Dual blockage of STAT3 and ERK1/2 eliminates radioresistant GBM cells.

Radiotherapy (RT) is the major modality for control of glioblastoma multiforme (GBM), the most aggressive brain tumor in adults with poor prognosis and low patient survival rate. To improve the RT efficacy on GBM, the mechanism causing tumor adaptive radioresistance which leads to the failure of tumor control and lethal progression needs to be further elucidated. Here, we conducted a comparative analysis of RT-treated recurrent tumors versus primary counterparts in GBM patients, RT-treated orthotopic GBM tumors xenografts versus untreated tumors and radioresistant GBM cells versus wild type cells. The results reveal that activation of STAT3, a well-defined redox-sensitive transcriptional factor, is causally linked with GBM adaptive radioresistance. Database analysis also agrees with the worse prognosis in GBM patients due to the STAT3 expression-associated low RT responsiveness. However, although the radioresistant GBM cells can be resensitized by inhibition of STAT3, a fraction of radioresistant cells can still survive the RT combined with STAT3 inhibition or CRISPR/Cas9-mediated STAT3 knockout. A complementally enhanced activation of ERK1/2 by STAT3 inhibition is identified responsible for the survival of the remaining resistant tumor cells. Dual inhibition of ERK1/2 and STAT3 remarkably eliminates resistant GBM cells and inhibits tumor regrowth. These findings demonstrate a previously unknown feature ofSTAT3-mediated ERK1/2 regulation and an effective combination of two targets in resensitizing GBM to RT

Microstructure and superelastic properties of FeNiCoAlTi single crystals with the <100> orientation under tension

The microstructure and superelastic response of an Fe41 Ni28 Co17 Al11.5 Ti2.5 (at.%) single crystal along the [removed] orientation was investigated under tension at room temperature after aging at 600◦ C for 24 h. From the superelastic results, the samples aged at 600◦ C for 24 h exhibited 4.5% recoverable strain at room temperature. The digital image correlation (DIC) method was used to observe the strain distribution during the 6.5% applied strain loading. The DIC results showed that the strain was uniformly distributed during the loading and unloading cycles. Only one martensite variant was observed from the DIC results. This was related to the aging heat treatment times. The martensite morphology became a single variant with a longer aging time. The thermo-magnetization results indicated that the phase transformation and temperature hysteresis was around 36◦ C. Increasing the magnetic field from 0.05 to 7 Tesla, the transformation temperatures increased. The maximum magnetization was 160 emu/g under the magnetic field of 7 Tesla. From the transmission electron microscopy results, the L12 precipitates were around 10 nm in size, and they were high in Ni content and low in Fe content

Coexistence of multiuser entanglement distribution and classical light in optical fiber network with a semiconductor chip

Building communication links among multiple users in a scalable and robust way is a key objective in achieving large-scale quantum networks. In realistic scenario, noise from the coexisting classical light is inevitable and can ultimately disrupt the entanglement. The previous significant fully connected multiuser entanglement distribution experiments are conducted using dark fiber links and there is no explicit relation between the entanglement degradations induced by classical noise and its error rate. Here we fabricate a semiconductor chip with a high figure-of-merit modal overlap to directly generate broadband polarization entanglement. Our monolithic source maintains polarization entanglement fidelity above 96% for 42 nm bandwidth with a brightness of 1.2*10^7 Hz/mW. We perform a continuously working quantum entanglement distribution among three users coexisting with classical light. Under finite-key analysis, we establish secure keys and enable images encryption as well as quantum secret sharing between users. Our work paves the way for practical multiparty quantum communication with integrated photonic architecture compatible with real-world fiber optical communication network

Development of a prognostic model to identify the metastatic nasopharyngeal carcinoma patients who may benefit from chemotherapy combination PD-1 inhibitor

BackgroundWe aimed to establish a prognostic model to identify suitable candidates for chemotherapy combination PD-1 inhibitor in metastatic nasopharyngeal carcinoma (NPC) patients.Patients and methodsIn this retrospective study, we included 524 patients (192 patients treated with chemotherapy combination PD-1 inhibitor and 332 received chemotherapy alone as first-line regimen) with metastatic NPC between January 2015 and March 2021. We developed a prognostic model to predict progression-free survival (PFS). A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores and two well-matched risk groups (low-risk and high-risk) were created using propensity score matching.ResultsA prognostic nomogram was established with good accuracy for predicting PFS (c-index values of 0.71; 95% confidence interval, 0.66-0.73). The survival curves were significantly different between low-risk and high-risk groups (median PFS: 9.8 vs. 22.8 months, P &lt; 0.001, respectively). After propensity matching analysis, chemotherapy combination PD-1 inhibitor was significantly associated with superior PFS as compared with chemotherapy alone (median PFS, 10.6 versus 9.3 months, P = 0.016) in the high-risk group. However, no significant difference between chemotherapy combination PD-1 inhibitor and chemotherapy was observed (P = 0.840) in the low-risk groups.ConclusionsOur novel prognostic model was able to stratify patients with metastatic NPC into low-risk or high-risk groups and identify candidates for PD-1 inhibitor therapy. These results are expected to be confirmed by a prospective clinical trial

Exploiting Magnetic Resonance Angiography Imaging Improves Model Estimation of BOLD Signal

