Preemptive inotuzumab ozogamicin eradicated measurable residual disease in Ph-negative acute lymphoblastic leukemia relapsed post CD19 CART therapy.

There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B-ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy.

Combination of venetoclax with BCR-ABL tyrosine kinase inhibitor as a therapeutic strategy for Philadelphia chromosome-positive leukemias.

OBJECTIVES: Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias. This combination may suggest a novel treatment strategy for Ph + leukemias. METHODS: We conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias. RESULT: A total of 18 patients with Ph + leukemias were enrolled in this study. At the time of venetoclax and TKI-based therapy, 5 patients were initially diagnosed, with Ph + acute myeloid leukemia (AML) (n = 1) and mixed phenotype acute leukemia (MPAL) (n = 4), 7 patients had chronic myeloid leukemia at blastic phase (CML-BP), and the remaining 6 patients had relapsed or refractory to prior therapy. The overall response rate (ORR) was 88.9% (9 CR, 2 CRi, 4 MLFS, 1 PR), and a major molecular response (MMR) (or better) was achieved in 7 (38.8%) of all patients. With a median follow-up of 7.0 months (range, 2.3-15.6), 15 (83.3%) were in continuous CR at the time of this analysis, with a 1-year OS of 85.6%, 1-year LFS of 76.7%, and 1-year CIR of 22.4%. Moreover, 10 of 18 patients were treated with venetoclax, TKI and hypomethylating agent (HMA) regimens, which also associated with a high ORR rate (6 CR, 1 CRi, 3 MLFS), and can be used for induction or salvage therapy. CONCLUSION: Venetoclax and TKI-based combination regimens may be a feasible approach for Ph + leukemias, and prospective studies are needed to properly assess the safety, tolerability and efficacy of this regimen.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

[Comparison of Therapeutic Efficacy between Hypomenthylating Agents Combined with Venetoclax and Half Dose Priming Regimen in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia].

OBJECTIVE: To compare the clinical efficacy and safety of hypomenthylating agents (HMA) combined with Venetoclax (VEN) and half dose priming regimen (CAG-like) in the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for intensive chemotherapy. METHODS: The clinical data of 43 newly diagnosed elderly patients with AML who were not suitable for intensive chemotherapy in our hospital from April 2019 to October 2020 were retrospectively analyzed. Among them, 16 cases received HMA-VEN regimen and 27 cases received HMA-CAG-like regimen. The remission rate, early mortality and survival were compared between the two groups. And, the patients were grouped according to HCT-CI score. The effects of two different regimens in different groups on the efficacy and survival of patients were compared, and the prognosis of patients was further analyzed. RESULTS: After one course of treatment, the total remission rate of HMA-VEN group and HMA-CAG-like group was 81.3% (13/16) and 51.9% (14/27), respectively, and the difference between the two groups was statistically significant (χ2=4.650, P=0.045). The median overall survival (OS) time of HMA-VEN group had not yet reached, while that of HMA-CAG-like group was 11.2 months, and the HMA-VEN group had a longer OS (P=0.055). There was no tumor lysis syndrome occurred in both groups. The main adverse reactions were digestive tract reaction, bone marrow suppression and infection. The amount of agranulocytosis infection, pulmonary infection and platelet infusion in HMA-VEN group were significantly lower than those in HMA-CAG-like group (P<0.05), while the time of agranulocytosis and amount of erythrocyte infusion were similar (P>0.05). In HMA-Ven group 1 case died early, while in HMA-CAG-like group 8 cases died early due to pulmonary infection, respiratory failure, cerebral hemorrhage, and alveolar hemorrhage, the mortality in HMA-CAG-like group was significantly higher than that in HMA-VEN group (P=0.043). Among 43 patients, there was a significant difference in OS between HCT score 0-2 group and ≥3 group (P=0.033). In HMA-CAG-like group, patients with HCT score ≥3 had a worse prognosis (P=0.01), while in HMA-VEN group patients showed no statistically significant difference in prognosis (P=0.681). In HCT score 0-2 group, 9 cases receiving HMA-VEN regimen and 22 cases receiving HMA-CAG-like regimen showed no statistical difference in OS (P=0.281). In HCT score ≥3 group, 7 cases receiving HMA-VEN regimen had a longer OS than 5 cases receiving HMA-CAG-like regimen (P=0.015). CONCLUSION: Venetoclax combined with HMA can achieve higher response rate, lower early mortality, and longer OS, especially in those with more comorbidities and poor tolerability.

