ABSTRACT
Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein or ß-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer's disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated ß-arrestin signaling modulates amyloid-ß (Aß) generation in vitro and that Gpr3 deficiency ameliorates Aß pathology in vivo. However, Gpr3-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated ß-arrestin signaling in vivo. In contrast to Gpr3-deficient mice, G protein-biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein-biased signaling reduces soluble Aß levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein-biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and ß-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD.
Subject(s)
Alzheimer Disease , Amyloidosis , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Disease Models, Animal , GTP-Binding Proteins/metabolism , Mice , Mice, Transgenic , Plaque, Amyloid/pathology , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , beta-Arrestins/metabolismABSTRACT
Pomegranate peel-derived extracellular nanovesicles(PPENs) were isolated and purified by ultra-high speed centrifugation and sucrose density gradient centrifugation. Their morphology and structure were characterized. In vitro α-glucosidase inhibition assay and model test of insulin resistance(IR) in HepG2 cells showed that PPENs had good anti-diabetic activity. The IC_(50) value of α-glucosidase inhibition was(35.3±1.1) µg·mL~(-1), significantly better than the positive drug acarbose. At a concentration of 100 µg·mL~(-1), PPENs could increase the glucose absorption of IR cells significantly. Lipidome, proteome, and metabolite analysis of PPENs were performed using chromatography-mass spectrometry. MicroRNA(miRNA) sequences were identified, and target genes of miRNA were predicted. The analysis results indicated that PPENs contained abundant lipids and transport proteins, providing a material basis for the transportation and distribution of PPENs in tissue. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis suggested that lipids and miRNAs may be the key components of PPENs to exert anti-diabetic activity.
Subject(s)
Hypoglycemic Agents , Pomegranate , Pomegranate/chemistry , Humans , Hep G2 Cells , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Extracellular Vesicles/chemistry , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , MicroRNAs/genetics , alpha-Glucosidases/genetics , alpha-Glucosidases/chemistry , alpha-Glucosidases/metabolism , Fruit/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Nanoparticles/chemistryABSTRACT
In the developed assay, multiorbital 3D DNA walker (MO DNA walker) was applied as signal amplified protocol for enhancing the detection signal of the photothermal biosensor, which was designed for sensitive detection of miRNA based on the H2S triggered conversation of photothermal reagent. When the target molecule is present, the DNA walking strand was released and then hybridize with track strands. The landing of walking particles (WPT) on the tracking particles (TPT) promotes the relative movement of the WPT around TPT, thus releasing large amount of horseradish peroxidase (HRP) with the aid of DNAzyme. After reacting with Na2S2O3 and H2O2, multiple H2S can be generated in situ based on the catalytic ability of HRP. Meanwhile, cubic Prussian blue (CPB) was synthesized and exhibited superior photothermal response, which can be served as efficient photothermal reagent and H2S responsive acceptor. Significantly, the photothermal signal of CPB could be obviously reduced after challenged with H2S ascribed to synchronous reaction between the ferric ion (Fe3+) and H2S. The improved walking area and freedom enable significant signal amplification, enhancing the biosensor's performance. Under ideal circumstances, the proposed photothermal assay demonstrated excellent performance for determination of miRNA-21.
Subject(s)
DNA, Catalytic , MicroRNAs , Hydrogen Peroxide , DNA , Horseradish PeroxidaseABSTRACT
ß-glucosidases (BGLs) play a crucial role in the degradation of lignocellulosic biomass as well as in industrial applications such as pharmaceuticals, foods, and flavors. However, the application of BGLs has been largely hindered by issues such as low enzyme activity, product inhibition, low stability, etc. Many approaches have been developed to engineer BGLs to improve these enzymatic characteristics to facilitate industrial production. In this article, we review the recent advances in BGL engineering in the field, including the efforts from our laboratory. We summarize and discuss the BGL engineering studies according to the targeted functions as well as the specific strategies used for BGL engineering.
