[Investigation of the immune profile of multiple myeloma patients achieving long-term survival after autologous stem cell transplantation].

Objective: To identify the characteristics of the bone marrow immune microenvironment associated with long-term survival in multiple myeloma (MM) patients. Methods: In the follow-up cohort of patients with newly diagnosed MM and who received "novel agent induction therapy and subsequent autologous stem cell transplantation and immunomodulator maintenance therapy" in the First Affiliated Hospital of Sun Yat-sen University, a cross-sectional study was carried out between August 2019 and May 2020. Using NanoString technology, the RNA expression of 770 bone marrow immune-related markers was compared between 16 patients who had progression-free survival ≥5 years and 5 patients with progressive disease. Among the 16 patients who achieved long-term survival, 9 achieved persistent minimal residual disease (MRD) negative while the other 7 had persistent positive MRD. The functional scores of each kind of immune cells were calculated based on the expression level of characteristic genes, so as to indirectly obtained the proportion of each immune cell subset. The Mann-Whitney U test and the Kruskal Wallis test were used for statistical analysis. Results: The proportion of neutrophils was significantly higher in long-surviving MM patients than in patients with progressive disease [functional scores, 13.61 (13.33, 14.25) vs. 12.93 (12.58, 13.38); Z=2.31, P=0.021]. Among long-surviving patients, those who were MRD-positive had a significantly greater number of mast cells compared with those who were MRD-negative [functional scores, 7.09 (6.49, 8.57) vs. 6.03 (5.18, 6.69); H=2.18, P=0.029]. Compared with patients with progressive disease, four genes (CTSG, IFIT2, S100B, and CHIT1) were significantly downregulated and six (C4B, TNFRSF17, CD70, IRF4, C2, and GAGE1) were upregulated in long-surviving patients. Among long-surviving patients, only gene CMA1 was significantly upgraded, 10 genes (ISG15, OAS3, MX1, IFIT2, DDX58, SIGLEC1, CXCL10, IL1RN, SERPING and TNFSF10) were significantly downregulated in the MRD-positive group compared with that in the MRD-negative group, the first 5 of which are related to the interferon response pathway. Conclusions: The increased neutrophil and mast cell numbers may be related to long-term survival in MM. Interferon signaling activation may be a key bone marrow immune profiling feature for MRD-negative, long-surviving patients with MM.

[The efficacy analysis of neurosurgical robot-assisted DBS in the treatment of elderly Parkinson's disease].

Objective: To investigate the surgical efficacy of neurosurgery robot deep brain stimulation(DBS) in the treatment of elderly Parkinson's disease(PD). Methods: The clinical data of elderly patients (≥75 years) with PD who underwent neurosurgical robot-assisted DBS surgery in the Department of Neurosurgery of the General Hospital of Northern Theater Command from September 2016 to September 2022 were collected retrospectively. Operation time, electrode implantation duration, postoperative pneumocephalus volume, electrode implantation accuracy, the Tao's DBS surgery scale, perioperative complications were analyzed.The unified Parkinson's disease rating scales (UPDRS), UPDRS-Ⅲ, tremor, rigidity, bradykinesia, axial, Barthel Activities of Daily Living (ADL-Barthel), Levodopa Equivalent Daily Dose (LEDD), Montreal Cognitive Assessment (MoCA), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scores and mortality were assessed respectively before operation, 6, 12 and 24 months after operation and last follow-up. Results: A total of 25 elderly patients were enrolled, including 14 males and 11 females, aged(78.3±3.2) years. Nine patients had underlying diseases. Nine patients (36%) underwent bilateral Globus Pallidus pars Interna deep brain stimulation (GPi-DBS) and 16 patients (64%) underwent bilateral subthalamic nucleus deep brain stimulation (STN-DBS).The operation time was (1.56±0.19) hours, the electrode implantation duration was (1.01±0.19) hours, the pneumocephalus volume was 9.8(4.7, 23.3) cm3, and the electrode implantation accuracy was (0.84±0.24) mm, the Tao's DBS surgery scale was (80.2±6.2).The follow-up time [M(Q1, Q3)] was 57.3(27.9, 75.7) months. No serious complications such as intracranial hemorrhage, infection or poor wound healing occurred during the perioperative period. The improvement rate of UPDRS, UPDRS-Ⅲ, rigidity, bradykinesia, and LEDD at 6 months after surgery was significantly higher than that at 24 months after surgery and at the last follow-up (all P<0.05); the improvement rate of axial symptoms, ADL-Barthel score, and MoCA score at 6 months after surgery was significantly higher than that at the last follow-up (P<0.05). HAMD and HAMA scores showed no significant improvement during follow-up after surgery (both P>0.05). At the last follow-up, 12 patients died, with death time of (35.1±20.2) months after operation, and the death age of [M(Q1, Q3)] 80(79, 83)years. Conclusions: Robot-assisted DBS surgery for elderly patients with PD is accurate and safe, and the postoperative symptoms are significantly improved, and they can benefit from neuromodulation for long term, and the risks are controllable.

