Summary
Multiple myeloma (MM) is the second most common haematological malignancy. Despite the development of new drugs and treatments in recent years, the therapeutic outcomes of patients are not ...satisfactory. It is necessary to further investigate the molecular mechanism underlying MM progression. Herein, we found that high E2F2 expression was correlated with poor overall survival and advanced clinical stages in MM patients. Gain‐ and loss‐of‐function studies showed that E2F2 inhibited cell adhesion and consequently activated cell epithelial‐to‐mesenchymal transition (EMT) and migration. Further experiments revealed that E2F2 interacted with the PECAM1 promoter to suppress its transcriptional activity. The E2F2‐knockdown‐mediated promotion of cell adhesion was significantly reversed by the repression of PECAM1 expression. Finally, we observed that silencing E2F2 significantly inhibited viability and tumour progression in MM cell models and xenograft mouse models respectively. This study demonstrates that E2F2 plays a vital role as a tumour accelerator by inhibiting PECAM1‐dependent cell adhesion and accelerating MM cell proliferation. Therefore, E2F2 may serve as a potential independent prognostic marker and therapeutic target for MM.
The abnormal immune response is an early change in the pathogenesis of Alzheimer's disease (AD). Microglial activation is a crucial regulator of the immune response, which contributes to progressive ...neuronal injury by releasing neurotoxic products. Therefore, finding effective drugs to regulate microglial homeostasis and neuroinflammation has become a new AD treatment strategy. Artemisinin has potent anti-inflammatory and immune activities. However, it is unclear whether Artemisinin contributes to the regulation of microglial activation, thereby improving AD pathology. This study found that Artemisinin significantly reduced amyloid beta-peptide 1-42 (Aβ
)-induced increases in nitric oxide and reactive oxygen species and inflammatory factors in BV2 cells. In addition, Artemisinin inhibited the migration of microglia and prevented the expansion of the inflammatory cascade. The mechanical studies showed Artemisinin inhibited neuroinflammation and exerted neuroprotective effects by regulating the Toll-like receptor 4 (TLR4)/Nuclear factor-kappa B (NF-κB) signaling pathway. Similar results were obtained in AD model mice, in which Artemisinin administration attenuated Aβ
-induced neuroinflammation and neuronal injury, reversing spatial learning and memory deficits. The anti-inflammatory effect of Artemisinin is also accompanied by the activation of the TLR4/NF-κB signaling pathway in the animal model. Our results indicate that Artemisinin attenuated Aβ
-induced neuroinflammation and neuronal injury by stimulating the TLR4/NF-κB signaling pathway. These findings suggest that Artemisinin is a potential therapeutic agent for AD.
Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus ...lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.
We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%.
At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.
The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.
ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.
Gut microbiota is closely related to the tumorigenesis and progression of colorectal cancer (CRC), especially Fusobacterium nucleatum (Fn) could promote colorectal tumor growth and cause ...chemoresistance. Here, we developed a tumor-triggered release drug delivery gel to inhibit CRC cell growth in situ by intestinal perfusion. Antibiotic metronidazole (MTZ) and 5-fluorouracil (5-FU), the first-line chemotherapy drug of CRC, are individually incorporated into metal polyphenol network-coated mesoporous silica nanoparticle (MSN), and then blended with carboxymethyl cellulose (CMC) to obtain an anti-CRC gel, AB-Gel. In vivo studies showed that AB-Gel could efficiently inhibit the growth and metastasis of CRC in an orthotopic mouse model attributing to the MTZ-induced modulation in the CRC-related microbiota. Chemotherapy efficacy against orthotopic CRC was significantly enhanced by the elimination of Fn. This strategy based on the combination of gut microbiota modulation and chemotherapy would be considered as an enhanced strategy for CRC treatment with potential use in the clinic.