Subject(s)
beta-Glucosidase , beta-Glucosidase/chemistryABSTRACT
This study compared the efficacy, safety and immunogenicity of ripertamab (SCT400) and rituximab (Mabthera® ) combined with CHOP as the first-line treatment for Chinese patients with CD20-positive diffuse large B cell lymphoma (DLBCL). This is a randomized, patient-blind, multicenter, active-control, non-inferiority study with parallel design. Patients were randomly (2:1) to receive ripertamab combined with CHOP (S-CHOP) or rituximab (Mabthera® ) combined with CHOP (R-CHOP) for up to 6 cycles. The primary endpoint was the Independent Review Committee (IRC) assessed objective response rate (ORR) in full analysis set (FAS) and the per protocol set (PPS). A total of 364 patients (243 in the S-CHOP and 121 in the R-CHOP groups) were enrolled in this study. In FAS, IRC-assessed ORRs were 93.8% (95% confidence interval (CI) 90.0%, 96.5%) and 94.2% (95% CI: 88.4%, 97.6%) in the S-CHOP and R-CHOP groups (p = 0.9633), respectively. The ORR difference between the two groups -0.4% (95% CI: -5.5%, 4.8%) met the pre-specified non-inferiority margin of -12%. There were no significant differences between the S-CHOP and R-CHOP groups in 1-year progression-free survival rates (81.1% vs. 83.2%, p = 0.8283), 1 year event-free survival rates (56.2% vs. 58.1%, p = 0.8005), and 3-year overall survival rates (81.0% vs. 82.8%, p = 0.7183). The results in PPS were consistent with those in FAS. The rates of treatment-emergent adverse events (TEAEs) and ≥ grade 3 TEAEs were 97.9% and 99.2%, 85.2% and 86.0% in the S-CHOP and R-CHOP groups, respectively in safety set. The percentage of anti-drug antibodies positive patients in the S-CHOP group was numerically lower than the R-CHOP group (10.9% vs. 16.0%). This study demonstrated that S-CHOP was not inferior to R-CHOP in the first-line treatment of Chinese patients with CD20-positive DLBCL in efficacy, safety and immunogenecity. S-CHOP could be an alternative first-line standard treatment regimen for this patient population.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Humans , Rituximab/adverse effects , Single-Blind Method , Lymphoma, Large B-Cell, Diffuse/drug therapyABSTRACT
Synthesis of inorganic nanomaterials such as metal nanoparticles (MNPs) using various biological entities as smart nanofactories has emerged as one of the foremost scientific endeavors in recent years. The biosynthesis process is environmentally friendly, cost-effective and easy to be scaled up, and can also bring neat features to products such as high dispersity and biocompatibility. However, the biomanufacturing of inorganic nanomaterials is still at the trial-and-error stage due to the lack of understanding for underlying mechanism. Dissimilatory metal reduction bacteria, especially Shewanella and Geobacter species, possess peculiar extracellular electron transfer (EET) features, through which the bacteria can pump electrons out of their cells to drive extracellular reduction reactions, and have thus exhibited distinct advantages in controllable and tailorable fabrication of inorganic nanomaterials including MNPs and graphene. Our aim is to present a critical review of recent state-of-the-art advances in inorganic biosynthesis methodologies based on bacterial EET using Shewanella and Geobacter species as typical strains. We begin with a brief introduction about bacterial EET mechanism, followed by reviewing key examples from literatures that exemplify the powerful activities of EET-enabled biosynthesis routes towards the production of a series of inorganic nanomaterials and place a special emphasis on rationally tailoring the structures and properties of products through the fine control of EET pathways. The application prospects of biogenic nanomaterials are then highlighted in multiple fields of (bio-) energy conversion, remediation of organic pollutants and toxic metals, and biomedicine. A summary and outlook are given with discussion on challenges of bio-manufacturing with well-defined controllability.
Subject(s)
Electron Transport , Electrons , Green Chemistry Technology/methods , Nanostructures/chemistry , Anti-Infective Agents/chemistry , Bacteria , Electrodes , Graphite , Metal Nanoparticles/chemistry , Metals/chemistry , Microbiological Techniques/methods , Shewanella/chemistry , Shewanella/metabolismABSTRACT
Microbial electrochemical system (MES) has attracted ever-growing interest as a promising platform for renewable energy conversion and bioelectrochemical remediation. Shewanella species, the dissimilatory metal reduction model bacteria with versatile extracellular electron transfer (EET) strategies, are the well-received microorganisms in diverse MES devices for various practical applications as well as microbial EET mechanism investigation. Meanwhile, the available genomic information and the unceasing established gene-editing toolbox offer an unprecedented opportunity to boost the applications of Shewanella species in MES. This review thoroughly summarizes the status quo of the applications of Shewanella species in microbial fuel cells for bioelectricity generation, microbial electrosynthesis for biotransformation of valuable chemicals and bioremediation of environment-hazardous pollutants with synoptical discussion on their EET mechanism. Recent advances in rational design and genetic engineering of Shewanella strains for either promoting the MES performance or broadening their applications are surveyed. Moreover, some emerging applications beyond electricity generation, such as biosensing and biocomputing, are also documented. The challenges and perspectives for Shewanella-based MES are also discussed elaborately for the sake of not only discovering new scientific lights on microbial extracellular respiratory but also propelling practical applications.
