High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we ...evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients (n = 37) was met, with 78% CRR (95% confidence interval (CI), 62-90) and 89% ORR (95% CI, 75-97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response; median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile.
Reactive astrocytosis develops in many neurologic diseases, including epilepsy. Astrocytotic contributions to pathophysiology are poorly understood. Studies examining this are confounded by ...comorbidities accompanying reactive astrocytosis. We found that high-titer transduction of astrocytes with enhanced green fluorescent protein (eGFP) via adeno-associated virus induced reactive astrocytosis without altering the intrinsic properties or anatomy of neighboring neurons. We examined the consequences of selective astrocytosis induction on synaptic transmission in mouse CA1 pyramidal neurons. Neurons near eGFP-labeled reactive astrocytes had reduced inhibitory, but not excitatory, synaptic currents. This inhibitory postsynaptic current (IPSC) erosion resulted from a failure of the astrocytic glutamate-glutamine cycle. Reactive astrocytes downregulated expression of glutamine synthetase. Blockade of this enzyme normally induces rapid synaptic GABA depletion. In astrocytotic regions, residual inhibition lost sensitivity to glutamine synthetase blockade, whereas exogenous glutamine administration enhanced IPSCs. Astrocytosis-mediated deficits in inhibition triggered glutamine-reversible hyperexcitability in hippocampal circuits. Thus, reactive astrocytosis could generate local synaptic perturbations, leading to broader functional deficits associated with neurologic disease.
Astrocytes modulate neuronal activity, synaptic transmission, and behavior by releasing chemical transmitters in a process termed gliotransmission. Whether this process impacts epilepsy in vivo is ...not known. We show that genetic impairment of transmitter release from astrocytes by the expression of a glial dominant-negative SNARE domain in mice reduced epileptiform activity in situ, delayed seizure onset after pilocarpine-induced status epilepticus, and attenuated subsequent progressive increase in seizure frequency in vivo. The reduced seizure frequency was accompanied by attenuation of hippocampal damage and behavioral deficits. As the delay in seizure onset and the reduced seizure frequency were mimicked by intracerebroventricular delivery of the NMDA receptor (NMDAR) antagonist d -(-)-2-amino-5-phosphonopentanoate in WT littermates and because dominant-negative SNARE expression leads to a hypofunction of synaptic NMDARs, we conclude that astrocytes modulate epileptogenesis, recurrent spontaneous seizures, and pathophysiological consequences of epilepsy through a pathway involving NMDARs.
Ppardδ, one of the lipid‐activated nuclear receptor expressed in many cell types to activate gene transcription, also regulates cellular functions other than lipid metabolism. The mechanism ...regulating the function of antigen‐presenting cells during the development of atherosclerosis is not fully understood. Here we aimed to study the involvement of PPARδ in CD11c+ cells in atherosclerosis. We used the Cre‐loxP approach to make conditional deletion of Ppard in CD11c+ cells in mice on Apoe–/– background, which were fed with high cholesterol diet to develop atherosclerosis. Ppard deficiency in CD11c+ cells attenuated atherosclerotic plaque formation and infiltration of myeloid‐derived dendritic cells (DCs) and T lymphocytes. Reduced lesion was accompanied by reduced activation of dendritic cells, and also a reduction of activation and differentiation of T cells to Th1 cells. In addition, DC migration to lymph node was also attenuated with Ppard deletion. In bone marrow‐derived DCs, Ppard deficiency reduced palmitic acid‐induced upregulation of co‐stimulatory molecules and pro‐inflammatory cytokine IL12 and TNFα. Our results indicated PPARδ activation by fatty acid resulted in the activation of myeloid DCs and subsequent polarization of T lymphocytes, which contributed to atherosclerosis in Apoe–/– mice. These findings also reveal the potential regulatory role of PPARδ in antigen presentation to orchestrate the immune responses during atherosclerosis.
Dysfunctional vascular smooth muscle (VSM) plays a vital role in the process of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Alpha-lipoic acid (ALA) can prevent the altered VSM ...induced by diabetes. However, the precise mechanism underlying the beneficial effect of ALA is not well understood. This study aimed to determine whether ALA ameliorates VSM function by elevating hydrogen sulfide (H2S) level in diabetes and whether this effect is associated with regulation of autophagy of VSM cells (VSMCs). We found decreased serum H2S levels in Chinese patients and rats with type 2 diabetes mellitus (T2DM). ALA treatment could increase H2S level, which reduced the autophagy-related index and activation of the 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, thereby protecting vascular function in rats with T2DM. Propargylglycine (PPG), a cystathionine-γ-lyase inhibitor, could weaken the ALA effect. In cultured VSMCs, high glucose level also reduced H2S level, upregulated the autophagy-related index and activated the AMPK/mTOR pathway, which were reversed by concomitant application of sodium hydrosulfide (NaHS, an H2S donor) or ALA. The protective effect of NaHS or ALA was attenuated by rapamycin (an autophagy activator), 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (an AMPK activator) or PPG. In contrast, Compound C (an AMPK inhibitor) enhanced the effect of ALA or NaHS. ALA may have a protective effect on VSMCs in T2DM by elevating H2S level and downregulating autophagy via the AMPK/mTOR pathway. This study provides a new target for addressing diabetic macroangiopathy.
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•Alpha-lipoic acid elevates serum H2S level in Chinese patients with type 2 diabetes.•Alpha-lipoic acid protects VSMCs under diabetic conditions by elevating H2S level.•Alpha-lipoic acid downregulates autophagy of VSMCs by elevating H2S level.•Alpha-lipoic acid downregulates AMPK/mTOR pathway in VSMCs by elevating H2S level.
Purpose
To explore the value of various diffusion parameters obtained from monoexponential, biexponential, and stretched exponential in assessing liver fibrosis in chronic hepatitis B (CHB).