A colonic perfusion gel with tumor-triggered drug release ability was designed for colorectal cancer therapy using combination of gut microbiota modulation and chemotherapy. Display omitted
•Developing a drug delivery gel (AB-Gel) to inhibit colorectal cancer (CRC) in situ by intestinal perfusion.•AB-Gel can inhibit CRC in orthotopic mouse model due to the combined effect of antibacterial and anticancer.•AB-Gel can form a sticky layer on colonic mucosa and prolong drug release time.
A large room‐temperature magnetoelectric response is crucial for the practical application of magnetoelectric materials. However, such a response has never been achieved in molecular–ionic ...ferroelectric‐based laminated magnetoelectric composites. Herein, the laminated magnetoelectric composite of Metglas/1 (1 = N(CH3)4GaBrCl3 and Metglas = an amorphous FeBSi alloy) is prepared by combining the molecular–ionic ferroelectric 1 with Metglas in the longitudinally magnetized and transversely poled (L–T) mode. The room‐temperature magnetoelectric response of the composite is up to 8.74 V Oe−1 cm−1 at the resonance frequency (≈45 kHz), representing the largest room‐temperature magnetoelectric response reported for the molecular–ionic ferroelectric‐based laminated magnetoelectric composites to date.
A laminated magnetoelectric composite is prepared by combining the molecular–ionic ferroelectric N(CH3)4GaBrCl3 with an amorphous FeBSi alloy (Metglas). The large room‐temperature magnetoelectric response of 8.74 V Oe−1 cm−1 at resonance frequency (≈45 kHz) is realized in the composites of Metglas/N(CH3)4GaBrCl3, indicating potential applications in the fields of sensors, energy harvesting, and so on.
Investigating space allocation patterns of plant secondary xylem along a latitudinal gradient is useful to evaluate structure-function tradeoffs in woody angiosperm xylem. An anatomical dataset ...including 700 woody angiosperm species across China was compiled together with latitudinal and climate data for each species. The relative tissue fractions of vessels, fibers, and parenchyma (including ray and axial parenchyma) in xylem were analyzed to determine the effect of latitudinal differences and phylogeny on anatomical variation. The analyses revealed a trade-off between vessel and non-vessel fraction across latitude, with tissue fraction trade-offs mainly occurring between vessels and fibers, and between fibers and total parenchyma. Among 13 climate variables, thermal indices generally had greater explanatory power than moisture indices in bi-variate models for all cell types, while mean annual temperature, mean temperature of the coldest month, and annual actual evapotranspiration were included in the top multi-variate models explaining variance of different tissue fractions. Phylogeny and climate together explained 57-73% of the total variation in xylem space occupancy, with phylogeny alone accounting for over 50% of the variation. These results contribute to our knowledge of wood structure-function and are relevant to better understand forest response to climate change.
Cognitive impairment is an independent predictor of technique failure and mortality in patients on peritoneal dialysis (PD) therapy. We investigated changes in cognitive function and factors ...associated with it in this population.
Multicenter prospective cohort study.
458 PD patients were enrolled and followed up for 2 years.
Global and specific domains of cognitive function were measured at baseline and after 2 years. The Modified Mini-Mental State Examination (3MS) was used for assessment of global cognitive function; Trail-Making Tests A and B, for executive function; and subtests of the Battery for the Assessment of Neuropsychological Status, for immediate and delayed memory, visuospatial skill, and language ability.
The primary outcome was change in cognitive function. Secondary outcomes included all-cause mortality, cardiovascular mortality, hospitalization, and transition to hemodialysis therapy.
Multivariable linear regression models.
The prevalence of cognitive impairment increased from 19.8% to 23.9%. 3MS scores significantly decreased (84.8 to 83.1), although executive function, immediate memory, and visuospatial skill improved over time. Delayed memory capacity and language ability were unchanged. Lower serum albumin level was associated with deteriorated delayed memory, visuospatial skill, and language ability, as well as with the decline in general cognitive function (β values of 0.64, 0.90, 0.80, and 0.44, respectively). Advanced age, lower education, and depression were also correlated with deterioration in general and specific cognitive function. After multivariable adjustment, both global and specific cognitive impairment at baseline were associated with a greater rate of hospitalization, and memory dysfunction was associated with a lower dialysis modality survival rate.