Subject(s)
Biodegradation, Environmental , Bioelectric Energy Sources , Electricity , Electron Transport , Shewanella/metabolism , Biosensing Techniques , Biotechnology/methods , Biotransformation , Electrodes , Electrons , Environmental Microbiology , Metals/metabolism , Shewanella/chemistryABSTRACT
The study is aimed to investigate the pathogenesis underlying the increased prevalence of thyroid nodule (TN) in different levels of metabolic syndrome (MetS) components and analyze the relationships between TN and MetS components. A total of 6,798 subjects, including 2201 patients with TN, were enrolled in this study. Anthropometric, biochemical, thyroid ultrasonographic, and other metabolic parameters were all measured. There was obviously sexual difference in the prevalence of TN (males 26.0%, females 38.5%, resp.). The prevalence of TN in hyperuricemia (45.7% versus 37.4%, P = 0.001), NAFLD (41.2% versus 36.4%, P < 0.05), and MetS (41.4% versus 35.4%, P < 0.001) groups was significantly increased only in females. Insulin resistance [OR = 1.31 (1.15, 1.49)], MetS [OR = 1.18 (1.03, 1.35)], and diabetes [OR = 1.25 (1.06, 1.48)] were all independent risk factors for TN in total subjects, whereas, after stratified analysis of gender, MetS [OR = 1.29, (1.09, 1.53)] and diabetes [OR = 1.47, (1.17, 1.84)] are still strongly and independently associated with the higher risks of TN in female subjects, but not in males. Our results suggest that the components of MetS might associate with the higher risks of TN in women than in men, but further cohort study of this gender disparity in the association between TN and MetS is required.
Subject(s)
Metabolic Syndrome/epidemiology , Aged , Cross-Sectional Studies , Female , Humans , Insulin Resistance/physiology , Male , Metabolic Syndrome/metabolism , Metabolic Syndrome/pathology , Middle Aged , Obesity/epidemiology , Obesity/metabolism , Obesity/pathology , Risk Factors , Sex Factors , Thyroid Gland/metabolism , Thyroid Gland/pathology , Thyroid Nodule/metabolism , Thyroid Nodule/pathologyABSTRACT
Blood samples were collected from patients with leukemia (n = 150) or lymphoma (n = 150) in the Cancer Hospital from March to September 2014. The specific antibodies (IgG, IgM) to, and circulating antigens (CAg) of Toxoplasma gondii were determined by ELISA. A 529 bp specific sequence was amplified by PCR from the genomic DNA of T. gondii. T. gondii-specific IgG positive rate in patients with leukemia and lymphoma were 16.0% (24/150) and 20.0% (30/150), respectively, which were significantly higher than that of healthy persons (6.4%, 7/110) (P < 0.05). IgM positive rate of the leukemia patients, lymphoma patients, and healthy persons was 2.7% (4/150), 1.3% (2/150), and 0.9% (1/110) (P > 0.05), respectively. No significant difference was found in IgM and CAg positive rate among leukemia patients, lymphoma patients, and healthy persons (P > 0.05). No specific band (529 bp) was detected in all samples.
Subject(s)
Leukemia , Lymphoma , Toxoplasma , Antibodies, Protozoan , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin G , Polymerase Chain ReactionABSTRACT
Dummy molecularly imprinted polymers (DMIPs) for aniline were synthesized by a thermal polymerization method using acrylamide as a functional monomer, ethylene dimethacrylate as a crosslinker, 2,2-azobisisobutyronitrile as a free radical initiator, acetonitrile as a porogenic solvent, and analogues of aniline, namely sulfadiazine, as the template. The DMIPs that were obtained showed a high affinity to aniline compared to non-imprinted polymers. It was proven that the DMIPs obtained using sulfadiazine as the template were much better than the molecularly imprinted polymers using aniline as the template. The results indicated that the Freundlich model was fit for the adsorption model of DMIP for aniline and the adsorption model of the DMIP for aniline was multilayer adsorption. Furthermore, the results showed that the DMIP synthesized by bulk polymerization could be used as a novel adsorbent for removal of aniline from contaminated water.
