Publications by authors named "Ming Qi"

258 Publications

CircRNA circFADS2 is Downregulated in Endometritis and its Overexpression Promotes miR-643 Maturation in Human Endometrial Epithelial Cells to Suppress Cell Apoptosis.

Reprod Sci 2021 Sep 3. Epub 2021 Sep 3.

Reproductive Medicine Center, Zhongda Hospital, Southeast University, No. 87 Dingjia Bridge, Gulou District, Nanjing City, Jiangsu Province, 210009, People's Republic of China.

CircRNA circFADS2 suppresses LPS-induced inflammation, which plays a critical role in endometritis. Our preliminary sequencing analysis revealed a positive correlation between circFADS2 and miR-643, which also play protective roles in LPS-induced inflammation. Therefore, this study was performed to explore the involvement of circFADS2 in endometritis with a focus on its interaction with miR-643. RT-qPCR was performed to analyze the levels circFADS2, mature miR-643, and premature miR-643 in plasma samples from endometritis patients (n = 66) and healthy controls (n = 66). Pearson's correlation coefficient was applied to analyze correlations between these genes. The effect of circFADS2 on miR-643 maturation was analyzed by measuring miR-643 and premature miR-643 levels in circFADS2-overexpressed human endometrial epithelial cell line HEnEpCs. The role of circFADS2 and miR-643 in HEnEpC apoptosis under LPS treatment was analyzed by cell apoptosis assay. CircFADS2 was downregulated in endometritis and was positively correlated with mature miR-643, but not premature miR-643. CircFADS2 overexpression in HEnEpCs increased the level of mature miR-643 but not premature miR-643. Cell apoptosis analysis showed that circFADS2 and miR-643 overexpression protected HEnEpCs from LPS-induced cell apoptosis, and miR-643 inhibition reduced the effect of circFADS2 overexpression. CircFADS2 is downregulated in endometritis, and it overexpression promotes miR-643 maturation in HEnEpCs to suppress cell apoptosis.
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http://dx.doi.org/10.1007/s43032-021-00720-1DOI Listing
September 2021

[Evaluation of the application of dexmedetomidine combined with flurbiprofen axetil in extraction of multiple complex teeth under local anesthesia].

Shanghai Kou Qiang Yi Xue 2021 Jun;30(3):302-305

Shanghai Stomatological Hospital, Fudan University. Shanghai 200001, China. E-mail:

Purpose: To evaluate the safety and efficacy of sedation and analgesia using dexmedetomidine combined with flurbiprofen axetil in multiple complex teeth extraction under local anesthesia.

Methods: According to the inclusion and exclusion criteria of the study, 40 patients scheduled for multiple complex teeth (4-6) extraction were randomly divided into 2 groups: experimental group (sedation and analgesia using dexmedetomidine combined with flurbiprofen axetil in addition to local anesthesia, n=20) and control group (local anesthesia, n=20). The mean arterial pressure(MAP), heart rate(HR), Ramsay sedation score, VAS pain score of each patient at T0(basis value), T1 (during local anesthesia), T2(during extraction), T3(10 minutes after extraction) and the follow-up results were recorded. SAS 8.0 software was used for statistical analysis.

Results: Compared to T0 and control group at the same time, the experimental group revealed more stable mood and hemodynamic manifestation and better analgesic effect (P<0.05), from T1 to T3, patients in the control group showed increased blood pressure, heart rate, emotional fluctuation, bodily and facial pain(P<0.05). The follow-up results showed 5 and 0 patients taking painkillers in the control and experimental group, respectively(P<0.05).

Conclusions: Sedation and analgesia using dexmedetomidine combined with flurbiprofen axetil in addition to local anesthesia is a safe and effective approach in multiple complex teeth extraction.
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June 2021

Engineering a Smart Agent for Enhanced Immunotherapy Effect by Simultaneously Blocking PD-L1 and CTLA-4.

Adv Sci (Weinh) 2021 Sep 2:e2102500. Epub 2021 Sep 2.

Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Combinations of immune checkpoint therapies show encouraging results in the treatment of many human cancers. However, the higher costs and greater side effects of such combinations compared with single-agent immunotherapies limit their further applications. In this work, a novel smart agent, [email protected] F-ZIF-8, is developed to overcome these limitations. KN046 is a novel recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody-Fc fusion protein, which can bind to both PD-L1 and CTLA-4 effectively. ZIF-8 is a smart delivery system, which can safely and effectively deliver KN406 to a tumor. In vitro and in vivo results demonstrate that the smart agent [email protected] F-ZIF-8 not only improves the immune response rate of the antibody drug in treatment of tumors but also reduces its toxic side effects, thereby achieving excellent antitumor efficacy. This study provides an engineering strategy for clinical applications of a more effective immunotherapy.
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http://dx.doi.org/10.1002/advs.202102500DOI Listing
September 2021

Synergic fabrication of succimer coated titanium dioxide nanomaterials delivery for proliferation and examination on human aortic endothelial cells.

Drug Deliv 2021 Dec;28(1):1785-1794

Department of Vascular Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.

The probable nanotoxicity to human health and the environment is a significant challenge for the sustainable application of nanomaterials in medicine. The cytototoxical effect of succimer (meso-2,3-dimercaptosuccinic acid-DMSA) coated titanium dioxide (DMSA-TiO) with cultured human aortic endothelial cells (HAoECs) was assessed in this investigation. Our findings have shown that DMSA-TiO can be accumulated in HAoECs and dispersed in a cytoplasm on the culture medium. DMSA-cytotoxicity TiO effects were dose-responsive, and the concentrations were of little toxicity, and MTT stain testing showed that they had only 0.02 mg ml. Meanwhile, the lactate dehydrogenase biomarker was not considerably more remarkable than the biomarker from untreated (control) cells (free DMSA-TiO). Though, also without any apparent signs of cell damage, the endocrine functions for prostacyclin I-2 and endothelin-1 and the urea transporter functions were modified. In addition, endothelial tube development has been shown that HAoECs could induce angiogenesis even with small amounts of DMSA-TiO (0.01 and 0.02 mg ml). Further, we have examined the toxicity and biochemical parameter by animal model. Furthermore, assessments designated that the resulting DMSA-TiO presented synergistic activities of angiogenesis activity. Overall, these findings show the cytotoxicity of DMSA-TiO and could induce adverse effects on normal endothelial cells.
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http://dx.doi.org/10.1080/10717544.2021.1960925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425759PMC
December 2021

Gene Therapy for -Associated Retinal Diseases Helps to Delay Retinal Degeneration and Vision Loss.

Drug Des Devel Ther 2021 17;15:3581-3591. Epub 2021 Aug 17.

Department of Cell Biology and Medical Genetics, School of Medicine Zhejiang University, Hangzhou, 310000, People's Republic of China.

Purpose: The aim of study was to establish -associated inherited retinal disease (-IRD) mouse model and to identify the best timepoint for gene therapy.

Methods: We induced retinal degeneration in mice using a bright light. We clarified the establishment of -IRD mouse model by analyzing the thickness of retinal layers and electroretinography (ERG). -IRD mice received a subretinal injection of adeno-associated virus 2/8-packaged cDNA for treatment. We evaluated the visual function and retinal structure in the treated and untreated eyes to identify the best timepoint for gene therapy.

Results: -IRD mice showed significant differences in ERG amplitudes and photoreceptor survival compared to mice. Preventive gene therapy not only maintained normal visual function but also prevented photoreceptor loss. Salvage gene therapy could not reverse the retinal degeneration phenotype of -IRD mice, but it could slow down the loss of visual function.

Conclusion: The light-induced retinal degeneration in our mice indicated that a defect in alone was sufficient to cause visual dysfunction and photoreceptor degeneration, which reproduced the phenotypes observed in -IRD patients. This model is suitable for gene therapy studies. Early treatment of the primary defect helps to delay the later onset of photoreceptor degeneration and maintains visual function in -IRD mice.
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http://dx.doi.org/10.2147/DDDT.S305378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380142PMC
August 2021

Ginkgo Biloba Extract Is Comparable With Donepezil in Improving Functional Recovery in Alzheimer's Disease: Results From a Multilevel Characterized Study Based on Clinical Features and Resting-State Functional Magnetic Resonance Imaging.

Front Pharmacol 2021 3;12:721216. Epub 2021 Aug 3.