[Efficacy and safety of autologous hematopoietic stem cell transplantation in elderly multiple myeloma patients: a single center retrospective study].

Objective: To evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (auto-HSCT) in elderly patients (≥65 years old) with multiple myeloma (MM) . Methods: From June 1, 2006 to July 31, 2020, 22 MM patients (≥65 years old) who were diagnosed in the First Affiliated Hospital, Sun Yat-sen University and received novel drug induction followed by auto-HSCT were analyzed retrospectively. These patients were evaluated for important organ functions before transplantation, and the International Myeloma Working Group frail score was used in 2016 to screen out transplant-eligible patients. Results: The median (interquartile range, IQR) age at the time of transplantation of the 22 patients was 66.75 (IQR 4.50) years. A total of 20 patients received stem cell mobilization. The median number of mononuclear cells collected was 4.53×10(8)/kg, that of CD34(+) cells was 3.37×10(6)/kg, and the median number of apheresis procedures performed was 2. After stem cell transfusion, the median time of neutrophil implantation was 11 days, that of platelet implantation was 13 days, and the treatment-related mortality was 0 at 100 days after transplantation. The median follow-up was 48.7 months. The median time to progression time was not reached, and the median overall survival time was 111.8 months. Conclusion: Auto-HSCT is a safe and effective treatment for selected elderly patients of 65 years or older with MM.

[New agents-based induction chemotherapy followed by autologous stem cell transplantation and maintenance treatment strategy for multiple myeloma: a single center retrospective study of 300 cases].

Objective: To examine the survival and influential factors of an integrated approach of novel agents, autologous hematopoietic stem cell (auto-HSCT) , and maintenance therapy in patients with multiple myeloma (MM) patients from a single center over the past 15 years. Methods: In our center, 300 MM patients who received an integrated strategy of new agents, auto-HSCT, and maintenance therapy over 15 years were retrospectively and prospectively analyzed. Results: The complete remission rates (CR) and ≥very good partial remission rates (VGPR) following induction therapy, transplantation, and maintenance therapy were respectively 35.3% and 55.2% , 72.4% and 80.0% , 89.2% , and 93.4% . When compared to patients receiving double-drug induction, the ≥VGPR and ORR of patients receiving triple-drug induction were improved. No difference existed in CR, ≥VGPR, and ORR between the PAD (bortezomib + liposome doxorubicin+ dexamethasone) and RAD (lenalidomide + liposome doxorubicin + dexamethasone) regimens, but the benefits speed differed. The negative rate of flow minimal residual disease following induction, transplantation, and maintenance was 18.8% (54 cases) , 41.4% (109 cases) , and 58.7% (142 cases) , respectively. The median time to progress (TTP) was 78.7 months and the median overall survival (OS) was 109 months. The median TTP for RISS-Ⅰ-Ⅲ patients were 111.8 months, 77.4 months, and 30.6 months, and the median OS was 118.8 months, 91.4 months, and 48.5 months, respectively. At various points during treatment, the TTP and OS of patients obtaining CR and MRD negative were longer than those of patients who did not obtain CR and MRD negative. TTP was noticeably shorter in high-risk cytogenetic patients compared to standard-risk patients even when CR was acquired during induction. There was no difference in TTP between patients with high-risk cytogenetics and those with standard-risk cytogenetics if MRD negative was acquired during induction. According to a multivariate analysis, the R-ISS stage was a poor predictor of TTP and OS at various treatment intervals. Therapeutic effectiveness was a newly independent prognostic factor following treatment. Conclusion: A median survival of almost 10 years is possible for MM patients who receive an integrated strategy of induction regimens followed by auto-HSCT and maintenance therapy, which significantly improves prognosis. However, this approach did not significantly benefit high-risk cytogenetic MM patients.