Methods
...DWI and intravoxel incoherent motion (IVIM) MRI were performed prospectively on liver for 146 patients with CHB and 21 healthy volunteers. ADC values were obtained from monoexponential model imaging. Diffusion coefficient (
D
), pseudodiffusion coefficient (
D
*), and perfusion fraction (
f
) obtained by biexponential model imaging, and stretched exponential model to obtain diffusion distribution coefficient (DDC) and diffusion heterogeneity index (
α
). Blood draw were performed on patients to obtain AST, ALT, and PLT, and then APRI and FIB-4 index were determined based on the serological diagnostic models. The fibrosis stage was staged (S0–S4) according to the pathology of liver puncture. Independent sample
t
test was used to compare the parameter values between liver fibrosis group and control group. One-way ANOVA was used to compare the parameters of different liver fibrosis grades. Bonferroni test was used for correcting multiple comparisons. Spearman correlation was used to analyze the correlation between each parameter and liver fibrosis grades. ROC was used to predict the diagnostic power of each parameter for liver fibrosis stages ≥ S2 and ≥ S3.
Results
ADC,
D
,
D
*,
f
, and DDC values were significantly different between normal control group and hepatic fibrosis group (
P
< 0.05). There were significant differences in ADC,
D
*,
f
, and DDC value among liver fibrosis groups (
P
< 0.05). D* and DDC values were moderately negatively correlated with the grades of liver fibrosis (
r
= − 0.483,
P
< 0.001;
r
= − 0.622,
P
< 0.001). ADC and
f
values were slightly negatively correlated with the grades of liver fibrosis (
r
= − 0.295,
P
< 0.001;
r
= − 0.312,
P
< 0.001). DDC values have the highest diagnostic efficiency in liver fibrosis stages ≥ S2 and ≥ S3. The areas under ROC curve (AUC) were 0.813 and 0.832 for ≥ S2 and ≥ S3, respectively, the sensitivity is 83.72% and 73.53%, and the specificity of 83.33% and 66.04%, which were better than APRI and FIB-4.
Conclusion
D
* obtained from biexponential and DDC obtained from stretched exponential DWI have better value in evaluating the degree of liver fibrosis in CHB.
The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients ...with severe COVID-19, who were recruited in our previous UC-MSC clinical trial.
In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102).
MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of −10.8% (95% CI: −20.7%, −1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups.
UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients.
The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.
Cancer patients are at increased risk of treatment- or disease-related admission to the intensive care unit. Over the past decades, both critical care and cancer care have improved substantially. Due ...to increased cancer-specific survival, we hypothesized that the number of cancer patients admitted to the intensive care unit (ICU) and survival have increased.
MIMIC-III was used to study trends and outcomes of cancer patients admitted to the ICU between 2002 and 2011. Multiple logistic regression analysis was performed to adjust for confounders of mortality.
Among 41,468 patients analyzed, 1,083 were hemato-oncologic, 4,330 were oncologic and 66 patients had both a hematological and solid malignancy. Admission numbers more than doubled and the proportion of cancer patients in the ICU increased steadily from 2002 to 2011. In both the univariate and multivariate analyses, solid cancers and hematologic cancers were strongly associated with 28-day mortality. This association was even stronger for 1-year mortality, with odds ratios of 4.02 (95% confidence interval CI, 3.69 to 4.38) and 2.25 (95% CI, 1.93 to 2.62), respectively. Over the 10-year study period, both 28-day and 1-year mortality decreased, with hematologic patients showing the strongest annual adjusted decrease in the odds of death. There was considerable heterogeneity among solid cancer types.
Between 2002 and 2011, the number of cancer patients admitted to the ICU more than doubled, while clinical severity scores remained overall unchanged, suggesting improved treatment. Although cancer patients had higher mortality rates, both 28-day and 1-year mortality of hematologic patients decreased faster than that of non-cancer patients, while mortality rates of cancer patients strongly depended on cancer type.
Background and Purpose
Panax ginseng is commonly used to treat cardiovascular conditions in Oriental countries. This study investigated the mechanisms underlying the vascular benefits of ginsenoside ...Rb3 (Rb3) in hypertension.
Experimental Approach
Rings of renal arteries were prepared from spontaneously hypertensive rats (SHRs) and normotensive Wistar‐Kyoto (WKY) rats and were cultured ex vivo for 8 h. Contractile responses of the rings were assessed with myograph techniques. Expression of NADPH oxidases was assessed by Western blotting and immunohistochemistry. Reactive oxygen species (ROS) were measured using dihydroethidium fluorescence imaging and production of NO was determined using the fluorescent NO indicator DAF‐FM diacetate in human umbilical vein endothelial cells.
Key Results
Ex vivo treatment with Rb3 concentration‐dependently augmented endothelium‐dependent relaxations, suppressed endothelium‐dependent contractions and reduced ROS production and expressions of NOX‐2, NOX‐4 and p67phox in arterial rings from SHR. Rb3 treatment also normalized angiotensin II (Ang II)‐stimulated elevation in ROS and expression of NOX‐2 and NOX‐4 in arterial rings from WKY rats. Rb3 inhibited Ang II‐induced reduction of NO production and phosphorylation of endothelial NOS in cultures of human umbilical vein endothelial cells. Rb3 also inhibited oxidative stress in renal arterial rings from hypertensive patients or in Ang II‐treated arterial rings from normotensive subjects.
Conclusion and Implications
Ex vivo Rb3 treatment restored impaired endothelial function in arterial rings from hypertensives by reversing over‐expression of NADPH oxidases and over‐production of ROS, and improved NO bioavailability. Our findings suggest that medicinal plants containing Rb3 could decrease oxidative stress and protect endothelial function in hypertension.
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