1 and the NPC host cell remains largely unknown. Here, we report that LMP1 is important to establish the Hox gene expression signature in NPC cell lines and tumor biopsies. LMP1 induces repression of several Hox genes in part via stalling of RNA polymerase II (RNA Pol II). Pol II stalling can be overcome by irradiation involving the epigenetic regulator TET3. Furthermore, we report that HoxC8, one of the genes silenced by LMP1, has a role in tumor growth. Ectopic expression of HoxC8 inhibits NPC cell growth in vitro and in vivo, modulates glycolysis and regulates the expression of tricarboxylic acid (TCA) cycle-related genes. We propose that viral latency products may repress via stalling key mediators that in turn modulate glycolysis.

Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival, and its overactivation drives cancer development. One important branch of EGFR signaling is through activation of GTPase Rac1, which further promotes cell proliferation, survival and cancer metastasis. Here, we show that EGFR activates Rac1 via inducing the accumulation of its specific guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (Tiam1) in non-small-cell lung cancer and colon cancer cells. Conversely, elevated Tiam1 is required for EGFR-induced tumorigenesis. In human lung adenocarcinoma and colon cancer specimens, Tiam1 expression strongly correlates with EGFR expression. We further reveal that AKT, a key downstream protein kinase of EGFR, phosphorylates Tiam1 at several consensus sites, facilitates the interaction of Tiam1 with scaffold proteins 14-3-3 and leads to an increase of Tiam1 stability. Subsequently, Tiam1 is dephosporylated and destabilized by PP2A. Together, our study identifies a bidirectional (phosphorylation and dephosphorylation) regulatory mechanism controlling Tiam1 stability and provides new insights on how EGFR signaling triggers Rac1 activation and cancer development.

The remarkable properties of graphene and transition metal dichalcogenides (TMDCs) have attracted increasing attention on two-dimensional materials, but the gate oxide, one of the key components of two-dimensional electronic devices, has rarely reported. We found the single-layer oxide can be used as the two dimensional gate oxide in 2D electronic structure, such as TiO2. However, the electrical performance is seriously influenced by the defects existing in the single-layer oxide. In this paper, a nondestructive and noncontact solution based on spectroscopic ellipsometry has been used to detect the defect states and energy level of single-layer TiO2 films. By fitting the Lorentz oscillator model, the results indicate the exact position of defect energy levels depends on the estimated band gap and the charge state of the point defects of TiO2.

Purpose: To study the correlation between glaucomatous visual field (VF) defects assessed by standard automated perimetry (SAP) and peripapillary retinal nerve fiber layer (RNFL) thinning measured by spectral domain optical coherence tomography (OCT) using a modified OCT-based peripapillary RNFL structure-function map., Patients and Methods: Perimetric glaucoma patients and age-matched normal control subjects were recruited from a university hospital clinic. All eyes underwent testing with the Spectralis spectral domain OCT and SAP on the same day. An OCT-based correspondence map, which correlated VF areas with peripapillary RNFL sectors was created to evaluate the relationship between glaucomatous RNFL thinning and VF loss in six nerve fiber layer bundle areas. Correlations of RNFL thinning with corresponding VF defects were examined using Spearman rank-order correlations. To demonstrate the association between localized VF defects and RNFL thickness, the theoretical curves were made according to an established log-linear model. The measured RNFL thickness values and VF defects were presented in the same scatterplot for each sector., Results: Fifty-six glaucoma patients and 85 normal subjects were included in the study. Significant association between localized VF loss and RNFL thinning was found in corresponding areas. Data from the current study fit well with established log-linear models, which compare RNFL thickness values with VF defects., Conclusion: Analysis of RNFL thinning in eyes with localized glaucomatous VF defects showed good structure-function correlation in a new OCT-based structure-function correspondence map.

Extracellular proteins are vital for cell activities, such as cell migration. Calumenin is highly conserved among eukaryotes, but its functions are largely unclear. Here, we identify extracellular calumenin as a suppressor of cell migration and tumor metastasis. Calumenin binds to and stabilizes fibulin-1, leading to inactivation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling. We further identify the minimal functional domain of calumenin (amino acids 74-138 and 214-280). Depletion of calumenin induces fibulin-1- and phospho-ERK1/2 (pERK1/2)-dependent promotion of cell migration. Consistently, in hepatocellular and pancreatic carcinoma, both calumenin and fibulin-1 are downregulated. Furthermore, we show that matrix metalloproteinase-13 (MMP-13) proteolyzes fibulin-1 and that calumenin protects fibulin-1 from cleavage by MMP-13. Calumenin, together with fibulin-1, also interacts with fibronectin and depends on both syndecan-4 and α5β1-integrin to suppress ERK1/2 signaling and inhibit cell migration. Thus, extracellular calumenin regulates fibulin-1 to have crucial roles in ERK1/2 signaling and cell migration.

