In a previous phase II trial, hepatic arterial infusion chemotherapy (HAIC) with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) yielded higher treatment responses than transarterial ...chemoembolization (TACE) in large unresectable hepatocellular carcinoma. We aimed to compare the overall survival of patients treated with FOLFOX-HAIC versus TACE as first-line treatment in this population.
In this randomized, multicenter, open-label trial, adults with unresectable hepatocellular carcinoma (largest diameter ≥ 7 cm) without macrovascular invasion or extrahepatic spread were randomly assigned 1:1 to FOLFOX-HAIC (oxaliplatin 130 mg/m
, leucovorin 400 mg/m
, fluorouracil bolus 400 mg/m
on day 1, and fluorouracil infusion 2,400 mg/m
for 24 hours, once every 3 weeks) or TACE (epirubicin 50 mg, lobaplatin 50 mg, and lipiodol and polyvinyl alcohol particles). The primary end point was overall survival by intention-to-treat analysis. Safety was assessed in patients who received ≥ 1 cycle of study treatment.
Between October 1, 2016, and November 23, 2018, 315 patients were randomly assigned to FOLFOX-HAIC (n = 159) or TACE (n = 156). The median overall survival in the FOLFOX-HAIC group was 23.1 months (95% CI, 18.5 to 27.7) versus 16.1 months (95% CI, 14.3 to 17.9) in the TACE group (hazard ratio, 0.58; 95% CI, 0.45 to 0.75;
< .001). The FOLFOX-HAIC group showed a higher response rate than the TACE group (73 46%
28 18%;
< .001) and a longer median progression-free survival (9.6 95% CI, 7.4 to 11.9
5.4 months 95% CI, 3.8 to 7.0,
< .001). The incidence of serious adverse events was higher in the TACE group than in the FOLFOX-HAIC group (30%
19%,
= .03). Two deaths in the FOLFOX-HAIC group and two in the TACE group were deemed to be treatment-related.
FOLFOX-HAIC significantly improved overall survival over TACE in patients with unresectable large hepatocellular carcinoma.
Breast cancer is the second cause of cancer mortality in women globally. Early detection, treatment, and metastasis monitoring are of great importance to favorable prognosis. Although conventional ...diagnostic methods, such as breast X-ray mammography and image positioning biopsy, are accurate, they could cause radioactive or invasive damage to patients. Liquid biopsy as a noninvasive method is convenient for repeated sampling in clinical cancer prognostic, metastatic evaluation, and relapse monitoring. MicroRNAs encased in exosomes circulating in biofluids are promising candidate cancer biomarkers because of their cancer-specific expression profiles. Here, we report an in situ detection of microRNA-1246 (miR-1246) in human plasma exosomes as breast cancer biomarker by a nucleic acid functionalized Au nanoflare probe. Needing neither time-consuming and costly isolation of exosomes from the plasma sample nor transfection means, the Au nanoflare probe can directly enter the plasma exosomes to generate fluorescent signal quantitatively by specifically targeting miR-1246. Only 40 μL of plasma is needed to incubate 4 h with the probe, giving signal sensitive enough to distinguish samples of breast cancer to normal control. Using plasma miR-1246 level detected by our assay as a marker, we differentiated 46 breast cancer patients from 28 healthy controls with 100% sensitivity and 92.9% specificity at the best cutoff. This simple, accurate, sensitive, and cost-effective liquid biopsy by the Au nanoflare probe is potent to be developed as a noninvasive breast cancer diagnostic assay for clinical adaption.
During the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in ...other parts of China have been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences.
Collaborating with the National Health Commission, we established a retrospective cohort to study hospitalised COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined.
At the data cut-off (31 January 2020), 1590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597 (92.3%) out of 647) were older (mean age 49.7
44.9 years), had more cases with comorbidity (32.9%
19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7
4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0%
11.1%, death rate 7.3%
0.3%, HR (95% CI) for critical illness 1.59 (1.05-2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4
4.7 days) and prognosis (HR (95%) 0.84 (0.40-1.80)) were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR (95%) 1.05 (1.01-1.08)).
