Background
Lenvatinib and atezolizumab plus bevacizumab(A + B) have been used for unresectable hepatocellular carcinoma (HCC) as first‐line therapy. Real‐world studies comparison of efficacy and ...safety in these two regimens are limited, we therefore conduct this study to investigate these issues.
Methods
We retrospectively reviewed patients received lenvatinib (n = 46) and A + B (n = 46) as first‐line systemic therapy for unresectable HCC in a tertiary medical center. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were evaluated according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Inverse probability weighting (IPW) was performed for baseline clinical features balance.
Results
A total of 92 patients with median age of 63.8 year‐old, 78.3% male, 85.9% viral hepatitis infected, 67.4% BCLC stage C were enrolled. The median treatment and follow‐up duration were 4.7 months and 9.4 months, respectively. There was no significant difference in ORR (26.1% vs. 41.3%, p = 0.1226), PFS (5.9 vs. 5.3 months, p = 0.4066), and OS (not reached vs. not reached, p = 0.7128) between the lenvatinib and A + B groups. After IPW, the results of survival and response rate were also compared. Subgroup analysis suggested that using lenvatinib was not inferior to A + B in regards of PFS, including those with elder, Child‐Pugh class B, beyond up‐to‐seven, or portal vein invasion VP4 patients. Among the lenvatinib treated patients, multivariate analysis showed patients elder than 65‐year‐old was an independent predictor associated with shorter PFS (adjust HR: 2.0850.914–4.753, p = 0.0213). The incidence rates of adverse events were similar between two groups (76 vs. 63%, p = 0.1740). Both of two regimens had similarly few impact on liver function by comparison of baseline, third month, and sixth month albumin‐bilirubin index and Child‐Pugh score.
Conclusions
The efficacy and safety of lenvatinib are similar to A + B as a first‐line systemic therapy for unresectable HCC.
This study provides real‐world experience of lenvatinib and A + B as firstline treatment for unresectable HCC. The data showed that compared survival, response rate, and adverse events between two regimens.
In order to develop a soft composite with high‐performance puncture resistance and self‐healing property property, herein, we introduced Pluronic F127 diacrylate (F127DA) into titania‐based ...nanocomposite hydrogels (PAMT) and then compounded hydrogel and aramid fabric to form gel‐matrix soft composites (GMSCs). The result shows that, with the addition of 5 wt% TiO2 nanoparticles, the hydrogels exhibited a fracture strain of 3898%, a toughness of 12.23 MJ/m3 and a self‐healing efficiency of 99.45% after healing at 100°C for 12 h, indicating multiple recycling feature. In addition, a series of mechanical tests had shown that the resultant GMSCs exhibited incredible spike puncture resistance and knife puncture resistance, 17.66 times and 13.78 times greater than that of pure fabrics, and could achieve 33.84% spike puncture self‐healing efficiency and 26.62% knife puncture self‐healing efficiency. The synergetic reinforcement mechanism of the hydrogel and fabrics was also analyzed. This study provides a valuable reference for designing a puncture resistant soft composite with rapid self‐healing and repeated recycling.
Threatened preterm labor (TPL) is an important obstetrical challenge. Pregnant women with TPL may develop psychological and physical problems such as mental health disorders, sleep disturbance, and ...hormonal circadian rhythm disruption. This study aimed to investigate the current state of mental health, sleep quality, and circadian rhythms of cortisol and melatonin secretion in pregnant women with TPL and normal pregnant women (NPW).
A prospective observational clinical study was conducted at a maternal and child health hospital in Fuzhou, China, between June and July 2022. A total of 50 women between 32 and 36 weeks of gestation (TPL group, n = 20; NPW group, n = 30) were recruited. Data on anxiety symptom (Zung's Self-rating Anxiety Scale, SAS), depression symptom (Edinburgh Postnatal Depression Scale, EPDS), subjective sleep quality (Pittsburgh Sleep Quality Index, PSQI) and objective sleep outcomes (measured by actigraphy) of the pregnant women were collected at the time of enrolment. Salivary samples were collected once every 6 h (i.e., at 06:00, 12:00, 18:00, and 00:00) during 2 consecutive days to measure the circadian rhythm of hormone (cortisol and melatonin).
There were no differences found in the total scores of SAS, EPDS scores, subjective sleep quality between the TPL and NPW groups (P > 0.05). In contrast, significant differences were found in sleep efficiency, total sleep time, wake time after sleep onset, and average awakening time between the groups (P < 0.05). The circadian rhythm of melatonin secretion was disrupted in the TPL group (P = 0.350); however, it was maintained in the NPW group (P = 0.044). The circadian rhythm of cortisol secretion was disrupted in both groups (P > 0.05).