Division of Brain Rehabilitation, Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Ginkgo biloba extract (GBE) and donepezil have been reported to be effective in patients with Alzheimer's disease (AD). Nonetheless, how these drugs impact spontaneous brain activities and how they consequently improve functional recovery are currently unclear. This study was to explore the efficacy of GBE vs. donepezil and their add-on efficacy on functional recovery and the adaption of spontaneous brain activities following pharmacologic treatment in patients with AD. Patients with AD were enrolled and assigned to the GBE group ( = 50), the donepezil group ( = 50), or the combined group ( = 50). Neuropsychological assessments, including minimum mental state examination (MMSE), Alzheimer's disease assessment scale-cognition (ADAS-Cog), instrumental activity of daily living (IADL), geriatric depression scale (GDS), neuropsychiatric inventory (NPI), and quality of life in Alzheimer's disease (QOL-AD), were conducted at baseline, 1 month, 3 months, and 6 months. Resting-state functional magnetic resonance imaging (rs-fMRI) was collected to compare the amplitude of low-frequency fluctuation (ALFF), percent amplitude of fluctuation (PerAF), regional homogeneity (ReHo), and degree centrality (DC) at baseline and 6 months. No major significant differences were detected in all comparisons between groups across all follow-up time points. For intragroup comparison, MMSE and ADAS-Cog scores differed significantly across all follow-ups in three groups. The combined group showed significant improvement of GDS scores between baseline and 6 months ( = 0.007). The GBE group ( = 0.044) and donepezil group ( = 0.012) demonstrated significant improvement of NPI scores between baseline and 6 months. Significant correlations were observed between IADL and ALFF in the right gyrus rectus ( = 0.03) and in the left superior cerebellum gyrus ( = 0.01), between GDS and ALFF in the right middle temporal gyrus ( = 0.01), between NPI and PerAF in the left fusiform gyrus ( = 0.03), and between MMSE and ReHo in right superior frontal gyrus ( = 0.04). GBE was comparable with donepezil in the improvement of functional recovery in patients with AD while the combined application of GBE and donepezil seems unnecessary. GBE-mediated improvement of functional recovery was characterized by decreased ALFF values in the right gyrus rectus and decreased PerAF values in the left fusiform gyrus. These featured variations of imaging metrics in specific brain regions may serve as biomarkers in the monitoring of the therapeutic efficacy of GBE.
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http://dx.doi.org/10.3389/fphar.2021.721216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369572PMC
August 2021

Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE.

Clin Lymphoma Myeloma Leuk 2021 Jun 18. Epub 2021 Jun 18.

Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Navarra, Spain.

Background: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.

Patients And Methods: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.

Results: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%).

Conclusion: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
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http://dx.doi.org/10.1016/j.clml.2021.06.005DOI Listing
June 2021

The Challenges and Pitfalls of Detecting Sleep Hypopnea Using a Wearable Optical Sensor: Comparative Study.

J Med Internet Res 2021 Jul 29;23(7):e24171. Epub 2021 Jul 29.

Center for Sleep Medicine, Sleep Research and Epileptology, Barmelweid, Switzerland.

Background: Obstructive sleep apnea (OSA) is the most prevalent respiratory sleep disorder occurring in 9% to 38% of the general population. About 90% of patients with suspected OSA remain undiagnosed due to the lack of sleep laboratories or specialists and the high cost of gold-standard in-lab polysomnography diagnosis, leading to a decreased quality of life and increased health care burden in cardio- and cerebrovascular diseases. Wearable sleep trackers like smartwatches and armbands are booming, creating a hope for cost-efficient at-home OSA diagnosis and assessment of treatment (eg, continuous positive airway pressure [CPAP] therapy) effectiveness. However, such wearables are currently still not available and cannot be used to detect sleep hypopnea. Sleep hypopnea is defined by ≥30% drop in breathing and an at least 3% drop in peripheral capillary oxygen saturation (Spo) measured at the fingertip. Whether the conventional measures of oxygen desaturation (OD) at the fingertip and at the arm or wrist are identical is essentially unknown.

Objective: We aimed to compare event-by-event arm OD (arm_OD) with fingertip OD (finger_OD) in sleep hypopneas during both naïve sleep and CPAP therapy.

Methods: Thirty patients with OSA underwent an incremental, stepwise CPAP titration protocol during all-night in-lab video-polysomnography monitoring (ie, 1-h baseline sleep without CPAP followed by stepwise increments of 1 cmHO pressure per hour starting from 5 to 8 cmHO depending on the individual). Arm_OD of the left biceps muscle and finger_OD of the left index fingertip in sleep hypopneas were simultaneously measured by frequency-domain near-infrared spectroscopy and video-polysomnography photoplethysmography, respectively. Bland-Altman plots were used to illustrate the agreements between arm_OD and finger_OD during baseline sleep and under CPAP. We used t tests to determine whether these measurements significantly differed.