Dietary protein and multiple health outcomes: An umbrella review of systematic reviews and meta-analyses of observational studies.

BACKGROUND & AIMS: Numerous studies have evaluated the effects of dietary protein on specific health outcomes. The aim of our umbrella review was to summarize the existing evidence between the intake of dietary proteins and multiple health outcomes, and assess their strength and validity. METHODS: Our study was registered at PROSPERO (No. CRD42021255938). We systematically searched PubMed, Embase, and Web of Science databases from inception to May 18, 2021, to identify relevant systematic reviews and meta-analyses of observational studies. The validated "A Measurement Tool to Assess Systematic Reviews" for assessing the methodological quality of included systematic reviews was utilized. For each association, we estimated the summary effect size using fixed and random effects methods, and the 95% confidence and prediction intervals. We also evaluated heterogeneity, evidence of small-study effects, and excess significance bias. RESULTS: Overall, 16 articles with 58 meta-analyses were included. All studies were categorized as over moderate quality. On employing the random-effects model, fourteen (24.1%) meta-analyses were found to be significant at P < 0.05, whereas only one (1.7%) remained significant at P < 10-6. Twenty-two (37.9%) meta-analyses had large or very large heterogeneity. Evidence of small-study effects and excess significance bias was found for three (5.2%) meta-analyses, respectively. One meta-analysis was supported by highly suggestive evidence, indicating that a 5% increase in energy intake from animal protein was associated with 12% higher risk of type 2 diabetes (95% confidence interval [CI]: 1.08-1.17). Of note, the intake of animal and plant proteins had different health effects on type 2 diabetes, all-cause mortality, and risk of cardiovascular disease mortality. CONCLUSIONS: Although the intake of dietary protein was associated with certain health outcomes, the strength of evidence was limited for most outcomes. Moreover, the source of dietary protein is an important factor that requires better consideration in future studies.

[The Role and Mechanism of Tfh and B Cell in Human Chronic Graft-Versus-Host-Disease].

AbstractObjective: To investigate the role and mechanism of circulating follicular helper T cells (cTfh), extrafollicular helper T cells, B cells and their subsets in chronic graft-versus-host disease (cGVHD) after transplantation. METHODS: Peripheral blood of cGVHD 64 patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the First Affiliated Hospital of Soochow University from 2016 to 2019 were collected. The percentage of cTfh cells, extrafollicular helper T cells, B cells and subsets were detected by flow cytometry. The healthy donors were detected as control. Percentage of each cell subpopulation between the two groups were compared by the two-tailed Students' T test. RESULTS: The percentage of circulating follicular helper T cells (cTfh, CD4+CXCR5+) was markedly decreased in patients with cGVHD as compared with that in the healthy donors (0.53%±0.10% vs 3.91%±0.60%, P<0.001). The percentage of extrafollicular helper T cells (CD44hiCD62LloPSGL-1loCD4+T) of the patients in cGVHD and the healthy donors were 8.86%±0.45% and 5.38%±0.79% (P=0.003). A significant change in B cell subsets was found in the patients with cGVHD. The two types of antigen-stimulate CD27+ B cell: the percentages of pre-GC B cells (CD19+IgD+CD38hiCD27+) and plasmablast/plasma cells (PB/PC, CD19+IgD-CD38hiCD27+) of patients with cGVHD were 20.91%±2.70% and 41.05%±5.00%, respectively, which were significantly higher than those in healthy donors (P=0.005, P=0.014). Meanwhile, the percentage of unstimulated CD27- B cells in patients with cGVHD was significantly reduced, especially the naive B cells (CD19+IgD+CD38loCD27-, 12.59%±2.63%, P=0.025). There was a positive correlation between the percentage of extrafollicular helper T cells and plasmablast/ plasma cells (PB/PC) in cGVHD patients (r=0.43). CONCLUSION: Compared with healthy donor, cTfh cells, extrafollicular helper T cells and B cell subsets in the peripheral blood of patients with cGVHD after transplantation changed in varying degress.

Rapid and Efficient Response to Gilteritinib and Venetoclax-Based Therapy in Two AML Patients with FLT3-ITD Mutation Unresponsive to Venetoclax Plus Azacitidine.

