Redox Enzymes P4HB and PDIA3 Interact with STIM1 to Fine-Tune Its Calcium Sensitivity and Activation.

Sensing the lowering of endoplasmic reticulum (ER) calcium (Ca2+), STIM1 mediates a ubiquitous Ca2+ influx process called the store-operated Ca2+ entry (SOCE). Dysregulated STIM1 function or abnormal SOCE is strongly associated with autoimmune disorders, atherosclerosis, and various forms of cancers. Therefore, uncovering the molecular intricacies of post-translational modifications, such as oxidation, on STIM1 function is of paramount importance. In a recent proteomic screening, we identified three protein disulfide isomerases (PDIs)-Prolyl 4-hydroxylase subunit beta (P4HB), protein disulfide-isomerase A3 (PDIA3), and thioredoxin domain-containing protein 5 (TXNDC5)-as the ER-luminal interactors of STIM1. Here, we demonstrated that these PDIs dynamically associate with STIM1 and STIM2. The mutation of the two conserved cysteine residues of STIM1 (STIM1-2CA) decreased its Ca2+ affinity both in cellulo and in situ. Knockdown of PDIA3 or P4HB increased the Ca2+ affinity of wild-type STIM1 while showing no impact on the STIM1-2CA mutant, indicating that PDIA3 and P4HB regulate STIM1's Ca2+ affinity by acting on ER-luminal cysteine residues. This modulation of STIM1's Ca2+ sensitivity was further confirmed by Ca2+ imaging experiments, which showed that knockdown of these two PDIs does not affect STIM1-mediated SOCE upon full store depletion but leads to enhanced SOCE amplitudes upon partial store depletion. Thus, P4HB and PDIA3 dynamically modulate STIM1 activation by fine-tuning its Ca2+ binding affinity, adjusting the level of activated STIM1 in response to physiological cues. The coordination between STIM1-mediated Ca2+ signaling and redox responses reported herein may have implications for cell physiology and pathology.

Boosting the removal of diesel soot particles by regulating the Pr-O strength over transition metal doped Pr6O11 catalysts.

The content of active lattice oxygen and oxygen vacancies is crucial for the catalytic oxidation of soot. Herein, we adjust the Pr-O bond strength in Pr6O11 by doping several common transition metals (Mn, Fe, Co, Ni) to promote the formation of oxygen vacancies and the activation of lattice oxygen. This strategy does not compromise its crystal structure, allowing for improved catalytic performance while maintaining stability. The Mn-doped Pr6O11 catalyst shows the best soot catalytic oxidation performance. Its T50 (the temperature of soot conversion reaching 50 %) value is 396 °C under loose contact. Further characterizations and density functional theory (DFT) calculations demonstrate that PMO possesses a large specific surface area. Additionally, the weakening the strength of the Pr-O bond leaded to an increase in oxygen vacancies, which in turn enhanced the redox ability of catalyst. This work will provide a reference for the development of Pr-based catalysts for soot combustion.

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism.

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

Exploring the dynamic behaviors of five pesticides in lettuce: Implications for consumer health through field and modeling experiments.

Lettuce, a globally consumed nutritious vegetable, is often linked to concerns regarding pesticide residues. To address this issue, we conducted field trials and utilized dynamiCROP modeling to examine the uptake, distribution, translocation, and dissipation of five pesticides (λ-cyhalothrin, difenoconazole, acetamiprid, dimethomorph, and ß-cypermethrin) commonly detected in lettuce. At harvest, pesticides residues were below the maximum residue limits (MRLs) at 0.05, 0.39, 0.047, 0.72, and 0.072 mg kg-1, respectively. Simulation results elucidated distinct behaviors of the pesticides following application to lettuce foliage across various compartments. However, all pesticides exhibited a common dissipation trend, initially stabilizing or increasing before gradually declining. For all five pesticides, the largest contribution of residues on lettuce leaves came from the leaf surface during the early period after application, and from the soil in the long term. Health risk assessments indicated negligible risks associated with consuming lettuce containing these pesticides, both in the short and long term.

Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

Synchronous removal of gaseous toluene and benzene and degradation process shifts in microbial fuel cell-biotrickling filter system.

Illustrating the biodegradation processes of multi-component volatile organic compounds (VOCs) will expedite the implication of biotechnology in purifying industrial exhaust. Here, performance shifts of microbial fuel cell and biotrickling filter combined system (MFC-BTF) are investigated for removing single and dual components of toluene and benzene. Synchronous removal of toluene (95 %) and benzene (97 %) are achieved by MFC-BTF accompanied with the output current of 0.41 mA. Elevated content of extracellular polymeric substance facilitates the mass transfer of benzene with the presence of toluene. Strains of Bacteroidota, Proteobacteria and Chloroflexi contribute to the removal of dual components VOCs. Empty bed reaction time and the VOCs concentration are the important factors influencing their dissolution in the system. The biodegradation of toluene and benzene proceeds with 2-hydroxymuconic semialdehyde and o-hydroxybenzoic acid as the main intermediates. These results provide a comprehensive understanding of multi-component VOCs removal by MFC-BTF and guide the system design, optimization, and scale-up.

First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL. METHODS: The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related. INTERPRETATION: Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL. FUNDING: National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.

Development of an immune-related diagnostic predictive model for oral lichen planus.

Oral lichen planus (OLP) was a chronic inflammatory disease of unknown etiology with a 1.4% chance of progressing to malignancy. However, it has been suggested in several studies that immune system disorders played a dominant role in the onset and progression of OLP. Therefore, this experiment aimed to develop a diagnostic prediction model for OLP based on immunopathogenesis to achieve early diagnosis and treatment and prevent cancer. In this study, 2 publicly available OLP datasets from the gene expression omnibus database were filtered. In the experimental group (GSE52130), the level of immune cell infiltration was assessed using MCPcounter and ssGSEA algorithms. Subsequently, differential expression analysis and gene set enrichment analysis were performed between the OLP and control groups. The resulting differentially expressed genes were intersected with immunologically relevant genes provided on the immunology database and analysis portal database (ImmPort) website to obtain differentially expressed immunologically relevant genes (DEIRGs). Furthermore, the gene ontology and kyoto encyclopedia of genes and genomes analyses were carried out. Finally, protein-protein interaction network and least absolute shrinkage and selection operator regression analyses constructed a model for OLP. Receiver operating characteristic curves for the experimental and validation datasets (GSE38616) were plotted separately to validate the model's credibility. In addition, real-time quantitative PCR experiment was performed to verify the expression level of the diagnostic genes. Immune cell infiltration analysis revealed a more significant degree of inflammatory infiltration in the OLP group compared to the control group. In addition, the gene set enrichment analysis results were mainly associated with keratinization, antibacterial and immune responses, etc. A total of 774 differentially expressed genes was obtained according to the screening criteria, of which 65 were differentially expressed immunologically relevant genes. Ultimately, an immune-related diagnostic prediction model for OLP, which was composed of 5 hub genes (BST2, RNASEL, PI3, DEFB4A, CX3CL1), was identified. The verification results showed that the model has good diagnostic ability. There was a significant correlation between the 5 hub diagnostic biomarkers and immune infiltrating cells. The development of this model gave a novel insight into the early diagnosis of OLP.

Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations.

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Autotrophic denitrification based on sulfur-iron minerals: advanced wastewater treatment technology with simultaneous nitrogen and phosphorus removal.

