ABSTRACT
Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Lymphoma, T-Cell , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm Staging , Lymphoma, T-Cell/etiology , Killer Cells, Natural , Clinical Trials, Phase II as TopicABSTRACT
BACKGROUND: Multiple myeloma is a disease of the older people, whose prognoses are highly heterogeneous. The International Myeloma Working Group (IMWG) proposed a geriatric assessment (GA) based on age, functional status and comorbidities to discriminate between fit and frail patients. Given the multidimensional nature of frailty and the relatively recent exploration of frailty in the field of MM, reaching a consensus on the measurement of frailty in MM patients remains challenging. OBJECTIVE: We sought to assess the feasibility of performing a comprehensive GA (CGA) in older MM patients in a real-world and multicentre setting and to evaluate their baseline CGA profiles. RESULTS: We studied 349 older patients with newly diagnosed MM (age range, 65-86 years). Our results showed that a CGA is feasible for older MM patients. Using the IMWG-GA criteria, we identified significantly more frail patients in our cohort comparing to in the IMWG cohort (43% vs 30%, P = 0.002). In the IMWG-GA 'fit' group, risk of malnutrition, depression and cognitive impairment remains. The median follow-up time was 26 months (range 1-38). The median overall survival (OS) was 34.7 months, and the estimated 3-year OS rate was 50%. A high MNA-SF score (MNA-SF ≥ 12), low GDS score (GDS ≤ 5) and high CCI score (CCI ≥ 2) can be used to predict the OS of older patients with newly diagnosed MM. This study is registered at www.clinicaltrials.gov (NCT03122327). CONCLUSIONS: Our study justifies the need for a CGA in older patients with newly diagnosed MM.
Subject(s)
Frailty , Multiple Myeloma , Aged , Aged, 80 and over , Frail Elderly , Frailty/diagnosis , Frailty/epidemiology , Geriatric Assessment , Humans , Multiple Myeloma/diagnosis , Prospective StudiesABSTRACT
Background: Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD. Methods: We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. Results: Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/ß, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid ß-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid ß-peptide (Aß) by reducing the expression of ß-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice. Conclusion: Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.
ABSTRACT
The excitotoxicity induced by kainic acid (KA) is thought to contribute to the development of Alzheimer's disease (AD); however, the mechanisms underlying this excitotoxicity remain unknown. In the current study, we investigated the dynamic changes in tau phosphorylation and their associations with the excitotoxicity induced by intraperitoneal injection of KA in the mouse brain. We found that KA-induced excitotoxicity led to sustained hyperphosphorylation of tau in MAPT transgenic (Tg) mice. By using cultured microglia and mouse brains, we showed that KA treatment specifically induced endoplasmic reticulum (ER) stress, which was characterized by activation of the major biomarkers of ER, such as ATF6, GRP78, and IRE1, and resulted in stimulation of inflammasomes. KA receptors (KARs), such as Girk1, were determined to be involved in this KA-induced ER stress. ER stress was also shown to activate inflammasomes by stimulating the expression of the two major components of inflammasomes, nucleotide binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) and nuclear factor (NF)-κB, and eventually causing the production of interleukin-1ß (IL-1ß). Inhibition of NLRP3 or NF-κB by Bay11-7082 resulted in reduction of KA-induced IL-1ß production. Our results also revealed the positive effects of IL-1ß on tau phosphorylation, which was blocked by Bay11-7082. Notably, the results indicate that Bay11-7082 acts against KA-induced neuronal degeneration, tau phosphorylation, and memory defects via inflammasomes, which further highlight the protective role of Bay11-7082 in KA-induced neuronal defects.