Subject(s)
Aniline Compounds/isolation & purification , Polymers/chemistry , Water Pollutants, Chemical/isolation & purification , Adsorption , Aniline Compounds/chemistryABSTRACT
Di-n-butyl phthalate (DBP) is one of the important phthalates detected commonly in soils and crops, posing serious threat to human health. Pseudochrobactrum sp. XF203 (XF203), a new strain related with DBP biodegradation, was first identified from a natural habitat lacking human disturbance. Genomic analysis coupled with gene expression comparison assay revealed this strain harbors the key aromatic ring-cleaving gene catE203 (encoding catechol 2,3-dioxygenase/C23O) involved DBP biodegradation. Following intermediates identification and enzymatic analysis also indicated a C23O dependent DBP lysis pathway in XF203. The gene directed ribosome engineering was operated and to generate a desirable mutant strain XF203R with highest catE203 gene expression level and strong DBP degrading ability. The X203R removed DBP in soil jointly by reassembling bacterial community. These results demonstrate a great value of XF203R for the practical DBP bioremediation application, highlighting the important role of the key gene-directed ribosome engineering in mining multi-pollutants degrading bacteria from natural habitats where various functional genes are well conserved.
Subject(s)
Biodegradation, Environmental , Dibutyl Phthalate , Ribosomes , Soil Pollutants , Soil Pollutants/metabolism , Dibutyl Phthalate/metabolism , Ribosomes/metabolism , Soil Microbiology , Gene Expression , Burkholderiaceae/metabolism , Burkholderiaceae/geneticsABSTRACT
Microbial reduction is an effective way to deal with hexavalent chromium [Cr(VI)] contamination in the environment, which can significantly mitigate the biotoxicity and migration of this pollutant. The present study investigated the influence of environmental factors on aqueous Cr(VI) removal by a newly isolated facultative anaerobic bacterium, Exiguobacterium sp. PY14, and revealed the reduction mechanism. This strain with a minimum inhibitory concentration of 400 mg/L showed the strongest Cr(VI) removal capacity at pH 8.0 because of its basophilic nature, which was obviously depressed by increasing the Cr(VI) initial concentration under both aerobic and anaerobic conditions. In contrast, the removal rate constant for 50 mg/L of Cr(VI) under anaerobic conditions (1.82 × 10-2 h-1) was 3.3 times that under aerobic conditions. The co-existence of Fe(III) and Cu(II) significantly promoted the removal of Cr(VI), while Ag(I), Pb(II), Zn(II), and Cd(II) inhibited it. Electron-shuttling organics such as riboflavin, humic acid, and anthraquinone-2,6-disulfonate promoted the Cr(VI) removal to varying degrees, and the enhancement was more significant under anaerobic conditions. The removal of aqueous Cr(VI) by strain PY14 was demonstrated to be due to cytoplasmic rather than extracellular reduction by analyzing the contributions of different cell components, and the end products existed in the aqueous solution in the form of organo-Cr(III) complexes. Several possible genes involved in Cr(VI) metabolism, including chrR and chrA that encode well-known Chr family proteins responsible for chromate reduction and transport, respectively, were identified in the genome of PY14, which further clarified the Cr(VI) reduction pathway of this strain. The research progress in the influence of crucial environmental factors and biological reduction mechanisms will help promote the potential application of Exiguobacterium sp. PY14 with high adaptability to environmental stress in Cr(VI) removal in the actual environment.