Cross-sectional associations of device-measured sedentary behaviour and physical activity with cardio-metabolic health in the 1970 British Cohort Study.

AIMS: This study aimed to examine the cross-sectional associations of thigh accelerometry-assessed sedentary behaviour and moderate-to-vigorous physical activity (MVPA) with cardio-metabolic health markers and prevalent diabetes in a population sample of middle-aged British adults. METHODS: Participants (n = 4892) from the age-46-to-48 wave of the 1970 British Cohort Study were fitted with a waterproofed activPAL3 micro device. Total/prolonged sedentary time, breaks and MVPA were the main exposures. We dichotomized prolonged sedentary time and MVPA based on the corresponding median, generating four combinations as categorical exposures. Outcomes comprised of diabetes and seven cardio-metabolic health markers. We used logistic regression and generalized linear models to examine independent/joint associations, conducting a minimally adjusted model including demographics and contextual covariates, and further adjusted for total sedentary time and/or MVPA as applicable. RESULTS: Each set of 10 sedentary breaks and 1 h of prolonged sedentary time were associated with HbA1c (mmol/mol) [B = -0.18 (-0.33, -0.03) and 2.35 (1.01, 3.69), respectively]. Each set of 10 sedentary breaks and 1 h of MVPA were favourably associated with diabetes [adjusted odds ratio (AOR): 0.80 (0.71, 0.99) and 0.42 (0.26, 0.67), respectively]. Joint analyses showed that only the low MVPA × long sedentary time combination had significantly higher odds for diabetes than the referent high MVPA × short sedentary time combination [AOR: 1.89 (1.17, 3.03)]. CONCLUSIONS: Each set of additional 10 sedentary breaks per day was associated with 20% lower odds for diabetes. A low physical activity level combined with long sedentary time might synergistically deteriorate cardio-metabolic health.

[High dose melphalan (HDM) is superior to cyclophosphamide plus etoposide and busulfan (CVB) as the conditioning regimen in autologous stem cell transplantation for multiple myeloma].

Objective: To compare the efficacy, response and survival between high-dose melphalan (HDM) and cyclophosphamide+ etoposide+ busulfan (CVB) as the conditioning regimen in autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) . Methods: Retrospectively enrolled 123 consecutive NDMM patients who had received PAD induction with subsequent ASCT from Jan 2011 to Aug 2017. The CVB group and HDM group had 82 and 41 patients respectively. Results: ①No differences existed between these 2 groups in non-hematological side effects. ②Patients of CVB group had faster neutrophil and platelet engraftment time, with the median neutrophil engraftment time of 10 (9-35) day vs 11 (9-12) day for patients of HDM group (z=-3.433, P=0.001) , and with median platelet engraftment time of 11 (7-55) day vs 13 (10-35) day for patients of HDM group (z=-3.506, P<0.001) . CVB group entered neutropenia and severe thrombocytopenia more earlier than the HDM group, resulting similar neutropenia duration and severe thrombocytopenia duration between the CVB group and HDM group. However, patients of CVB group had significantly longer fever persistent time and antibiotic administration time. ③The response rate was significantly lower in patients of CVB group vs. patients of HDM group (9/46 vs 14/28, P=0.021) . Further, the minimal residual disease (MRD) negative rate at 3(rd) month post-transplantation seemed to be lower in CVB group than that in HDM group (31.7%vs 48.8%, P=0.065) . ④Both the univariate and multivariate analysis showed that HDM and CVB groups had similar duration to progression (TTP) (P=0.619) and overall survival (OS) (P=0.295) . Conclusion: HDM conditioning regimen is superior to CVB regimen in hematological side effects, tumor burden reduction and administration convenience. However, these two regimen had similar TTP and OS in MM patients receiving ASCT.