Autotrophic denitrification technology has many advantages, including no external carbon source addition, low sludge production, high operating cost efficiency, prevention of secondary sewage pollution, and stable treatment efficiency. At present, the main research on autotrophic denitrification electron donors mainly includes sulfur, iron, and hydrogen. In these autotrophic denitrification systems, pyrite has received attention due to its advantages of easy availability of raw materials, low cost, and pH stability. When pyrite is used as a substrate for autotropic denitrification, sulfide (S2-) and ferrous ion (Fe2+) in the substrate will provide electrons to convert nitrate (NO3-) in sewage first to nitrite (NO2-), then to nitrogen (N2), and finally to discharge the system. At the same time, sulfide (S2-) loses electrons to sulfate (SO42-) and ferrous ion (Fe2+) loses electrons to ferric iron (Fe3+). Phosphates (PO43-) in wastewater are chemically combined with ferric iron (Fe3+) to form ferric phosphate (FePO4) precipitate. This paper aims to provide a detailed and comprehensive overview of the dynamic changes of nitrogen (N), phosphorus (P), and other substances in the process of sulfur autotrophic denitrification using iron sulfide, and to summarize the factors that affect wastewater treatment in the system. This work will provide a relevant research direction and theoretical basis for the field of sulfur autotrophic denitrification, especially for the related experiments of the reaction conversion of various substances in the system.

Anlotinib as a third-line or further treatment for recurrent or metastatic nasopharyngeal carcinoma: a single-arm, phase 2 clinical trial.

BACKGROUND: Treatment options beyond the first-line setting for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are limited. The role of the multitarget tyrosine kinase inhibitor anlotinib in RM-NPC is unclear. METHODS: In this prospective, single-arm, phase 2 trial, patients with histologically confirmed RM-NPC and failure of at least two lines of prior systemic treatments were eligible. Anlotinib was given at 12 mg once daily on days 1-14 every 3 weeks until disease progression or intolerable toxicities. The primary end point was disease control rate, defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria. RESULTS: From April 2019 to March 2021, 39 patients were enrolled and received a median of 4 cycles (range, 0.5-20) of anlotinib treatment. Partial response and stable disease were observed in 8 and 20 patients, respectively. The disease control rate was 71.8%, and objective response rate was 20.5%. With a median follow-up of 17.2 months, the median progression-free survival was 5.7 months. The 12-month overall survival was 58.3%, and the median overall survival was not reached. The most frequent grade 3/4 treatment-related adverse events were hand-foot syndrome (23.7%), oral mucositis (21.0%), hypertension (7.9%), and triglyceride elevation (7.9%). Hemorrhage, all grade 1 or 2, occurred in 34.2% of the patients. CONCLUSIONS: Anlotinib monotherapy exhibited promising anti-tumor activities and disease control for heavily pretreated RM-NPC patients with a tolerable toxicity profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03906058.

Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma.

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorly understood. Herein, we found that the expression of PAK1 was significantly higher in T-LBL cell lines (Jurkat, SUP-T1, and CCRF-CEM) compared to the human T-lymphoid cell line. Moreover, PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse (P = .012). T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1, P = .028; PAK2, P = .027; PAK1/2, P = .032). PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. Besides, PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo. Mechanistically, through western blotting and RNA sequencing, we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1, NF-κB and cell adhesion signaling pathways in T-LBL cell lines. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.

Microbial Diversity and Characteristic Quality Formation of Qingzhuan Tea as Revealed by Metagenomic and Metabolomic Analysis during Pile Fermentation.

In order to analyze the changes in the microbial community structure during the pile fermentation of Qingzhuan tea and their correlation with the formation of quality compounds in Qingzhuan tea, this study carried out metagenomic and metabolomic analyses of tea samples during the fermentation process of Qingzhuan tea. The changes in the expression and abundance of microorganisms during the pile fermentation were investigated through metagenomic assays. During the processing of Qingzhuan tea, there is a transition from a bacterial dominated ecosystem to an ecosystem enriched with fungi. The correlation analyses of metagenomics and metabolomics showed that amino acids and polyphenol metabolites with relatively simple structures exhibited a significant negative correlation with target microorganisms, while the structurally complicated B-ring dihydroxy puerin, B-ring trihydroxy galloyl puerlin, and other compounds showed a significant positive correlation with target microorganisms. Aspergillus niger, Aspergillus glaucus, Penicillium in the Aspergillaceae family, and Talaromyces and Rasamsonia emersonii in Trichocomaceae were the key microorganisms involved in the formation of the characteristic qualities of Qingzhuan tea.

Role of STIM1 in the Regulation of Cardiac Energy Substrate Preference.