Results: In total, 534 obstructive apneas and 2185 hypopneas were recorded. Of the 2185 hypopneas, 668 (30.57%) were collected during baseline sleep and 1517 (69.43%), during CPAP sleep. The mean difference between finger_OD and arm_OD was 2.86% (95% CI 2.67%-3.06%, t=28.28; P<.001; 95% limits of agreement [LoA] -2.27%, 8.00%) during baseline sleep and 1.83% (95% CI 1.72%-1.94%, t=31.99; P<.001; 95% LoA -2.54%, 6.19%) during CPAP. Using the standard criterion of 3% saturation drop, arm_OD only recognized 16.32% (109/668) and 14.90% (226/1517) of hypopneas at baseline and during CPAP, respectively.

Conclusions: arm_OD is 2% to 3% lower than standard finger_OD in sleep hypopnea, probably because the measured arm_OD originates physiologically from arterioles, venules, and capillaries; thus, the venous blood adversely affects its value. Our findings demonstrate that the standard criterion of ≥3% OD drop at the arm or wrist is not suitable to define hypopnea because it could provide large false-negative results in diagnosing OSA and assessing CPAP treatment effectiveness.
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http://dx.doi.org/10.2196/24171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367170PMC
July 2021

De novo HBB frameshift mutation in a patient with dominant β-thalassemia major.

Int J Lab Hematol 2021 Jul 29. Epub 2021 Jul 29.

Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China.

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http://dx.doi.org/10.1111/ijlh.13669DOI Listing
July 2021

Comparative analysis of fecal microbiota composition diversity in Tibetan piglets suffering from diarrheagenic Escherichia coli (DEC).

Microb Pathog 2021 Sep 24;158:105106. Epub 2021 Jul 24.

Animal Science College, Tibet Agriculture & Animal Husbandry University, Linzhi, China. Electronic address:

This study was ascertained to investigate the adverse effects of pathogenic E. coli on gut microbiota of Tibetan piglets with history of yellow and white dysentery. For this purpose, a total of 18 fecal samples were collected from infected and healthy Tibetan piglets for 16S rRNA gene amplification and sequencing of V3-V4 region. Results showed that Firmicutes, Bacteroidia Fusobacteriota, Proteobacteria and Actinobacteriota were the predominant bacteria in Tibetan piglets at the level of phylum classification. Results on classification at family level showed that Lactobacillus, Bacteroidota, Fusobacteriota and Enterobacteriaceae were the dominant bacteria. Results on classification of bacteria at phylum level compared with normal piglets indicated that Bacteroidota, Actinobacteriota, Euryarchaota and Spirochaetota in fecal microbial community in Tibetan piglets showing yellow dysenteric and diarrhea group were significantly decreased (P ≤ 0.05). Compared with the feces of healthy Tibetan piglets, the abundance of Escherichia-Shigella, Lactobacillus and Enterococcus increased significantly in feces of Tibetan piglets having yellow dysentery and white dysentery. Moreover, results exhibited that the Proteobacteria and Fusobacteriota were significantly increased (P ≤ 0.05) suggesting dominant microbial community. Results revealed that E. coli induced different pathological alterations in intestine including damage to intestinal epithelial cells, infiltration of inflammatory cells, presence of red blood cells in spaces of tissues, hemorrhages and necrosis of intestinal villi in piglets with history of yellow dysentery. This study for the first time reported the composition, characteristics, and differences of the fecal microflora diversity of Tibetan piglets with yellow and white dysentery in Qinghai-Tibet Plateau, which can provide a suitable support for effective control of diarrhoeal disease in these animals.
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http://dx.doi.org/10.1016/j.micpath.2021.105106DOI Listing
September 2021

Sustained Minimal Residual Disease Negativity With Daratumumab in Newly Diagnosed Multiple Myeloma: MAIA and ALCYONE.

Blood 2021 Jul 16. Epub 2021 Jul 16.

Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).
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http://dx.doi.org/10.1182/blood.2020010439DOI Listing
July 2021

Serum biochemical parameters and amino acids metabolism are altered in piglets by early-weaning and proline and putrescine supplementations.

Anim Nutr 2021 Jun 17;7(2):334-345. Epub 2021 Mar 17.