There were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.
The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that primary cilia are required for ...intercellular coupling among SCN neurons to maintain the robustness of the internal clock in mice. Cilia in neuromedin S-producing (NMS) neurons exhibit pronounced circadian rhythmicity in abundance and length. Genetic ablation of ciliogenesis in NMS neurons enabled a rapid phase shift of the internal clock under jet-lag conditions. The circadian rhythms of individual neurons in cilia-deficient SCN slices lost their coherence after external perturbations. Rhythmic cilia changes drive oscillations of Sonic Hedgehog (Shh) signaling and clock gene expression. Inactivation of Shh signaling in NMS neurons phenocopied the effects of cilia ablation. Thus, cilia-Shh signaling in the SCN aids intercellular coupling.
Genetic studies have elucidated critical roles of Piwi proteins in germline development in animals, but whether Piwi is an actual disease gene in human infertility remains unknown. We report germline ...mutations in human Piwi (Hiwi) in patients with azoospermia that prevent its ubiquitination and degradation. By modeling such mutations in Piwi (Miwi) knockin mice, we demonstrate that the genetic defects are directly responsible for male infertility. Mechanistically, we show that MIWI binds the histone ubiquitin ligase RNF8 in a Piwi-interacting RNA (piRNA)-independent manner, and MIWI stabilization sequesters RNF8 in the cytoplasm of late spermatids. The resulting aberrant sperm show histone retention, abnormal morphology, and severely compromised activity, which can be functionally rescued via blocking RNF8-MIWI interaction in spermatids with an RNF8-N peptide. Collectively, our findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis.
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•Hiwi ubiquitination-deficient D-box mutations are detected in azoospermia patients•D-box mutant knockin mice display spermatogenic failure at late spermiogenesis•Stabilized MIWI ties RNF8 up in the cytoplasm to prevent histone ubiquitination•Blocking MIWI-RNF8 interaction functionally rescues defective spermiogenesis
Male infertility in mice and humans can result from mutations that stabilize the Piwi protein in late spermatids: sperm defects are due to aberrant histone retention, not piRNA misregulation.
Stroke is a disease characterized by sudden cerebral ischemia and is the second leading cause of death worldwide. We aimed to develop and validate a nomogram model to predict mortality in intensive ...care unit patients with stroke.
All data involved in this study were extracted from the Medical Information Mart for Intensive Care III database (MIMIC-III). The data were analyzed using multivariate Cox regression, and the performance of the novel nomogram, which assessed the patient's overall survival at 30, 180, and 360 days after stroke, was evaluated using Harrell's concordance index (C-index) and the area under the receiver operating characteristic curve. A calibration curve and decision curve were introduced to test the clinical value and effectiveness of our prediction model.
A total of 767 patients with stroke were randomly divided into derivation (n = 536) and validation (n = 231) cohorts at a 7:3 ratio. Multivariate Cox regression showed that 12 independent predictors, including age, weight, ventilation, cardiac arrhythmia, metastatic cancer, explicit sepsis, Oxford Acute Severity of Illness Score or OASIS score, diastolic blood pressure, bicarbonate, chloride, red blood cell and white blood cell counts, played a significant role in the survival of individuals with stroke. The nomogram model was validated based on the C-indices, calibration plots, and decision curve analysis results.
The plotted nomogram accurately predicted stroke outcomes and, thus may contribute to clinical decision-making and treatment as well as consultation services for patients.