ABSTRACT
Cyclodipeptide (CDP) composed of two amino acids is the simplest cyclic peptide. These two amino acids form a typical diketopiperazine (DKP) ring by linking each other with peptide bonds. This characteristic stable ring skeleton is the foundation of CDP to display extensive and excellent bioactivities, which is beneficial for CDPs' pharmaceutical research and development. The natural CDP products are well isolated from actinomycetes. These bacteria can synthesize DKP backbones with nonribosomal peptide synthetase (NRPS) or cyclodipeptide synthase (CDPS). Moreover, actinomycetes could produce a variety of CDPs through different enzymatic modification. The presence of these abundant and diversified catalysis indicates that actinomycetes are promising microbial resource for exploring CDPs. This review summarized the pathways for DKP backbones biosynthesis and their post-modification mechanism in actinomycetes. The aim of this review was to accelerate the genome mining of CDPs and their isolation, purification and structure identification, and to facilitate revealing the biosynthesis mechanism of novel CDPs as well as their synthetic biology design.
Subject(s)
Actinobacteria , Biological Products , Actinobacteria/genetics , Actinobacteria/metabolism , Actinomyces/metabolism , Biological Products/metabolism , Bacteria/metabolism , Diketopiperazines/chemistry , Diketopiperazines/metabolism , Amino AcidsABSTRACT
Introduction: Little is known about the first line induction chemotherapy cycles for HIV-associated diffuse large B-cell lymphoma (DLBCL) as these are less common than HIV-negative lymphoma. Currently, the optimal treatment cycles option remains undefined. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-associated DLBCL patients in different treatment modes in China. Methods: Totally 273 newly diagnosed HIV-associated DLBCL patients at eleven large academic centers from October 2008 to October 2021, were analyzed. Results: In the entire cohort, the median age was 47 years (range, 21-90) at lymphoma diagnosis, and 223 patients were male (81.7%). One hundred and ninety-four (71.1%) patients were germinal center B-cell-like lymphoma (GCB) subtype. Most patients (65.2%, 178/273) had elevated lactate dehydrogenase (LDH), and advanced Ann Arbor stage (78.9% 213/273) at diagnosis. High international prognostic index (IPI) score (3-5) at diagnosis was found in 65.2% (178/273) of patients. One hundred and fifty-five patients (56.8%) had extranodal involvement. The median CD4 cell count was 168/µl (range, 2-1067), of whom 174 (63.7%) had a CD4 cell count below 200/µl. The median follow-up of our cohort was 10.1 (0.1-160) months. The overall 2-year OS rates 58.0%. Median OS times in the 0, 1-3, 4-6, and >6 cycles chemotherapy cohort were 7.1 months, 20.0 months, not reached, and not reached, respectively (Hazard Ratio (HR)=0.549, 95% Confidence interval (CI) 0.451-0.667; p<0.001). Cox multivariate analysis showed that age ≥60 (HR=2.207, 95%CI 1.321-3.690; p=0.003), high IPI score (3-5) (HR=2.926, 95% CI 1.716-4.988; p<0.001), B symptoms (HR=1.928, 95%CI 1.192-3.119; p=0.007), elevated LDH (HR=1.696, 95%CI 1.031-2.791; p=0.038) and received less than 4 cycles chemotherapy (HR=0.520, 95%CI 0.424-0.637; p<0.001) were independent risk factor for adverse prognosis based on overall survival (OS). Discussion: These results demonstrated that 4-6 cycles chemotherapy were significantly associated with improved outcomes in HIV-associated DLBCL patients. However, >6 cycles chemotherapy did not further improve the survival of patients.
Subject(s)
Acquired Immunodeficiency Syndrome , Lymphoma, AIDS-Related , Lymphoma, Large B-Cell, Diffuse , Humans , Male , Middle Aged , Female , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Prognosis , B-Lymphocytes/pathologyABSTRACT
Paeoniae Radix Alba (PRA), as a Traditional Chinese Medicine, is widely used in Chinese cuisine due to high health-benefits and nutrition, but the effect of different polarity of solvents on the extraction of antioxidant and hypoglycemic constituents, as well as the major active compounds remain unclear. In this research, 40, 70, and 95% ethanol were firstly applied to extract the polyphenols from PRA, the extraction yields, total phenolics, and total flavonoids content, free radical scavenging ability, α-glucosidase inhibition ability, and anti-glycation ability of extracts were evaluated spectroscopically. The oxidative damage protection, hypoglycemic activity, and alleviation on peripheral nerve damage were evaluated by H2O2-induced HepG2 cells and hyperglycemic zebrafish models. UPLC-QTOF-MS/MS was used to identify the major chemical constituents. The results showed that 40, 70, and 95% ethanol exhibited insignificant difference on the extraction of phenolics and flavonoids from PRA. All extracts showed promising DPPHâ and ABTSâ + scavenging ability, α-glucosidase inhibition and anti-glycation ability. In addition, PRA extracts could restore the survival rate of HepG2 cells induced by H2O2, and alleviate the oxidative stress by reducing the content of MDA and increasing the levels of SOD, CAT, and GSH-Px. The 70% ethanol extract could also mitigate the blood glucose level and peripheral motor nerve damage of hyperglycemic zebrafish. Thirty-five compounds were identified from 70% ethanol extract, gallotannins, gallic acid and its derivatives, and paeoniflorin and its derivatives were the dominant bioactive compounds. Above results could provide important information for the value-added application of PRA in functional food and medicinal industry.