College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, Hunan, China.

The study was to investigate the effect of early-weaning stress and proline (Pro) and putrescine (Put) supplementations on serum biochemical parameters and amino acids (AA) metabolism in suckling and post-weaning pigs. Blood and small intestinal mucosa were harvested from suckling piglets at 1, 7, 14, and 21 d of age and piglets on d 1, 3, 5, and 7 after weaning at 14 d of age, as well as from piglets received oral administration of Pro and Put from 1 to 14 d old. In suckling piglets, the serum glucose, albumin and total cholesterol levels were increased ( < 0.05) with increasing age, whereas the serum globulin, urea nitrogen (BUN), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels were lowered ( < 0.05). The concentrations of most serum AA and the AA transporters related gene expressions were highest in 7-d-old piglets ( < 0.05), whereas the phosphorylation status of the mammalian target of the rapamycin (mTOR) signaling pathway in the small intestine increased in piglets from 1 to 21 d old ( < 0.05). Weaning at 14 d old increased ( < 0.05) the BUN and triglycerides levels in serum, as well as jejunal solute carrier family 7 member 6 (), ileal and mRNA abundances at d 1 or 3 post-weaning. Weaning also inhibited ( < 0.05) the phosphorylation levels of mTOR and its downstream ribosomal protein S6 kinase 1 (S6K1) and 4E-binding protein-1 (4EBP1) in the small intestine of weanling pigs. Oral administration of Put and Pro decreased ( < 0.05) serum ALP levels and increased ( < 0.05) intestinal and mRNA abundances and mTOR pathway phosphorylation levels in post-weaning pigs. Pro but not Put treatment enhanced ( < 0.05) serum Pro, arginine (Arg) and glutamine (Gln) concentrations of weaning-pigs. These findings indicated that early-weaning dramatically altered the biochemical blood metabolites, AA profile and intestinal mTOR pathway activity, and Pro and Put supplementations improved the AA metabolism and transportation as well as activated the intestinal mTOR pathway in weanling-pigs. Our study has an important implication for the broad application of Pro and Put in the weaning transition of piglets.
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http://dx.doi.org/10.1016/j.aninu.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245818PMC
June 2021

Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study.

Clin Lymphoma Myeloma Leuk 2021 Sep 24;21(9):e699-e709. Epub 2021 Apr 24.

Peking University People's Hospital, National Clinical Research Center for Hematologic Disease, Beijing, China; Collaborative Innovation Center of Hematology, Soochow, China. Electronic address:

Background: Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM.

Patients And Methods: Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS).

Results: A total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR.

Conclusion: These data support the use of D-Vd in Chinese patients with RRMM.
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http://dx.doi.org/10.1016/j.clml.2021.04.012DOI Listing
September 2021

Correction to: The Design of the AZO Conductive Layer on Microchannel Plate.

Nanoscale Res Lett 2021 Jun 9;16(1):103. Epub 2021 Jun 9.

State Key Laboratory of Particle Detection and Electronics, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China.

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http://dx.doi.org/10.1186/s11671-021-03556-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190213PMC
June 2021

[A review of consensus statements, practice resources, standards and guidelines for clinical applications of next-generation sequencing technologies in the United States].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Jun;38(6):513-520

Department of Genetics, Yale University School of Medicine, New Haven CT 06511, USA.

The use of whole exome sequencing (WES) for the detection of disease-causing variants of genetic diseases and for non-invasive prenatal screening (NIPS) of fetal aneuploidies are two major clinical applications of next generation sequencing (NGS). This article has summarized the official documents developed and updated by the American College of Medical Genetics and Genomics (ACMG) on governing WES and NIPS. These include the development of expert consensus policies and position statements on an ongoing basis to guide clinical application of NGS technology and variant analysis, establish evidence-based practical resources, as well as standards and guidelines to govern diagnosis and screening. These ACMG documents are valuable references to Chinese geneticists, but direct adoption of these standards and guidelines may not be practical due to the differences in disease-associated variant frequencies in Chinese population, socioeconomic status, and medical practice between the two countries. It is hoped that this review could facilitate the development of NGS and NIPS standards and guidelines that are consistent with international standards and concordant with medical genetics practice in China to provide high-quality, efficient and safe clinical services for patients and their families with genetic diseases.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200924-00691DOI Listing
June 2021

Fullerene C60 Protects Against Intestinal Injury from Deoxynivalenol Toxicity by Improving Antioxidant Capacity.