The change of BOLD signal relies heavily upon the resting blood volume fraction () associated with regional vasculature. However, existing hemodynamic data assimilation studies pretermit such concern. They simply assign the value in a physiologically plausible range to get over ill-conditioning of the assimilation problem and fail to explore actual . Such performance might lead to unreliable model estimation. In this work, we present the first exploration of the influence of on fMRI data assimilation, where actual within a given cortical area was calibrated by an MR angiography experiment and then was augmented into the assimilation scheme. We have investigated the impact of on single-region data assimilation and multi-region data assimilation (dynamic cause modeling, DCM) in a classical flashing checkerboard experiment. Results show that the employment of an assumed in fMRI data assimilation is only suitable for fMRI signal reconstruction and activation detection grounded on this signal, and not suitable for estimation of unobserved states and effective connectivity study. We thereby argue that introducing physically realistic in the assimilation process may provide more reliable estimation of physiological information, which contributes to a better understanding of the underlying hemodynamic processes. Such an effort is valuable and should be well appreciated

Novel Neuroprotective Mechanisms of Memantine: Increase in Neurotrophic Factor Release from Astroglia and Anti-Inflammation by Preventing Microglial Activation

Memantine provides clinically relevant efficacy in patients with Alzheimer's disease and Parkinson’s diseases. In addition to blockade of N-methyl-D-aspartate receptor on neurons, memantine has neurotrophic and neuroprotective effects in in vivo and in vitro studies, however, the mechanism underlying these effects remains unclear. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminegic neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on dopaminergic neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia-dependent, since memantine failed to show any positive effect on dopaminergic neurons in neuron-enriched cultures. More specifically, it appears that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of GDNF. Mechanistic studies revealed that GDNF upregulaton was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced dopaminergic neuronal damage through its inhibition of microglia over-activation revealed by both OX-42 immunostaining and by the reduction of pro-inflammatory factors production such as extracelluar superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E2, and tumor necrosis factor-α. These results suggest that memantine therapy for neurodegenerative diseases acts in part through alternative novel mechanisms by reducing microglia-associated inflammation and stimulating the release of neurotrophic factors from astroglia

Fourteen-day vonoprazan and low- or high-dose amoxicillin dual therapy for eradicating Helicobacter pylori infection: A prospective, open-labeled, randomized non-inferiority clinical study

Background and aimWe previously reported that vonoprazan-amoxicillin (VA) dual therapy for 7 or 10 days is not satisfactorily efficacious for Helicobacter pylori (H. pylori) eradication. We aimed to explore the efficacy of VA dual therapy for 14 days as a first-line treatment for H. pylori infection.MethodsThis was a single center, prospective, open-labeled, randomized non-inferiority clinical study conducted in China. Treatment naïve H. pylori infected patients were randomized into two groups: 20 mg vonoprazan (VPZ) b.i.d. in combination with low-dose (1000 mg b.i.d.) or high-dose (1000 mg t.i.d) amoxicillin for 14 days. 13C-urea breath tests were used to access the cure rate at least 4 weeks after treatment.ResultsA total of 154 patients were assessed and 110 subjects were randomized. The eradication rate of VPZ with b.i.d. amoxicillin or t.i.d. amoxicillin for 14 days was 89.1% and 87.3% by intention-to-treat analysis, respectively, and 94.1% and 95.9% by per-protocol analysis, respectively. The eradication rate and incidence of adverse events were not different between the two groups.ConclusionVPZ with b.i.d. or t.i.d. amoxicillin for 14 days provides satisfactory efficacy as a first-line treatment for H. pylori infection in China

Does tea consumption during early pregnancy have an adverse effect on birth outcomes?

Background Tea, a common beverage, has been suggested to exhibit a number of health benefits. However, one of its active ingredients, caffeine, has been associated with preterm birth and low birthweight. We investigated whether tea consumption during early pregnancy is associated with an increased risk of preterm birth and abnormal foetal growth. Methods A total of 8775 pregnant women were included from the Born in Guangzhou Cohort Study. Tea consumption (type, frequency and strength) during their first trimester and social and demographic factors were obtained via questionnaires administered during pregnancy. Information on birth outcomes and complications during pregnancy was obtained from hospital medical records. Results Overall habitual tea drinking (≥1 serving/week) prevalence among pregnant women was low, at 16%. After adjustment for potential confounding factors (e.g. maternal age, educational level, monthly income) tea drinking during early pregnancy was not associated with an increased risk of preterm birth, small or large for gestational age (p>0.05). Conclusions We did not identify a consistent association between frequency of tea consumption or tea strength and adverse birth outcomes among Chinese pregnant women with low tea consumption. Our findings suggest that occasional tea drinking during pregnancy is not associated with increased risk of preterm birth or abnormal foetal growth. Given the high overall number of annual births in China, our findings have important public health </p

New Perspectives on Host-Parasite Interplay by Comparative Transcriptomic and Proteomic Analyses of Schistosoma japonicum

Schistosomiasis remains a serious public health problem with an estimated 200 million people infected in 76 countries. Here we isolated ~ 8,400 potential protein-encoding cDNA contigs from Schistosoma japonicum after sequencing circa 84,000 expressed sequence tags. In tandem, we undertook a high-throughput proteomics approach to characterize the protein expression profiles of a number of developmental stages (cercariae, hepatic schistosomula, female and male adults, eggs, and miracidia) and tissues at the host-parasite interface (eggshell and tegument) by interrogating the protein database deduced from the contigs. Comparative analysis of these transcriptomic and proteomic data, the latter including 3,260 proteins with putative identities, revealed differential expression of genes among the various developmental stages and sexes of S. japonicum and localization of putative secretory and membrane antigens, enzymes, and other gene products on the adult tegument and eggshell, many of which displayed genetic polymorphisms. Numerous S. japonicum genes exhibited high levels of identity with those of their mammalian hosts, whereas many others appeared to be conserved only across the genus Schistosoma or Phylum Platyhelminthes. These findings are expected to provide new insights into the pathophysiology of schistosomiasis and for the development of improved interventions for disease control and will facilitate a more fundamental understanding of schistosome biology, evolution, and the host-parasite interplay