Organic substrates and biochar are important in controlling arsenic release from sediments and soils; however, little is known about their impact on arsenic-reducing bacteria and genes during arsenic ...transformation in flooded paddy soils. In this study, microcosm experiments were established to profile transcriptional activity of As(V)-respiring gene (arrA) and arsenic resistance gene (arsC) as well as the associated bacteria regulated by lactate and/or biochar in anaerobic arsenic-contaminated paddy soils. Chemical analyses revealed that lactate as the organic substrate stimulated microbial reduction of As(V) and Fe(III), which was simultaneously promoted by lactate+biochar, due to biochar’s electron shuttle function that facilitates electron transfer from bacteria to As(V)/Fe(III). Sequencing and phylogenetic analyses demonstrated that both arrA closely associated with Geobacter (>60%, number of identical sequences/number of the total sequences) and arsC related to Enterobacteriaceae (>99%) were selected by lactate and lactate+biochar. Compared with the lactate microcosms, transcriptions of the bacterial 16S rRNA gene, Geobacter spp., and Geobacter arrA and arsC genes were increased in the lactate+biochar microcosms, where transcript abundances of Geobacter and Geobacter arrA closely tracked with dissolved As(V) concentrations. Our findings indicated that lactate and biochar in flooded paddy soils can stimulate the active As(V)-respiring bacteria Geobacter species for arsenic reduction and release, which probably increases arsenic bioavailability to rice plants.
The coronavirus disease 2019 (COVID-19) outbreak impacts physical and mental health. The purpose of this study was to explore the association between the levels of social support and mental health ...among Chinese adolescents during the outbreak.
A total of 7,202 adolescents aged 14–18 years completed online survceys from March 8 to 15, 2020, in China. Researchers assessed the associations between depression symptoms (Patient Health Questionnaire-9), anxiety symptoms (Chinese version of the 7-item Generalized Anxiety Disorder scale), and social support (Social Support Rate Scale).
COVID-19 exposure was associated with a higher prevalence of depression symptoms (odds ratio OR = 1.38, 95% confidence interval CI: 1.14–1.66) and anxiety symptoms (OR = 1.26, 95% CI: 1.04–1.52). Only 24.6% of adolescents reported high levels of social support. Most adolescents (70%) reported medium levels of support, and 5.4% reported low support. Low support was associated with higher prevalence of depression (OR = 4.24, 95% CI: 3.38–5.33) and anxiety symptoms (OR = 3.18, 95% CI: 2.54–3.98), while controlling for gender, grade, living situation, and COVID-19 exposure; similarly, medium support was associated with higher prevalence of depression (OR = 2.79, 95% CI: 2.48–3.15) and anxiety (OR = 2.19, 95% CI: 1.94–2.48) symptoms.
This study indicates there is a higher prevalence of mental health problems among adolescents with medium and low levels of social support in China during the outbreak of COVID-19.
The adsorption and electrooxidation of CO molecules at well‐defined Pt(hkl) single‐crystal electrode surfaces is a key step towards addressing catalyst poisoning mechanisms in fuel cells. Herein, we ...employed in situ electrochemical shell‐isolated nanoparticle‐enhanced Raman spectroscopy (SHINERS) coupled with theoretical calculation to investigate CO electrooxidation on Pt(hkl) surfaces in acidic solution. We obtained the Raman signal of top‐ and bridge‐site adsorbed CO* molecules on Pt(111) and Pt(100). In contrast, on Pt(110) surfaces only top‐site adsorbed CO* was detected during the entire electrooxidation process. Direct spectroscopic evidence for OH* and COOH* species forming on Pt(100) and Pt(111) surfaces was afforded and confirmed subsequently via isotope substitution experiments and DFT calculations. In summary, the formation and adsorption of OH* and COOH* species plays a vital role in expediting the electrooxidation process, which relates with the pre‐oxidation peak of CO electrooxidation. This work deepens knowledge of the CO electrooxidation process and provides new perspectives for the design of anti‐poisoning and highly effective catalysts.
CO electrooxidation on Pt(hkl) surfaces in acidic solution has been investigated using in situ shell‐isolated nanoparticle‐enhanced Raman spectroscopy (SHINERS). Direct spectroscopic evidence for OH* and COOH* species was observed and further confirmed by deuterium isotopic experiments and DFT calculations.
VEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 ...that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients.
Immunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan-Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2.
When overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor.
Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects.
Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.
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