Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
During the spring of 2013, a novel avian-origin influenza A (H7N9) virus emerged and spread among humans in China. Data were lacking on the clinical characteristics of the infections caused by this ...virus.
Using medical charts, we collected data on 111 patients with laboratory-confirmed avian-origin influenza A (H7N9) infection through May 10, 2013.
Of the 111 patients we studied, 76.6% were admitted to an intensive care unit (ICU), and 27.0% died. The median age was 61 years, and 42.3% were 65 years of age or older; 31.5% were female. A total of 61.3% of the patients had at least one underlying medical condition. Fever and cough were the most common presenting symptoms. On admission, 108 patients (97.3%) had findings consistent with pneumonia. Bilateral ground-glass opacities and consolidation were the typical radiologic findings. Lymphocytopenia was observed in 88.3% of patients, and thrombocytopenia in 73.0%. Treatment with antiviral drugs was initiated in 108 patients (97.3%) at a median of 7 days after the onset of illness. The median times from the onset of illness and from the initiation of antiviral therapy to a negative viral test result on real-time reverse-transcriptase-polymerase-chain-reaction assay were 11 days (interquartile range, 9 to 16) and 6 days (interquartile range, 4 to 7), respectively. Multivariate analysis revealed that the presence of a coexisting medical condition was the only independent risk factor for the acute respiratory distress syndrome (ARDS) (odds ratio, 3.42; 95% confidence interval, 1.21 to 9.70; P=0.02).
During the evaluation period, the novel H7N9 virus caused severe illness, including pneumonia and ARDS, with high rates of ICU admission and death. (Funded by the National Natural Science Foundation of China and others.).
Current evidence suggests high serum uric acid may increase the risk of type 2 diabetes, but the association is still uncertain. The aim of the study was to evaluate the association between serum ...uric acid and future risk of type 2 diabetes by conducting a meta-analysis of prospective cohort studies.
We conducted a systematic literature search of the PubMed database through April 2012. Prospective cohort studies were included in meta-analysis that reported the multivariate adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs) for the association between serum uric acid and risk of type 2 diabetes. We used both fix-effects and random-effects models to calculate the overall effect estimate. The heterogeneity across studies was tested by both Q statistic and I(2) statistic. Begg's funnel plot and Egger's regression test were used to assess the potential publication bias.
We retrieved 7 eligible articles derived from 8 prospective cohort studies, involving a total of 32016 participants and 2930 incident type 2 diabetes. The combined RR of developing type 2 diabetes for the highest category of serum uric acid level compared with the lowest was 1.56(95% CI, 1.39-1.76). Dose-response analysis showed the risk of type 2 diabetes was increased by 6% per 1 mg/dl increment in serum uric acid level (RR 1.06, 95% CI: 1.04-1.07). The result from each subgroup showed a significant association between serum uric acid and risk of type 2 diabetes. In sensitive analysis, the combined RR was consistent every time omitting any one study. Little evidence of heterogeneity and publication bias was observed.
Our meta-analysis of prospective cohort studies provided strong evidence that high level of serum uric acid is independent of other established risk factors, especially metabolic syndrome components, for developing type 2 diabetes in middle-aged and older people.
In recent years, molecular ferroelectrics have received great attention due to their low weight, mechanical flexibility, easy preparation and excellent ferroelectric properties. Among them, ...crown‐ether‐based molecular ferroelectrics, which are typically composed of the host crown ethers, the guest cations anchored in the crown ethers, and the counterions, are of great interest because of the host‐guest structure. Such a structure allows the components to occur order‐disorder transition easily, which is beneficial for inducing ferroelectric phase transition. Herein, we summarized the research progress of crown ether host‐guest molecular ferroelectrics, focusing on their crystal structure, phase transition, ferroelectric‐related properties. In view of the small spontaneous polarization and uniaxial nature, we outlook the chemical design strategies for obtaining high‐performance crown‐ether‐based molecular ferroelectrics. This minireview will be of guiding significance for the future exploration of crown ether host‐guest molecular ferroelectrics.
Crown‐ether‐based molecular ferroelectrics are attractive for the host‐guest structure, where the guest cation is anchored in the host crown ether and the anion acts as the counterion. Their crystal structure, phase transition and ferroelectric properties are discussed in this minireview. Additionally, an outlook on the chemical design of high‐performance crown ether host‐guest molecular ferroelectrics is given.
It has been accepted that kidney function is connected with brain activity. In clinical studies, chronic kidney disease (CKD) patients have been found to be prone to suffering cognitive decline and ...Alzheimer’s disease (AD). The cognitive function of CKD patients may improve after kidney transplantation. All these indicators show a possible link between kidney function and dementia. However, little is known about the mechanism behind the relation of CKD and AD. This review discusses the associations between CKD and AD from the perspective of the pathophysiology of the kidney and complications and/or concomitants of CKD that may lead to cognitive decline in the progression of CKD and AD. Potential preventive and therapeutic strategies for AD are also presented. Further studies are warranted in order to confirm whether the setting of CKD is a possible new determinant for cognitive impairment in AD.