Life (Basel) 2021 May 27;11(6). Epub 2021 May 27.

Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China.

Oxidative stress is involved in a wide variety of pathologies, and fullerene has been shown to have an antioxidant ability. Mycotoxins exert toxic effects through induction of excessive reactive oxygen species (ROS). Here, we evaluated water-soluble fullerene C60 for its anti-mycotoxin and antioxidant effects in vitro and in vivo. Intestinal epithelial cells were cultured with fullerene during deoxynivalenol (DON) exposure. The results revealed that fullerene C60 significantly promoted cell viability, decreased apoptosis and necrotic cell number, and significantly reduced intracellular ROS levels during DON exposure ( < 0.05). To investigate the role of fullerene in antioxidant capacity in vivo further, 40 three-week-old male C57BL/6 mice were randomly divided into four groups. There were no significant differences between the control and fullerene groups ( > 0.05). In mice exposed to DON, supplementation with fullerene C60 significantly improved growth performance, and enhanced the total antioxidant status and the activities of SOD and GPX in the intestine and liver ( < 0.05). In addition, fullerene C60 supplementation improved intestinal morphology, as indicated by a higher villus height and tight junction protein expression ( < 0.05). Furthermore, fullerene supplementation decreased serum concentrations of inflammatory cytokine and lipopolysaccharide (LPS; a penetrability marker) compared to the DON-challenged group ( < 0.05). The current study suggests that fullerene C60 improves intestinal antioxidant status against DON-induced oxidative stress in vitro and in vivo.
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http://dx.doi.org/10.3390/life11060491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229202PMC
May 2021

Long Noncoding RNA Activates Canonical Wnt/β-Catenin Signaling Through Small Heat Shock Proteins HSPA6 and CRYAB.

Front Cell Dev Biol 2021 10;9:660576. Epub 2021 May 10.

Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Congenital heart defects (CHDs) are the most common birth defects worldwide. 22q11.2 deletion syndrome is the most common microdeletion disorder that has been frequently associated with conotruncal malformations. By now, the dosage-sensitive gene has been adopted as the major pathogenic gene responsible for 22q11.2 deletion, which is regulated by canonical Wnt/β-catenin signaling pathway in heart outflow tract development. Here, we report the long noncoding RNA (lncRNA) , which is encompassed in the 22q11.2 region, that can activate canonical Wnt/β-catenin signaling by protecting β-catenin from degradation, which could result from decreased ubiquitination. Such effects were mediated by two short heat shock proteins HSPA6 and α-β-crystallin (CRYAB), whose expression was regulated by through a competing endogenous RNA (ceRNA) mechanism. In clinical practice, the pathogenesis of copy number variation (CNV) was always attributed to haploinsufficiency of protein-coding genes. Here, we report that the 22q11.2 lncRNA significantly activated canonical Wnt/β-catenin signaling, which has major roles in cardiac outflow tract development and should act upstream of . Our results suggested that lncRNAs should contribute to the etiology of CNV-related CHD.
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http://dx.doi.org/10.3389/fcell.2021.660576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141806PMC
May 2021

Overcoming chemotherapy resistance using pH-sensitive hollow MnO nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma.

J Nanobiotechnology 2021 May 26;19(1):157. Epub 2021 May 26.

Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.

Background: Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO nanoshells on metastatic cancer is still uncertain.

Result: Here, intelligent "theranostic" platforms were synthesized based on hollow mesoporous MnO (H-MnO) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (HO) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1α expression was decreased, suggesting that the accumulation of MnO in the tumor caused the decomposition of HO into O and alleviated the hypoxia of the tumor.

Conclusion: In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions.
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http://dx.doi.org/10.1186/s12951-021-00901-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157461PMC
May 2021

Perivascular cell-derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs.

J Extracell Vesicles 2021 05 21;10(7):e12096. Epub 2021 May 21.

College of Pharmacy Jinan University Guangzhou China.

Antiangiogenic tyrosine kinase inhibitors (AA-TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA-TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA-TKI therapy withdrawal-induced tumour revascularization frequently occurs, hampering the clinical application of AA-TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA-TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA-TKI cessation experimental settings. Mechanistically, tumour perivascular cell-derived extracellular vehicles (TPC-EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off-AA-TKI-induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long-lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.
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http://dx.doi.org/10.1002/jev2.12096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138700PMC
May 2021

Emerging roles of circular RNAs in thyroid cancer.