Identification of the genes that are differentially expressed between radiosensitive and radioresistant cancers by global gene analysis may help to elucidate the mechanisms underlying tumor radioresistance and improve the efficacy of radiotherapy. An integrated analysis was conducted using publicly available GEO datasets to detect differentially expressed genes (DEGs) between cancer cells exhibiting radioresistance and cancer cells exhibiting radiosensitivity. Gene Ontology (GO) enrichment analyses, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) networks analysis were also performed. Five GEO datasets including 16 samples of radiosensitive cancers and radioresistant cancers were obtained. A total of 688 DEGs across these studies were identified, of which 374 were upregulated and 314 were downregulated in radioresistant cancer cell. The most significantly enriched GO terms were regulation of transcription, DNA-dependent (GO: 0006355, P=7.00E-09) for biological processes, while those for molecular functions was protein binding (GO: 0005515, P=1.01E-28), and those for cellular component was cytoplasm (GO: 0005737, P=2.81E-26). The most significantly enriched pathway in our KEGG analysis was Pathways in cancer (P=4.20E-07). PPI network analysis showed that IFIH1 (Degree=33) was selected as the most significant hub protein. This integrated analysis may help to predict responses to radiotherapy and may also provide insights into the development of individualized therapies and novel therapeutic targets.

Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.

Constitutive heterochromatin (HC) is important for maintaining chromosome stability, but also delays the repair of DNA double-strand breaks (DSBs). DSB repair in complex mammalian genomes involves a fast phase (2-6 h) in which most of the breaks are rapidly repaired, and a slow phase (up to 24 h) in which the remaining damages in HC are repaired. We found that p53 deficiency delays the slow-phase DNA repair after ionizing irradiation. p53 deficiency prevents downregulation of histone H3K9 trimethylation at the pericentric HC after DNA damage. Moreover, p53 directly induces expression of the H3K9 demethylase Jumonji domain 2 family demethylase (JMJD2b) through promoter binding. The p53 activation also indirectly downregulates expression of the H3K9 methyltransferase SUV39H1. Depletion of JMJD2b or sustained expression of SUV39H1 delays the repair of HC DNA and reduces clonogenic survival after ionizing irradiation. The results suggest that by regulating JMJD2b and SUV39H1 expression, p53 not only controls transcription but also promotes HC relaxation to accelerate a rate-limiting step in the repair of complex genomes.

Previous studies have demonstrated that microRNA (miRNA) expression is altered in human cancer. However, the molecular mechanism underlying these changes in miRNA expression remains unclear. In this study, we investigated the epigenetic modification of miR-124 genes and the potential function of miR-124 in pancreatic cancer. Using pyrosequencing analysis, we found that miR-124 genes (including miR-124-1, miR-124-2 and miR-124-3) are highly methylated in pancreatic cancer tissues compared with in non-cancerous tissues. Hypermethylation mediated the silencing of miR-124, which was a frequent event in pancreatic duct adenocarcinoma (PDAC). Furthermore, miR-124 downregulation was significantly associated with worse survival of PDAC patients. Functional studies showed that miR-124 inhibited cell proliferation, invasion and metastasis. Furthermore, we characterized Rac1 as a direct target of miR-124, and miR-124 interacted with the 3'-untranslated region of Rac1, which we showed to be a putative tumor promoter in pancreatic cancer. Thus, the miR-124-mediated downregulation of Rac1 led to the inactivation of the MKK4-JNK-c-Jun pathway. Therefore, our study demonstrates that miR-124 is a tumor suppressor miRNA that is epigenetically silenced in pancreatic cancer. Our findings suggest a previously unidentified molecular mechanism involved in the progression and metastasis of pancreatic cancer.