Background and Aims
The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3–5‐cm HCC over time.
Approach and Results
From ...2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008–2019 (n = 335 in each group) and 2014–2019 (n = 257 in each group) cohorts, respectively. For cohort 2008–2019, during a median follow‐up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65–1.19, p = 0.420), and MWA was inferior to LLR regarding disease‐free survival (DFS) (HR 1.36, 95% CI 1.05–1.75, p = 0.017). For cohort 2014–2019, there was comparable OS (HR 0.85, 95% CI 0.56–1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98–1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1–4.0‐cm HCCs (HR 0.88, 95% CI 0.53–1.47, p = 0.630) and 4.1–5.0‐cm HCCs (HR 0.77, 95% CI 0.37–1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p > 0.05), shorter hospitalization, and lower cost to LLR (all p < 0.001).
Conclusions
MWA might be a first‐line alternative to LLR for solitary 3–5‐cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.
Uranium is a key resource for the development of the nuclear industry, and extracting uranium from the natural seawater is one of the most promising ways to address the shortage of uranium resources. ...Herein, a semiconducting covalent organic framework (named NDA‐TN‐AO) with excellent photocatalytic and photoelectric activities was synthesized. The excellent photocatalytic effect endowed NDA‐TN‐AO with a high anti‐biofouling activity by generating biotoxic reactive oxygen species and promoting photoelectrons to reduce the adsorbed UVI to insoluble UIV, thereby increasing the uranium extraction capacity. Owing to the photoinduced effect, the adsorption capacity of NDA‐TN‐AO to uranium in seawater reaches 6.07 mg g−1, which is 1.33 times of that in dark. The NDA‐TN‐AO with enhanced adsorption capacity is a promising material for extracting uranium from the natural seawater.
Photoelectric and photocatalytic effects endow the covalent organic framework NDA‐TN‐AO with good anti‐biofouling activity. This occurs by generating biotoxic reactive oxygen species and promoting photoelectrons to reduce the adsorbed UVI to insoluble UIV, thereby improving the uranium adsorption capacity.
Anthropogenic environments have been implicated in enrichment and exchange of antibiotic resistance genes and bacteria. Here we study the impact of confined and controlled swine farm environments on ...temporal changes in the gut microbiome and resistome of veterinary students with occupational exposure for 3 months. By analyzing 16S rRNA and whole metagenome shotgun sequencing data in tandem with culture-based methods, we show that farm exposure shapes the gut microbiome of students, resulting in enrichment of potentially pathogenic taxa and antimicrobial resistance genes. Comparison of students' gut microbiomes and resistomes to farm workers' and environmental samples revealed extensive sharing of resistance genes and bacteria following exposure and after three months of their visit. Notably, antibiotic resistance genes were found in similar genetic contexts in student samples and farm environmental samples. Dynamic Bayesian network modeling predicted that the observed changes partially reverse over a 4-6 month period. Our results indicate that acute changes in a human's living environment can persistently shape their gut microbiota and antibiotic resistome.
Increased vascular permeability facilitates metastasis. Emerging evidence indicates that secreted microRNAs (miRNAs) may mediate the crosstalk between cancer and stromal cells. To date, whether and ...how secreted miRNAs affect vascular permeability remains unclear. Based on deep sequencing and quantitative PCR, we found that higher level of serum miR‐103 was associated with higher metastasis potential of hepatocellular carcinoma (HCC). The in vitro endothelial permeability and transendothelial invasion assays revealed that the conditioned media or exosomes derived from high miR‐103‐expressing hepatoma cells increased the permeability of endothelial monolayers, but this effect was attenuated if exosome secretion of hepatoma cells was blocked by silencing ALIX and HRS or if miR‐103 within hepatoma or endothelial cells was antagonized. Most importantly, pretreating endothelial monolayers with exosomes that were from stable miR‐103‐expressing hepatoma cells facilitated the transendothelial invasion of tumor cells, and this role of exosomes was abrogated by inhibiting miR‐103 in endothelial cells. Further in vivo analyses disclosed that mice with xenografts of stable miR‐103‐expressing hepatoma cells exhibited higher vascular permeability in tumor, higher level of exosomal miR‐103 and greater number of tumor cells in blood circulation, and increased rates of hepatic and pulmonary metastases, compared to control mice. Mechanism investigations revealed that hepatoma cell‐secreted miR‐103 could be delivered into endothelial cells via exosomes, and then attenuated the endothelial junction integrity by directly inhibiting the expression of VE‐Cadherin (VE‐Cad), p120‐catenin (p120) and zonula occludens 1. Moreover, miR‐103 could also promote tumor cell migration by repressing p120 expression in hepatoma cells. Conclusion: Hepatoma cell‐secreted exosomal miR‐103 increases vascular permeability and promotes tumor metastasis by targeting multiple endothelial junction proteins, which highlights secreted miR‐103 as a potential therapeutic target and a predictive marker for HCC metastasis. (Hepatology 2018).
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