In the third trimester of pregnancy, women with TPL suffer from poorer sleep quality and disruption of circadian rhythm of melatonin secretion compared with NPW. Nevertheless, there were no differences found in mental health (i.e., anxiety and depression) and circadian rhythm of cortisol secretion. Large-scale studies should be conducted to evaluate these changes in women with TPL.
The study was registered from Chinese Clinical Trial Registry (Number: ChiCTR2200060674) on 07/06/2022.
The origin and evolution of the domestic dog remains a controversial question for the scientific community, with basic aspects such as the place and date of origin, and the number of times dogs were ...domesticated, open to dispute. Using whole genome sequences from a total of 58 canids （12 gray wolves, 27 primitive dogs from Asia and Africa, and a collection of 19 diverse breeds from across the world）, we find that dogs from southern East Asia have significantly higher genetic diversity compared to other populations, and are the most basal group relating to gray wolves, indicating an ancient origin of domestic dogs in southern East Asia 33 000 years ago. Around 15 000 years ago, a subset of ancestral dogs started migrating to the Middle East, Africa and Europe, arriving in Europe at about 10 000 years ago. One of the out of Asia lineages also migrated back to the east, creating a series of admixed populations with the endemic Asian lineages in northern China before migrating to the New World. For the first time, our study unravels an extraordinary journey that the domestic dog has traveled on earth.
Neonatal hypoxic–ischaemic (HI) injury is a serious complication of neonatal asphyxia and the leading cause of neonatal acute death and chronic neurological injury, and the effective therapeutic ...method is lacking to improve patients' outcomes. We reported in this study that panax notoginseng saponin (PNS) may provide a treatment option for HI. HI model was established using neonatal Sprague–Dawley rats and then intraperitoneally injected with different dosage of PNS, once a day for 7 days. Histological staining and behavioural evaluations were performed to elucidate the pathological changes and neurobehavioural variation after PNS treatment. We found PNS administration significantly reduced the infarct volume of brain tissues and improved the autonomous activities of neonatal rats, especially with higher dosage. PNS treatment at 40 mg/kg reduced neuronal damage, suppressed neuronal apoptosis and depressed astroglial reactive response. Moreover, the long‐term cognitive and motor functions were also improved after PNS treatment at 40 mg/kg. Importantly, PNS treatment elevated the levels of BDNF and TrkB but decreased the expression of p75NTR both in the cortex and hippocampus of HI rats. The therapeutic efficacy of PNS might be correlated with PNS‐activated BDNF/TrkB signalling and inactivation of p75NTR expression, providing a novel potential therapy for alleviating HI injury.
PNS ameliorated the acute cerebral injury induced by HI in neonatal rats. PNS treatment suppressed the neuronal apoptosis in neonatal HI rats and alleviated GFAP‐mediated inflammatory response. The long‐term neurological dysfunctions in neonatal HI rats were relieved after PNS treatment.
Objective. To evaluate the analgesic efficacy and safety of different does of intravenous ibuprofen (IVIB) in the treatment of postoperative acute pain. Methods. Patients with an intravenous (IV) ...patient-controlled analgesia device after abdominal or orthopedic surgery were randomly divided into placebo, IVIB 400 mg, and IVIB 800 mg groups. The first dosage of study medicines was given intravenously 30 minutes (min) before surgery ended, followed by six hours (h) intervals for a total of eight doses following surgery. The demographic characteristics and procedure data, cumulative morphine consumption, the visual analog scale (VAS), the area under the curve (AUC) of VAS, patient satisfaction score (PSS), the rates of treatment failure (RTF), and adverse events (AEs) and serious adverse event (SAEs) were recorded during the period of trial. Result. A total of 345 patients were enrolled in the full analysis set (FAS), and of 326 participants were valid data set (VDS). Demographic characteristics, disease features, and medical history of patients were not significantly different between groups. Total morphine consumption of the IVIB 400 mg group (11.14 ± 7.14 mg; P = 0.0011) and the IVIB 800 mg group (11.29 ± 6.45 mg; P = 0.0014) was significantly reduced compared with the placebo group (14.51 ± 9.19 mg) for 24 h postoperatively, there was no significant difference between the IVIB 400 mg and IVIB 800 mg groups (P = 0.9997). The placebo group had significantly higher VAS and the AUCs of VAS than those in the IVIB 400 mg and the IVIB 800 mg groups at rest and movement for 24 h postoperatively (P < 0.05), and there was no significant difference between the IVIB 400 mg and IVIB 800 mg groups (P > 0.05). RTF was slightly higher in the placebo group than IVIB 400 mg group and 800 mg group, and no statistical significance (P < 0.690). PSS in the IVIB 400 mg (P = 0.0092) and the IVIB 800 mg groups (P = 0.0011) was higher than the placebo group for pain management, there was also no significant difference between the IVIB 400 mg and IVIB 800 mg groups (P = 0.456). The incidence of RTF (P = 0.690) and AEs (P > 0.05) were not different among the three groups. Conclusion. Intermittent IV administration of ibuprofen 400 mg or 800 mg within 24 h after surgery in patients undergoing abdominal and orthopedic surgery significantly decreased morphine consumption and relieved pain, without increasing the incidence of AEs.
Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent μ agonists and ...displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined.
The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test.
Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit.
The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.
The antiparasitic agent niclosamide has been demonstrated to inhibit the arthropod-borne Zika virus. Here, we investigated the antiviral capacity of niclosamide against dengue virus (DENV) serotype 2 ...infection in vitro and in vivo.
Niclosamide effectively retarded DENV-induced infection in vitro in human adenocarcinoma cells (A549), mouse neuroblastoma cells (Neuro-2a), and baby hamster kidney fibroblasts (BHK-21). Treatment with niclosamide did not retard the endocytosis of DENV while niclosamide was unable to enhance the antiviral type I interferon response. Furthermore, niclosamide did not cause a direct effect on viral replicon-based expression. Niclosamide has been reported to competitively inhibit the mTOR (mammalian target of rapamycin), STAT3 (signal transducer and activator of transcription 3), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways; however, selective inhibitors of those pathways did not reduce DENV infection. Similar to the vacuolar-type H+-ATPase inhibitor bafilomycin A1, both niclosamide and other protonophores, such as CCCP (carbonyl cyanide m-chlorophenyl hydrazone), and FCCP (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone), effectively reduced endosomal acidification and viral dsRNA replication. Co-administration of a single dose of niclosamide partially decreased viral replication, viral encephalitis, and mortality in DENV-infected ICR suckling mice.
These results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.
Introduction
L‐glutamine is an antioxidant that plays a role in a variety of biochemical processes. Given that oxidative stress is a key component of stroke pathology, the potential of L‐glutamine in ...the treatment of ischemic stroke is worth exploring.
Aims
In this study, we investigated the effect and mechanisms of action of L‐glutamine after cerebral ischemic injury.
Results
L‐glutamine reduced brain infarct volume and promoted neurobehavioral recovery in mice. L‐glutamine administration increased the expression of heat‐shock protein 70 (HSP70) in astrocytes and endothelial cells. Such effects were abolished by the coadministration of Apoptozole, an inhibitor of the ATPase activity of HSP70. L‐glutamine also reduced oxidative stress and neuronal apoptosis, and increased the level of superoxide dismutase, glutathione, and brain‐derived neurotrophic factor. Cotreatment with Apoptozole abolished these effects. Cell culture study further revealed that the conditioned medium from astrocytes cultured with L‐glutamine reduced the apoptosis of neurons after oxygen‐glucose deprivation.
Conclusion
L‐glutamine attenuated ischemic brain injury and promoted functional recovery via HSP70, suggesting its potential in ischemic stroke therapy.
Dingoes are wild canids living in Australia, originating from domestic dogs. They have lived isolated from both the wild and the domestic ancestor, making them a unique model for studying ...feralization. Here, we sequence the genomes of 10 dingoes and 2 New Guinea Singing Dogs. Phylogenetic and demographic analyses show that dingoes originate from dogs in southern East Asia, which migrated via Island Southeast Asia to reach Australia around 8300 years ago, and subsequently diverged into a genetically distinct population. Selection analysis identifies 50 positively selected genes enriched in digestion and metabolism, indicating a diet change during feralization of dingoes. Thirteen of these genes have shifted allele frequencies compared to dogs but not compared to wolves. Functional assays show that an A-to-G mutation in ARHGEF7 decreases the endogenous expression, suggesting behavioral adaptations related to the transitions in environment. Our results indicate that the feralization of the dingo induced positive selection on genomic regions correlated to neurodevelopment, metabolism and reproduction, in adaptation to a wild environment.
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