The presence of FLT3-ITD mutation is associated with relapse and poor survival in AML patients. Venetoclax combined with hypomethylating agents (VEN+HMA) was approved for the frontline treatment of elderly or unfit AML patients, which leads to noteworthy impacts on AML management. The combination therapy is associated with encouraging efficacy in FLT3-mutated AML among both newly diagnosed unfit and relapsed/refractory patients. However, we found that two AML patients with FLT3-ITD mutation did not respond to venetoclax plus azacitidine (VEN+AZA). Given that the combined efficacy of venetoclax and the FLT3 inhibitor has been proved in pre-clinical models of FLT3+ AML, it is a scientific rationale to investigate venetoclax combined with the FLT3 inhibitor in AML patients with FLT3-ITD mutation. This is the first report of assessing the safety and response of gilteritinib (the first and only targeted second-generation FLT3 tyrosine kinase inhibitor approved by the US FDA) and venetoclax-based therapy in two AML patients with FLT3-ITD mutation unresponsive to VEN+AZA, which may bring new hope to FLT3 mutated patients who are unresponsive to VEN+HMA.

A Phase II Trial of the Double Epigenetic Priming Regimen Including Chidamide and Decitabine for Relapsed/Refractory Acute Myeloid Leukemia.

OBJECTIVE: To explore the role of chidamide, decitabine plus priming regimen in the salvage treatment of relapsed/refractory acute myeloid leukemia. METHODS: A clinical trial was conducted in relapsed/refractory acute myeloid leukemia patients using chidamide, decitabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor, termed CDIAG, a double epigenetic priming regimen. RESULTS: Thirty-five patients were recruited. Three patients received 2 treatment cycles. In 32 evaluable patients and 35 treatment courses, the completed remission rate (CRR) was 42.9%. The median OS time was 11.7 months. The median OS times of responders were 18.4 months, while those of nonresponders were 7.4 months (P = 0.015). The presence of RUNX1 mutations was associated with a high CRR but a short 2-year OS (P = 0.023) and PFS (P = 0.018) due to relapse after treatment. The presence of IDH mutations had no effect on the remission rate (80.0% vs. 73.3%), but showed a better OS (2-year OS rate: 100.0% vs. 28.9%). Grade 3/4 nonhematological adverse events included pneumonia, hematosepsis, febrile neutropenia, skin and soft tissue infection and others. CONCLUSION: The double epigenetic priming regimen (CDIAG regimen) showed considerably good antileukemia activity in these patients. Adverse events were acceptable according to previous experience. The study was registered as a clinical trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier:NCT03985007.

Staphylococcal enterotoxin B administration in pregnant rats alters the splenic lymphocyte response in adult offspring rats.

BACKGROUND: Our previous study suggested that SEB exposure in pregnant rats could lead to the change of T cells subpopulation in both peripheral blood and thymus of the offspring rats. However, rarely is known about the influence of SEB exposure in pregnant rats on T cell subpopulation in the spleens of offspring rats. RESULTS: SEB was intravenously administered to the pregnant rats at gestational day 16 in this study. The percentages, in vivo and in vitro responses of CD4 and CD8 T cells were investigated with flow cytometry. The prenatal SEB exposure obviously increased splenic CD4 T cell percentages of both neonates and adult offspring rats, and obviously reduced splenic CD8 T cell percentages of both the fifth day neonates and adult offspring rats. After spleens in the adult offspring rats were re-stimulated with SEB in vivo or in vitro, in vivo SEB stimulation could lead to the marked decrease of splenic CD4 T cell percentage and the marked increase of splenic CD8 T cell percentage. While in vitro SEB stimulation to the cultured splenocytes markedly decreased the proliferation of the splenic lymphocytes and the CD4 T cell percentage, and had no influence on CD8 T cell percentage. CONCLUSION: The prenatal SEB exposure could alter the percentages of CD4/CD8 T cell subpopulation and the response of CD4 and CD8 T cells to the in vivo and in vitro secondary SEB stimulation in the splenocytes of adult offspring rats.

[Detection of Late Blight Disease on Potato Leaves Using Hyperspectral Imaging Technique].