Exp Cell Res 2021 07 21;404(2):112626. Epub 2021 May 21.

Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Thyroid and Breast Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Thyroid Surgery, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang, 310009, China. Electronic address:

As the most common endocrine-related malignant tumor, the prevalence of thyroid cancer (TC) has soared strikingly over the past thirty years then verged to stabilization or even descension temporally. Distributed in a cell-specific manner, circular RNAs (circRNAs) is a novel class of non-coding RNAs characterized by its covalently closed loop without 5'-terminal cap and 3'-terminal poly A tail, which guarantee its distinctive evolutionary conservation and exonucleases resistance. Emerging evidence indicates that circRNA participates in the pathogenesis and carcinogenesis of several cancers including thyroid cancer. In this review, we concentrated on the connection between circRNAs and thyroid cancer so as to obtain a more profound understanding. We aim to discuss this relationship between TC and circRNAs by summarizing the effect of various circRNAs on tumor biological behaviors and clinical application, and systematically outlook the conceivable application of circRNAs in TC diagnosis and therapy.
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http://dx.doi.org/10.1016/j.yexcr.2021.112626DOI Listing
July 2021

[Carrier screening model for Duchenne muscular dystrophy for women of reproductive age based on a pre-pregnancy birth defect control platform].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 May;38(5):485-487

Hangzhou Health Service Center for Children and Women, Hangzhou, Zhejiang 310006, China.

Objective: To establish a screening model for females of reproductive age carrying Duchenne muscular dystrophy (DMD) variants based on a current community health examination platform.

Methods: A total of 61 870 participants were recruited between October 2017 and October 2019. Serum creatine kinase (CK) was measured with a Roche Cobasc 701/702 using an enzymatic rate method. Genetic testing was offered to those with a CK level of ≥ 200 U/L. For carriers of DMD variants, genetic counseling and follow up were provided.

Results: For the 61 870 females participating in the program, 1078 were found with raised serum CK (≥ 200 U/L), of which 618 (57.33%) accepted CK re-measurement after at least a two-week interval. One hundred and twenty cases were found with sustained serum CK elevation, of which 6 were confirmed to be definite DMD carriers regardless of family history. Genetic testing was provided to 33 females with a family history for DMD, and 13 were determined as definite carriers. An affected fetus was detected by prenatal diagnosis. After genetic counseling, the parents had opted induced abortion.

Conclusion: Large-scale DMD carrier screening through a three-step approach based on the current community health examination platform is both feasible and cost effective.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200331-00223DOI Listing
May 2021

Aberrant TGF-β1 signaling activation by MAF underlies pathological lens growth in high myopia.

Nat Commun 2021 04 8;12(1):2102. Epub 2021 Apr 8.

Eye Institute, Eye & ENT Hospital, Fudan University, Shanghai, China.

High myopia is a leading cause of blindness worldwide. Myopia progression may lead to pathological changes of lens and affect the outcome of lens surgery, but the underlying mechanism remains unclear. Here, we find an increased lens size in highly myopic eyes associated with up-regulation of β/γ-crystallin expressions. Similar findings are replicated in two independent mouse models of high myopia. Mechanistic studies show that the transcription factor MAF plays an essential role in up-regulating β/γ-crystallins in high myopia, by direct activation of the crystallin gene promoters and by activation of TGF-β1-Smad signaling. Our results establish lens morphological and molecular changes as a characteristic feature of high myopia, and point to the dysregulation of the MAF-TGF-β1-crystallin axis as an underlying mechanism, providing an insight for therapeutic interventions.
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http://dx.doi.org/10.1038/s41467-021-22041-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032689PMC
April 2021

GABA transporter sustains IL-1β production in macrophages.

Sci Adv 2021 Apr 7;7(15). Epub 2021 Apr 7.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China.

Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3-ASC-caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.
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http://dx.doi.org/10.1126/sciadv.abe9274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026138PMC
April 2021

The Design of the AZO Conductive Layer on Microchannel Plate.

Nanoscale Res Lett 2021 Apr 7;16(1):55. Epub 2021 Apr 7.

State Key Laboratory of Particle Detection and Electronics, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China.