Subject(s)
Brain/metabolism , Excitatory Amino Acid Agonists/toxicity , Inflammasomes/metabolism , Kainic Acid/toxicity , tau Proteins/metabolism , Animals , Brain/drug effects , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/physiology , Inflammasomes/drug effects , Mice , Mice, Transgenic , Phosphorylation , tau Proteins/drug effects , tau Proteins/geneticsABSTRACT
OBJECTIVE: To investigate the effects of matrix metalloproteinase-9 (MMP-9) on granulocyte colony stimulation factor (G-CSF)-induced hematopoietic stem/progenitor cell (HSPC) mobilization in healthy donors of hematopoietic stem cells. METHODS: Peripheral blood (PB) samples and bone marrow (BM) blood samples were collected from 12 healthy donors of hematopoietic stem cell before and 5 days after G-CSF-induced mobilization. CD34(+) cells were isolated and purified. ELISA was used to detect the protein expression of MMP-9 in the peripheral blood and BM blood of the healthy donors. The protein expression of MMP-9 in the BM blood was detected by ELISA and immunohistochemistry, and the stromal cell-derived factor-1 (SDF-1) level in the BM blood was detected by ELISA. The mRNA expression of MMP-9 in the BM blood samples was detected by RT-PCR. HT1080 cells rich in MMP-9 were cultured. CD34(+) cells were co-cultured with the supernatant of HT1080 cell culture fluid. CD34(+) cells cultured in Iscove's modified Dulbecco's medium were used as control group. Fluorescence-activated cell sorter was used to detect the CXCR4 expression on the surface of the CD34(+) cells. In the transwell experiment CD34(+) cells were divided into 4 groups: control group, o-phenanthroline (MMP-9 chemical inhibitor, MPI) group, HT1080 sup group, and HT1080 + MPI group to be co-cultured with buffer, o-phenanthroline, supernatant of culture fluid of HT1080 cells, or supernatant of culture fluid of HT1080 cells Flow cytometry was used to calculate the cell migration capacity. RESULTS: The MMP-9 level of BM and PB of the healthy donors 5 days after G-CSF mobilization were 278 ng/ml +/- 34 ng/ml and 392 ng/ml +/- 284 ng/ml respectively, both significantly higher than those before G-CSF mobilization (42 ng/ml +/- 17 ng/ml and 27 ng/ml +/- 12 ng/ml respectively (P < 0.01 and P < 0.05). Western blotting showed that the SDF-1 level in the supernatant 5 days after G-CSF mobilization was 5.9 ng/ml +/- 1.0 ng/ml, significantly lower than that before G-CSF mobilization (7.2 ng/ml +/- 0.7 ng/ml, P < 0.05). The CXCR4 levels of the CD34(+) cell from both PB and BM blood were up-regulated after co-culture with the supernatant of HT1080 cells (both P < 0.05). The migration capacity of CD34(+) cells cultured in the supernatant of HT1080 cells was increased significantly (P < 0.05), however, this effect could be inhibited by MIP (P < 0.05). The PB WBC numbers of the G-CSF group and G-CSF + MPI group were 14.9 x 10(6)/L +/- 4.3 x 10(6)/L and 12.3 x 10(6)/L +/- 1.2 x 10(6)/L respectively, the PB WBC numbers of the G-CSF + MPI group was significantly lower than that of the G-CSF group (P < 0.05), however, significantly higher than that of the negative control group (6.8 x 10(6)/L +/- 2.5 x 10(6)/L, P < 0.05). The CFU of the G-CSF group was (84 +/- 10) U/2 x 10(5) MNC, significantly higher than that of the G-CSF + MPI group, (69 +/- 3) U/2 x 10(5) MNC (P < 0.05). The BM MNC number of the G-CSF group was 12.7 x 10(6)/L +/- 0.7 x 10(6)/L, not significantly different from that of the G-CSF + MPI groups (13.1 x 10(6)/L +/- 1.3 x 10(6)/L; P > 0.05). CONCLUSION: MMP-9 probably facilitates HSPC mobilization by degrading SDF-1, up-regulating CXCR4 expression on the CD34(+) cells, and increasing the migration ability of CD34(+) cells.