Hyperspectral imaging feature on potato leaves stressed by late blight was studied in the present paper. The experiment used 60 potato leaves. Among those 60 potato leaves, 48 leaves were vitro inoculated with pathogen of potato late blight, the rest 12 leaves were used as control samples. The leaves were observed for 7 continuous days before and after inoculated and samples including healthy and infested were acquired. Hyperspectral data of healthy and infected potato samples of different disease severity were obtained by the hyperspectral imaging system from 374 to 1,018 nm and then extract spectral data of region of interest (ROI) from those hyperspectral data by the ENVI software. In order to improve the signal-to-noise ratio, the spectral data were preprocessed using different pretreatment methods such as moving average smoothing, normalization, derivative, baseline etc. The least squares-support vector machine(LS-SVM) models were developed based on the raw and those preprocessed data. Among the nine models, the model that used the raw data and the data after the spectroscopic transformation performed best with the discrimination of 94.87%. It was demonstrated that it is realized to determine the potato late blight disease of different disease severity using hyperspectral imaging technique.

[Pollution Characteristics and Emission Coefficient of Volatile Organic Compounds from Shoe-making Industry in Zhejiang Province].

To explore the pollution characteristics and emission coefficient of volatile organic compounds (VOCs) released from the shoe-making industry in Zhejiang province, this paper used the survey data of 490 shoe enterprises obtained in 2015 to analyze the current VOCs treatment status of shoe-making industry, and further screened 178 key enterprises to study the emission coefficient of shoe-making industry. The results showed that more than 95% of shoe enterprises failed to effectively dispose VOCs, because most shoe enterprises did not have treatment facilities. Moreover, solvent-based materials such as adhesive and primer were still commonly used in approximately 90% of shoe-making industry. Meanwhile, the main pollutants of VOCs in shoe-making industry were 2-butanone, toluene, acetone, cyclohexanone, ethyl acetate, xylene, dichloromethane and cyclohexane. Furthermore, the VOCs emission coefficient of shoe-making industry in Zhejiang was 29.5 g-1, while it was affected by the production processes, and the cemented construction techniques was higher than the injection techniques, which VOCs emission coefficients were 35.9 g-1 and 23.8 g-1, respectively. Furthermore, the major polluting stage of shoe-making industry was sole attaching, in which VOCs emission coefficient could reach 20.8 g-1.

[Study on the emission characteristics and potential environment hazards of the heat-setting machine of the typical dyeing and finishing enterprise].

To explore the emission characteristics and potential environment hazards of volatile organic compounds (VOCs) released from the heat-setting machine of the textile dyeing and finishing process, this paper selected five typical printing and dyeing enterprises in Zhejiang province as the monitoring subjects, and analyzed the actual emissions of 12 kinds of VOCs from the heat-setting machine (such as benzene methanol, formaldehyde, etc.), and then preliminarily estimated the emissions of VOCs from heat-setting machines of the whole province. Through analysis of the ozone generating potential, this paper preliminarily evaluated its harm to the environment. The results showed that although the concentration of VOCs was low, it contained benzene and formaldehyde, and the highest detection concentration could reach 1.53 mg x m(-3) and 15.4 mg x m(-3), which might cause serious environmental and human health hazards, Moreover, the VOCs emission from heat-setting machines in Zhejiang province was between 200. 9 t x a(-1) and 2 239.3 t x a(-1), which was dominated by formaldehyde, accounting for about 50%. The O3 yield generated from VOCs was between 860.4 t and 16 715. 5 t, with the average of 7 729.6 t. The main contribution of VOCs was xylene, toluene and formaldehyde, which could account for more than 90%. Furthermore, the VOCs emission from heat-setting machines in Shaoxing industry agglomeration area could have great influence on the ambient air quality, especially for the O3 concentration and the minimum contribution rate was 3.1%.

[Emission characteristics and hazard assessment analysis of volatile organic compounds from chemical synthesis pharmaceutical industry].

In this study, volatile organic compounds (VOCs) released from chemical synthesis pharmaceutical industry in Taizhou, Zhejiang province were analyzed quantitatively and qualitatively. The total volatile organic compounds (TVOCs) was in the range of 14.9-308.6 mg · m(-3). Evaluation models of ozone formation potentials (OFP) and health risk assessment were adopted to preliminarily assess the environmental impact and health risk of VOCs. The results showed that the values of OFP of VOCs were in the range of 3.1-315.1 mg · m(-3), based on the maximum incremental reactivity, the main principal contribution was toluene, tetrahydrofuran (THF), acetic ether etc. The non-carcinogenic risk and the carcinogen risk fell in the ranges of 9.48 x 10(-7)-4.98 x 10(-4) a(-1) and 3.17 x 10(-5)- 6.33 x 10(-3). The principal contribution of VOCs was benzene, formaldehyde and methylene chloride.