When the resistivity of the AZO conductive layer is within the MCP resistance requirement, the interval of the Zn content is very narrow (70-73%) and difficult to control. Aiming at the characteristics of the AZO conductive layer on the microchannel plate, an algorithm is designed to adjust the ratio of the conductive material ZnO and the high resistance material Al2O3. We put forward the concept of the working resistance of the MCP (i.e., the resistance during the electron avalanche in the microchannel). The working resistance of AZO-ALD-MCP (Al2O3/ZnO atomic layer deposition microchannel plate) was measured for the first time by the MCP resistance test system. In comparison with the conventional MCP, we found that the resistance of AZO-ALD-MCP in working state and non-working state is very different, and as the voltage increases, the working resistance significantly decreases. Therefore, we proposed a set of analytical methods for the conductive layer. We also proposed to adjust the ratio of the conductive material of the ALD-MCP conductive layer to the high-resistance material under the working resistance condition, and successfully prepared high-gain AZO-ALD-MCP. This design opens the way for finding better materials for the conductive layer of ALD-MCP to improve the performance of MCP.
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http://dx.doi.org/10.1186/s11671-021-03515-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026805PMC
April 2021

MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC.

J Nanobiotechnology 2021 Mar 20;19(1):80. Epub 2021 Mar 20.

Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China.

Background: The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as "self", evade the surveillance of the immune system, and accumulate to the tumor sites actively.

Results: Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate-an derivative of indocyanine green to fabricate [email protected], which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of [email protected] and [email protected] (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of [email protected] Importantly, the constructed [email protected] exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy.

Conclusions: These results proved that [email protected] could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.
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http://dx.doi.org/10.1186/s12951-021-00823-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981797PMC
March 2021

Precise engineering of cetuximab encapsulated gadollium nanoassemblies: ultrasound diagnosis and thyroid cancer therapy.

Drug Deliv 2021 Dec;28(1):569-579

Ultrasound Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.

We report the formulation of nanoassemblies (NAs) comprising C225 conjugates Gd-PFH-NAs (C-Gd-PFH-NAs) for low-intensity focused ultrasound diagnosis ablation of thyroid cancer. C-Gd-PFH-NAs showed excellent stability in water, phosphate-buffered saline (PBS), and 20% rat serum. Transmission electron microscopy (TEM) images also revealed the effective construction of C-Gd-PFH-NAs as common spherical assemblies. The incubation of C625 thyroid carcinoma with C-Gd-PFH-NAs triggers apoptosis, as confirmed by flow cytometry analysis. The C-Gd-PFH-NAs exhibited antitumor efficacy in human thyroid carcinoma xenografts, where histopathological results further confirmed these outcomes. Furthermore, we were able to use low-intensity focused ultrasound diagnosis imaging (LIFUS) to examine the efficiency of C-Gd-PFH-NAs in thyroid carcinoma . These findings clearly show that the use of LIFUS agents with high performance imaging in different therapeutic settings will have extensive potential for future biomedical applications.
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http://dx.doi.org/10.1080/10717544.2021.1889721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971338PMC
December 2021

Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN.

Blood Adv 2021 02;5(4):1092-1096

Dana-Farber Cancer Institute, Boston, MA.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.
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http://dx.doi.org/10.1182/bloodadvances.2020003642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903234PMC
February 2021

Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study.

Ann Hematol 2021 Apr 18;100(4):1065-1077. Epub 2021 Feb 18.

Division of Hematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (C). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of C was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the C concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.
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http://dx.doi.org/10.1007/s00277-021-04405-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960612PMC
April 2021

Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study.

J Hematol Oncol 2021 02 15;14(1):25. Epub 2021 Feb 15.

Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, 06351, South Korea.

Background: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL.

Methods: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification).

Results: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab.

Conclusions: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.
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http://dx.doi.org/10.1186/s13045-020-01020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885403PMC
February 2021

Health-related quality of life maintained over time in patients with relapsed or refractory multiple myeloma treated with daratumumab in combination with bortezomib and dexamethasone: results from the phase III CASTOR trial.

Br J Haematol 2021 05 8;193(3):561-569. Epub 2021 Feb 8.

Janssen Research & Development, LLC, Raritan, NJ, USA.

In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D-Vd) significantly extended progression-free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient-reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed-effects model. After Cycle 8, PROs were only collected for patients in the D-Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ-C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health-related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long-term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D-Vd in patients with RRMM and support its use in this patient population.
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http://dx.doi.org/10.1111/bjh.17321DOI Listing
May 2021
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