Subject(s)
Granulocyte Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cell Mobilization/methods , Matrix Metalloproteinase 9/blood , Antigens, CD34/blood , Bone Marrow Cells/cytology , Bone Marrow Cells/enzymology , Bone Marrow Cells/metabolism , Cell Line, Tumor , Enzyme-Linked Immunosorbent Assay , Gene Expression/drug effects , Humans , Immunohistochemistry , Matrix Metalloproteinase 9/genetics , Phenanthrolines/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, CXCR4/blood , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
OBJECTIVE: To explore the role of stromal cell-derived factor (SDF-1) and its specific receptor CXCR4 in the G-CSF-induced hematopoietic stem/progenitor cells (HSPCs) mobilization in human healthy donor. METHODS: The changes of SDF-1/CXCR4 in bone marrow (BM) and peripheral blood (PB) of healthy donors during G-CSF-induced mobilization were detected by enzyme-linked immunosorbent assay (ELISA), immunohistological staining and flow cytometry. SDF-1 neutralizing antibody wes injected into BALB/c mice to further test its effect on mobilization. RESULTS: SDF-1 concentration in mobilized BM (mBM), steady state BM (ssBM) and PB were(7.23 +/- 0.66) microg/L, (5.43 +/- 0.35) microg/L and (5.42 +/- 0.52) microg/L, respectively. SDF-1 protein levels were decreased in the BM (P < 0.05) after 5-day G-CSF injection, and its concentration gradient between BM and PB disappeared (P > 0.05). Significant up-regulation of CXCR4 expression was observed on mBM CD34 cells in healthy donors. The rate of CXCR4 expression on CD34 cells in ssBM, mBM and mobilized PB were (40.98 +/- 21.56)%, (65.80 +/- 24.68)% and (27.54 +/- 26.03)%, respectively. Comparing with that in ssBM and mBM, CXCR4 expression on mobilized PB CD34+ cells were significantly decreased (P < 0.05). Inhibition of SDF-1 signal by blocking monoclonal antibodies significantly reduced G-CSF-induced mobilization in BALB/c mice. This resulted in significant decrease of white blood cell count and progenitors mobilized into peripheral circulation. CONCLUSION: G-CSF induces HSPCs mobilization by decreasing bone marrow SDF-1 and down-regulating CXCR4 expression on HSPCs.
Subject(s)
Chemokine CXCL12/physiology , Hematopoietic Stem Cell Mobilization/methods , Receptors, CXCR4/physiology , Animals , Chemokine CXCL12/metabolism , Granulocyte Colony-Stimulating Factor/pharmacology , Humans , Mice , Mice, Inbred BALB C , Receptors, CXCR4/metabolismABSTRACT
OBJECTIVE: To evaluate the effectiveness of chemotherapy (CT) and autologous hematopoietic stem cell transplantation (ASCT) as post-remission treatment for adult acute lymphoblastic leukemia (AL) patients. METHODS: Seventy-four ALL patients achieved first complete remission (CR(1)) with induction therapy, and then received early-stage sequential intensive consolidation chemotherapy. After that, 40 patients received chemotherapy (CT group) and 34 received ASCT (ASCT group) as post-remission treatment. The median follow-up was 20.5 months. The rates of leukemia free survival (LFS), overall survival (OS) and relapse were compared between the two groups. RESULTS: (1) The median LFS and OS were 14.0 and 20.6 months respectively for CT group and both were more than 53.5 months for ASCT groups. (2) Relapse occurred in 28 patients (70%) in CT group in a median time of 8.5 months (range, 1-72 months) and 20 of them (71.43%) relapsed within 1 year. Eleven patients (32.35%) relapsed in ASCT group, in a median time of 6 (2-30) months after transplantation. (3) There was no statistic difference in LFS, OS and relapse rate at 1 year between CT and ASCT groups (P > 0.05), whereas both LFS and OS at 3 and 5 years for ASCT group were significantly better than those for CT group (P < 0.05). Relapse rate for ASCT group was lower than that for CT group. (4) Higher LFS and OS and lower relapse rate were found for those who received monoclonal antibody purged autografts followed by immunotherapy and (or) maintenance therapy after ASCT (P < 0.05). CONCLUSIONS: Early sequential intensive consolidation chemotherapy followed by auto-HSCT could significantly reduce late relapse rate for adult ALL patients, and those received ex vivo purged autografts and immunotherapy and (or) maintenance therapy after ASCT have lower late relapse rate and superior survival.