ABSTRACT
BACKGROUND: Despite the introduction of combined antiretroviral therapy, the clinical outcomes of HIV-associated Burkitt lymphoma (BL) remain poor. METHODS: To evaluate the clinical characteristics, prognostic factors, and outcomes of HIV-associated BL, we conducted a retrospective analysis of patients from multiple centers in China. RESULTS: The study included 41 patients from 8 medical centers. Among the included population, male patients accounted for 87.8%, with 75.6% in advanced stages. Notably, 46.3% of cases involved bone marrow, while 19.5% involved the central nervous system (CNS). The most commonly used chemotherapy regimen was DA-EPOCH ± R, accounting for 53.6% of cases. The overall response rates for patients receiving DA-EPOCH ± R and R-Hyper-CVAD were 59% and 58.2%, respectively. Interestingly, patients receiving regimens containing rituximab had similar complete remission rates (25% vs. 23.5%) and overall survival time (45.69 ± 11.58 vs. 47.79 ± 11.72 months, P = 0.907) compared to those without rituximab, but differed in progression rates (33.3% vs. 47.1%). For the entire cohort, the 1-year progression-free survival (PFS) and overall survival (OS) rates were 52% and 67%, respectively. CNS involvement was independent risk factors for survival, with 1-year PFS and OS rates of 0% and 38% for patients with CNS involvement, and PFS and OS rates of 66% and 75% for patients without CNS involvement. CONCLUSIONS: HIV-associated BL patients in China have poor prognosis and show limited response to current treatment regimens. The absence of CNS involvement significantly improves clinical outcomes. The use of rituximab is not significantly associated with improved outcomes but can reduce disease progression.
ABSTRACT
Phthalates (PAEs) are ubiquitous in soils and food products and thus pose a high risk to human health. Herein, genome mining revealed a great diversity of bacteria with PAEs-degrading potential. Mining of the genome of Raoultella ornithinolytica XF201, a novel strain isolated from Dongxiang wild rice rhizosphere, revealed the presence of two silenced tandem genes pcdGH (encoding protocatechuate 3,4-dioxygenase, 3,4-PCD), key aromatic ring-cleaving genes in PAEs biodegradation. Ribosome engineering was successfully utilized to activate the expression of pcdGH genes to produce 3,4-PCD in the mutant XF201-G2U5. The mutant XF201-G2U5 showed high 3,4-PCD activity and could remove 94.5 % of di-n butyl phthalate (DBP) in 72 h. The degradation kinetics obeyed the first-order kinetic model. Strain XF201-G2U5 could also degrade the other PAEs and the main intermediate metabolites, ultimately leading to tricarboxylic acid cycle. Therefore, this strategy facilitates novel bacterial resources discovery for bioremediation of PAEs and other emerging contaminants.
Subject(s)
Diethylhexyl Phthalate , Phthalic Acids , Humans , Biodegradation, Environmental , Esters/metabolism , Phthalic Acids/metabolism , Dibutyl Phthalate/metabolismABSTRACT
PURPOSE: Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti-PD-L1 monoclonal antibody, in R/R ENKTL. METHODS: Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. RESULTS: At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee-assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. CONCLUSION: Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.
Subject(s)
Lymphoma, Extranodal NK-T-Cell , Humans , Lymphoma, Extranodal NK-T-Cell/drug therapy , Treatment Outcome , Antibodies, Monoclonal , Killer Cells, NaturalABSTRACT
γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-ß (Aß) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aß production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aß over the baseline after a transient reduction (known as Aß-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aß-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and ß-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aß-rebound, possibly because of the lack of accumulation of ß-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aß-rebound.