A relatively short observation period, small number of deaths, and potential selection bias due to patients unavailable for the second assessment.
In a PD population, global cognitive function declined over 2 years, though some specific cognitive domains improved. Besides well-recognized factors, hypoalbuminemia and depression were also risk factors for cognitive impairment.
Diabetes and retinopathy have been considered as risk factors of cognitive impairment (CI) in previous studies. We investigated both of these two factors and their relationship with global and ...specific cognitive functions in end stage renal disease patients under peritoneal dialysis (PD).
In this multicenter cross-sectional study, 424 clinically stable patients were enrolled from 5 PD units, who performed PD for at least three months and completed fundoscopy examination if they had diabetes. Global cognitive function was measured using the Modified Mini-Mental State Examination (3MS), Trail-Making Test forms A and B for executive function, and subtests of the Battery for the Assessment of Neuropsychological Status for immediate and delayed memory, visuospatial skills, and language ability.
PD Patients with DM and Retinopathy had significantly higher prevalence of CI, executive dysfunction, impaired immediate memory and visuospatial skill, compared with patients in non-DM group. By multivariate logistic regression analyses, DM and retinopathy rather than DM only were significantly associated with increased risk for CI, executive dysfunction, impaired immediate memory and visuospatial skill, odds ratios(ORs) and 95% confidence intervals were 2.091.11,3.92, 2.891.55,5.37, 2.16 1.15,4.06 and 2.371.32,4.22, respectively (all P < 0.05).
Diabetic PD patients with retinopathy were at two times risk for overall cognitive impairment, executive dysfunction, impaired immediate memory and visuospatial skill as compared to non-diabetic PD patients.
Intratumor heterogeneity (ITH) in non‐small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The ...recognition of ITH helps identify high‐risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12‐paired normal‐tumor tissues were subjected to whole‐genome/whole‐exome sequencing. From these, 367 non‐silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non‐mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.
What's new?
Intratumor heterogeneity (ITH) in non‐small cell lung cancer (NSCLC) may account for resistance during targeted treatment. Identifying ITH could help make effective treatment decisions, but ITH studies have so far been hampered by confounding factors. To reduce the interference of interpatient heterogeneity and passenger mutations, the authors recruited NSCLC patients with TP53 mutations and selected potential driver mutations. They identified extensive ITH of driver mutations in all NSCLC tumors and demonstrated the late molecular acquisition of TP53 mutation during tumor progression in most patients. The data highlight the clinical potential of limiting the impact of ITH for NSCLC targeted treatment.
The application of artificial intelligence (AI) technology in the medical field has experienced a long history of development. In turn, some long-standing points and challenges in the medical field ...have also prompted diverse research teams to continue to explore AI in depth. With the development of advanced technologies such as the Internet of Things (IoT), cloud computing, big data, and 5G mobile networks, AI technology has been more widely adopted in the medical field. In addition, the in-depth integration of AI and IoT technology enables the gradual improvement of medical diagnosis and treatment capabilities so as to provide services to the public in a more effective way. In this work, we examine the technical basis of IoT, cloud computing, big data analysis and machine learning involved in clinical medicine, combined with concepts of specific algorithms such as activity recognition, behavior recognition, anomaly detection, assistant decision-making system, to describe the scenario-based applications of remote diagnosis and treatment collaboration, neonatal intensive care unit, cardiology intensive care unit, emergency first aid, venous thromboembolism, monitoring nursing, image-assisted diagnosis, etc. We also systematically summarize the application of AI and IoT in clinical medicine, analyze the main challenges thereof, and comment on the trends and future developments in this field.
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