[Health risk assessment and ozone formation potentials of volatile organic compounds from pharmaceutical industry in Zhejiang Province].

In the present study, the main source and characteristics of volatile organic compounds (VOCs) released from pharmaceutical industry in Zhejiang Province were analyzed quantitatively and qualitatively. Based on these results, the internationally recognized evaluation model for health risk assessment and ozone formation potentials (OFP) was adopted to preliminarily assess the environmental impact and health risk of those VOCs. The results showed that the OFP of VOCs was in the range of 16.1-79, 2 mL x m(-3), based on the maximum incremental reactivity. The principal contribution of VOCs was from nine kinds of substances including ethyl acetate, acetone, toluene and xylene, etc. Moreover, the health risk of VOCs was mainly generated from benzene, ethylene oxide, dichloromethane and formaldehyde owing to their carcinogenicity, which could account for more than 69% in the value of non-carcinogenic risk and 100% in the cancer risk. Additionally, according to the comparison of these assessments, the environmental hazards and health risk produced by VOCs could not be neglected during the development of VOCs emissions standards, especially in the screening of the control factors for the standards.

[Characterization of volatile organic compounds (VOCs) emission from recycled waste polymethyl methacrylate (PMMA) industry].

In the present study, the main source and characteristics of volatile organic compounds (VOCs) released from recycled waste polymethyl methacrylate (PMMA) in Zhejiang province was analyzed quantitatively and qualitatively. Based on those results, the internationally recognized evaluation model of health risk assessment was adopted in the preliminary assessment of the health risk of those VOCs. The results showed that methanol (MeOH) and methyl methacrylate (MMA) were the main pollutants. Emission from part of enterprises exceeded the national standards in MeOH and MMA, especially for fugitive emissions of odor concentration. Moreover, health risk value of fugitive emissions was very low and did not cause harm to human health. Additionally, to better accelerate industrial upgrading and environment pollution treatment, the emission limits of MeOH, MMA and odor concentration were suggested and the values of existing/new (fugitive emission) limitations were 45/30 (0.5) mg x m(-3), 30/25 (0.5) mg x m(-3), and 1000/800 (20), respectively.

[Randomized controlled clinical trails on treatment of knee osteoarthritis with acupuncture combined with blood-letting therapy].

OBJECTIVE: To observe the therapeutic effect of acupuncture combined with blood-letting therapy for knee osteoarthritis (KOA) and to analyze the synergism of the blood-letting therapy. METHODS: Sixty-three cases of KOA patients were randomized into a treatment group (n=31) and a control group (n=32). Patients of treatment group were treated with routine acupuncture at Ashi-points, Dubi (ST 35) and Neixiyan (EX-LE 4), Zusanli (ST 36), Yanglingquan (GB 34), etc. on the affected side, 3 times a week for 4 weeks, in combination with blood-letting (at the superficial veins around popliteal fossa) once a week for 4 weeks. Patients of control group were treated with routine acupuncture only. Western Ontario and McMaster Universities osteoarthritis index scores (WOMAC) and clinical therapeutic effects served as the objective indexes for evaluating the efficacy of blood-letting therapy. RESULTS: After the treatment, of the 32 and 31 KOA patients in control and treatment groups, 4 (12.50%) and 5 (16. 13) were under control in their symptoms, 14 (43.75%) and 17(54.84%) experienced marked improvement, 10 (31.25%) and 6 (19.35%) had an improvement, and 4 (12.50%) and 3 (9.68%) were failed, with the total effective rates being 87.50% and 90.32% respectively. No significant difference was found between the two groups in the therapeutic effect (P > 0.05). In comparison with pre-treatment, WOMAC scores, pain index, and physiological integral scores in treatment and control groups after the first and the last treatment decreased significantly (P < 0.001), and their joint stiffness index of the last treatment also lowered considerably (P < 0.001). The difference values of the integral scores between post- and pre-treatment in WOMAC, pain index, and physiological function of treatment group were remarkably higher than those of control group (P < 0.05). CONCLUSION: Acupuncture combined with blood-letting therapy can effectively improve KOA patients' physiological function and reduce joint pain especially in the early stage.