Recent analysis of satellite data obtained during the 9 October 2012 geomagnetic storm identified the development of peaks in electron phase space density, which are compelling evidence for local electron acceleration in the heart of the outer radiation belt, but are inconsistent with acceleration by inward radial diffusive transport. However, the precise physical mechanism responsible for the acceleration on 9 October was not identified. Previous modelling has indicated that a magnetospheric electromagnetic emission known as chorus could be a potential candidate for local electron acceleration, but a definitive resolution of the importance of chorus for radiation-belt acceleration was not possible because of limitations in the energy range and resolution of previous electron observations and the lack of a dynamic global wave model. Here we report high-resolution electron observations obtained during the 9 October storm and demonstrate, using a two-dimensional simulation performed with a recently developed time-varying data-driven model, that chorus scattering explains the temporal evolution of both the energy and angular distribution of the observed relativistic electron flux increase. Our detailed modelling demonstrates the remarkable efficiency of wave acceleration in the Earth's outer radiation belt, and the results presented have potential application to Jupiter, Saturn and other magnetized astrophysical objects.

The current-induced motion of magnetic domain walls (DWs) confined to nanostructures is of great interest for fundamental studies as well as for technological applications in spintronic devices. Here, we present magnetic images showing the depinning properties of pulse-current-driven domain walls in well-shaped Permalloy nanowires obtained using photoemission electron microscopy combined with x-ray magnetic circular dichroism. In the vicinity of the threshold current density (Jth = 4.2 × 10(11) A.m(-2)) for the DW motion, discontinuous DW depinning and motion have been observed as a sequence of "Barkhausen jumps". A one-dimensional analytical model with a piecewise parabolic pinning potential has been introduced to reproduce the DW hopping between two nearest neighbour sites, which reveals the dynamical nature of the current-driven DW motion in the depinning regime.

Telomerase activation through induction of telomerase reverse transcriptase (hTERT) contributes to malignant transformation by stabilizing telomeres. Clinical studies demonstrate that higher hTERT expression is associated with cancer progression and poor outcomes, but the underlying mechanism is unclear. Because epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are key factors in cancer metastasis and relapse, and hTERT has been shown to exhibit multiple biological activities independently of its telomere-lengthening function, we address a potential role of hTERT in EMT and CSCs using gastric cancer (GC) as a model. hTERT overexpression promotes, whereas its inhibition suppresses, EMT and stemness of GC cells, respectively. Transforming growth factor (TGF)-β1 and β-catenin-mediated EMT was abolished by small interfering RNA depletion of hTERT expression. hTERT interacts with β-catenin, enhances its nuclear localization and transcriptional activity, and occupies the β-catenin target vimentin promoter. All these hTERT effects were independent of its telomere-lengthening function or telomerase activity. hTERT and EMT marker expression correlates positively in GC samples. Mouse experiments demonstrate the in vivo stimulation of hTERT on cancer cell colonization. Collectively, hTERT stimulates EMT and induces stemness of cancer cells, thereby promoting cancer metastasis and recurrence. Thus, targeting hTERT may prevent cancer progression by inhibiting EMT and CSCs.

Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous MCA205 sarcomas in vivo. Optimal antitumor efficacy of mDC.Tbet-based gene therapy was dependent on host natural killer (NK) cells and CD8(+) T cells, and required mDC.Tbet expression of major histocompatibility complex class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce proinflammatory cytokines (interleukin-12 family members or interferon-γ) or to migrate to tumor-draining lymph nodes based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3(-/-)) deficiency in host antigen-crosspresenting DC did not diminish the therapeutic action of intratumorally delivered wild-type mDC.Tbet. Interestingly, we observed that intratumoral delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naive CD45RB(+) T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T-cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after intratumoral delivery of mDC.Tbet-based gene therapy.

Tumor metastasis is responsible for most cancer patients' deaths. Understanding the mechanism of metastasis is crucial for improving the cure rate for cancer. Here, we report that Gankyrin, a chaperone of ubiquitin-proteasome, has an essential role in breast cancer metastasis. We find that Gankyrin is highly overexpressed in human breast cancers and the expression correlates strongly with lymph node metastasis. Knocking down Gankyrin expression in highly metastatic human breast cancer cells significantly decreases cancer cell migration and invasion. Furthermore, we demonstrate that depletion of Gankyrin inhibits intrinsic Rac1 activity and induces large focal adhesions. Overexpression of Gankyrin accelerates focal adhesion turnover and increases cell migration. Notably, reduction of Gankyrin expression in mouse mammary tumor cell significantly decreases tumor metastasis to lung in animal models. Therefore, our findings suggest that Gankyrin is crucial for breast cancer metastasis and highlight the potential of Gankyrin as a therapeutic target for tumor metastasis.