[Bortezomib-based induction chemotherapy followed by autologous hematopoietic stem cell transplantation and maintenance in 200 patients with multiple myeloma: long-term follow-up results from single center].

Objective: To study the efficacy, safety and long-term outcomes of integrated strategy of bortezomib-based induction regimens followed by autologous hematopoietic stem cell (ASCT) and maintenance therapy in Chinese multiple myeloma (MM) patients. Methods: 200 MM patients receiving integrated strategy of bortezomib--based induction regimens followed by ASCT and maintenance therapy were retrospectively and prospectively analyzed from December 1. 2006 to April 30. 2018. Results: The complete remission rates (CR) and better than very good partial remission rates (VGPR) after induction therapy, transplantation and maintenance therapy were respectively 31% and 75.5%, 51.8% and 87.7%,73.6% and 93.4%. There was no difference between 4 cycles and more than 5 cycles induction chemotherapy. The negative rate of MRD detection by flow cytometry was 17.6% and 38.2% respectively after induction and 3 months after transplantation. The negative rate of MRD gradually increased during the maintenance therapy. The success rate of high dose CTX combined with G-CSF mobilization was 95.5% and transplantation related mortality (TRM) was zero. The median time to progress (TTP) was 75.3 months and the median overall survival (OS) was 99.5 months. TTP of patients obtaining CR and negative MRD after induction were longer that those of no CR and positive MRD. TTP and OS of patients receiving triple-drug induction and ASCT in early stage were longer than those of double-drug induction and ASCT in late stage. LDH≥240 U/L, high risk cytogenetics, ISS II+III stage and HBsAg positive were prognostic factors at diagnosis. However, only MRD and high risk cytogenetics were independent prognostic factors after transplantation and maintenance therapy. The clinical characteristics of patients of TTP ≥6 years were listed below: light-chain type M protein, ISS I stage, normal level of hemoglobin and platelet, normal LDH, HBsAg negative, chromosome 17p-negative, good response and sustained good response. Conclusions: Integrated strategy of bortezomib-based induction regimens followed by ASCT and maintenance therapy can significantly improve the short-term and long-term efficacy. The prognostic factors of TTP in different disease stages were different. Response to treatment, especially MRD, played a more important role in prognostic factors.

PRAP1 is a novel executor of p53-dependent mechanisms in cell survival after DNA damage.

p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments.

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1.

Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

American ginseng extract reduces scopolamine-induced amnesia in a spatial learning task.

OBJECTIVE: To determine if HT-1001, an extract of American ginseng, affects scopolamine-induced memory and performance deficits in a spatial learning task, alters brain concentrations of aminergic neurotransmitters, and alters choline uptake in synaptosome preparations. DESIGN: Animal study. ANIMALS: 48 Sprague Dawley rats. INTERVENTIONS: Long-term oral administration of a test material or control solution. Intraperitoneal administration of scopolamine (2 mg/kg) 30 minutes before testing. OUTCOME MEASURES: Performance on Morris water maze task, choline uptake, aminergic neurotransmitter analysis, in vitro monoamine oxidase analysis (of compounds). RESULTS: HT-1001 protected against scopolamine-induced amnesia and increased choline uptake in synaptosomal preparations. HT-1001 did not alter brain concentrations of norepinephrine, dopamine, 5-HT (serotonin), 3,4-dihydroxyphenylacetic acid or 5-hydroxyindoleactic acid. HT-1001 had a very weak ability to inhibit monoamine oxidase activity in vitro. CONCLUSIONS: HT-1001 demonstrates a capacity to protect against scopolamine-induced memory deficits.