As the consequence of complex interactions between different parts of an organ, shape can be used as a predictor of structural-functional relationships implicated in changing environments. Despite such importance, however, it is no surprise that little is known about the genetic detail involved in shape variation, because no approach is currently available for mapping quantitative trait loci (QTLs) that control shape. Here, we address this problem by developing a statistical model that integrates the principle of shape analysis into a mixture-model-based likelihood formulated for QTL mapping. One state-of-the-art approach for shape analysis is to identify and analyze the polar coordinates of anatomical landmarks on a shape measured in terms of radii from the centroid to the contour at regular intervals. A procrustes analysis is used to align shapes to filter out position, scale and rotation effects on shape variation. To the end, the accurate and quantitative representation of a shape is produced with aligned radius-centroid-contour (RCC) curves, that is, a function of radial angle at the centroid. The high dimensionality of the RCC data, crucial for a comprehensive description of the geometric feature of a shape, is reduced by principal component (PC) analysis, and the resulting PC axes are treated as phenotypic traits, allowing specific QTLs for global and local shape variability to be mapped, respectively. The usefulness and utilization of the new model for shape mapping in practice are validated by analyzing a mapping data collected from a natural population of poplar, Populus szechuanica var tibetica, and identifying several QTLs for leaf shape in this species. The model provides a powerful tool to compute which genes determine biological shape in plants, animals and humans.

The aim of this study is to evaluate clinical benefits of recombinant adenoviral human p53 (rAd-p53) gene therapy combined with radiotherapy in prevention of oral cancer recurrence after a radical resection. A total of 51 patients with tongue cancer (TCa) and 56 patients with gingival carcinoma (GCa) satisfying the inclusion criteria were randomly assigned to two groups: the experiment group (EG) and the control group (CG). The EG group received multipoint injections of rAd-p53 into the surgical wound surface at a dose of 1 × 10¹² viral particles after a radical resection. Patients in both EG and CG were given radiotherapy at a total dose of 60 Gy at 3 weeks after surgery. All these patients were followed up for at least 3 years. Two cases (2/27) of TCa and 2 (2/30) in GCa patients had a local recurrence in EG, but 8 (8/24) TCa and 8 (8/26) GCa patients in CG had a local recurrence. Both recurrent rates of TCa (33.3%) and GCa (30.8%) in CG are statistically significantly higher than those of TCa (7.4%) and GCa (6.7%) in EG, respectively. The overall recurrent rate in EG is 7%, which is also statistically significantly lower than that (32%) in CG. The 3-year overall survival (OS) rate and 3-year disease-free survival (DFS) rate of EG is 100% and 93%, respectively. The 3-year OS and DFS rates of CG are 94 and 68%, respectively. Mild or medium fever and flu-like symptoms were more frequently observed in EG and were considered to be associated with application of rAd-p53. Post-tumorectomy wound surface injection of rAd-p53 combining with radiotherapy is a safe and effective regimen for the patients with TGa or GCa.

The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.

Purpose: The purpose of this study was to review the microbiological profile, in vitro antibiotic susceptibility and visual outcomes of paediatric microbial keratitis in Shanghai, China over the past 6 years., Methods: Medical records of patients aged ≤16 years were reviewed, who were diagnosed as having bacterial keratitis between 1 January 2005 and 31 December 2010. Bacterial culture results and in vitro antibiotic susceptibility were analysed. A logistic regression analysis was conducted to evaluate the relationship between visual impairment and possible risk factors., Results: Eighty consecutive cases of paediatric bacterial keratitis cases were included, among which 59 were identified as having positive culture. Staphylococcus epidermidis was the most commonly isolated organism (n=23; 39.0%), followed by Streptococcus pneumoniae (n=11; 18.6%) and Pseudomonas aeruginosa (n=6; 10.2%). Antibiotic sensitivities revealed that tested bacteria had low resistance rates to fluoroquinolones and aminoglycosides (8.3-18.4% and 12.5-24.4%, respectively). Multivariate logistic regression analysis proved that visual impairment was significantly associated with Gram-negative bacterial infection (odds ratio (OR)=7.626; P=0.043) and an increasing number of resistant antibiotics (OR=0.385; P=0.040)., Conclusions: S. epidermidis was the most common isolated organism in Shanghai paediatric keratitis. The fluoroquinolones and aminoglycosides remained good choices for treating these patients. Gram-negative bacterial infection and an increasing number of resistant antibiotics were associated with worse visual prognoses in paediatric keratitis.