The heart requires a variety of energy substrates to maintain proper contractile function. Glucose and long-chain fatty acids (FA) are the major cardiac metabolic substrates under physiological conditions. Upon stress, a shift of cardiac substrate preference toward either glucose or FA is associated with cardiac diseases. For example, in pressure-overloaded hypertrophic hearts, there is a long-lasting substrate shift toward glucose, while in hearts with diabetic cardiomyopathy, the fuel is switched toward FA. Stromal interaction molecule 1 (STIM1), a well-established calcium (Ca2+) sensor of endoplasmic reticulum (ER) Ca2+ store, is increasingly recognized as a critical player in mediating both cardiac hypertrophy and diabetic cardiomyopathy. However, the cause-effect relationship between STIM1 and glucose/FA metabolism and the possible mechanisms by which STIM1 is involved in these cardiac metabolic diseases are poorly understood. In this review, we first discussed STIM1-dependent signaling in cardiomyocytes and metabolic changes in cardiac hypertrophy and diabetic cardiomyopathy. Second, we provided examples of the involvement of STIM1 in energy metabolism to discuss the emerging role of STIM1 in the regulation of energy substrate preference in metabolic cardiac diseases and speculated the corresponding underlying molecular mechanisms of the crosstalk between STIM1 and cardiac energy substrate preference. Finally, we briefly discussed and presented future perspectives on the possibility of targeting STIM1 to rescue cardiac metabolic diseases. Taken together, STIM1 emerges as a key player in regulating cardiac energy substrate preference, and revealing the underlying molecular mechanisms by which STIM1 mediates cardiac energy metabolism could be helpful to find novel targets to prevent or treat cardiac metabolic diseases.

Synergistic effects on oxidative stress, apoptosis and necrosis resulting from combined toxicity of three commonly used pesticides on HepG2 cells.

The widespread use of pesticides performs a vital role in safeguarding crop yields and quality, providing the opportunity for multiple pesticides to co-exist, which poses a significant potential risk to human health. To assess the toxic effects caused by exposures to individual pesticides (chlorpyrifos, carbofuran and acetamiprid), binary combinations and ternary combinations, individual and combined exposure models were developed using HepG2 cells and the types of combined effects of pesticide mixtures were assessed using concentration addition (CA), independent action (IA) and combination index (CI) models, respectively, and the expression of biomarkers related to oxidative stress, apoptosis and cell necrosis was further examined. Our results showed that both individual pesticides and mixtures exerted toxic effects on HepG2 cells. The CI model indicated that the toxic effects of pesticide mixtures exhibited synergistic effects. The results of the lactate dehydrogenase (LDH) release and apoptosis assay revealed that the pesticide mixture increased the release of LDH and apoptosis levels. Moreover, our results also showed that individual pesticides and mixtures disrupted redox homeostasis and that pesticide mixtures produced more intense oxidative stress effects. In conclusion, we have illustrated the enhanced combined toxicity of pesticide mixtures by in-vitro experiments, which provides a theoretical basis and scientific basis for further toxicological studies.

Treatment patterns and clinical outcomes of mantle cell lymphoma: A retrospective cohort study by CHOICE.

Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B.

Switch-on Fluorescence Analysis of Protease Activity with the Assistance of a Nickel Ion-Nitrilotriacetic Acid-Conjugated Magnetic Nanoparticle.

Heterogeneous protease biosensors show high sensitivity and selectivity but usually require the immobilization of peptide substrates on a solid interface. Such methods exhibit the disadvantages of complex immobilization steps and low enzymatic efficiency induced by steric hindrance. In this work, we proposed an immobilization-free strategy for protease detection with high simplicity, sensitivity and selectivity. Specifically, a single-labeled peptide with oligohistidine-tag (His-tag) was designed as the protease substrate, which can be captured by a nickel ion-nitrilotriacetic acid (Ni-NTA)-conjugated magnetic nanoparticle (MNP) through the coordination interaction between His-tag and Ni-NTA. When the peptide was digested by protease in a homogeneous solution, the signal-labeled segment was released from the substrate. The unreacted peptide substrates could be removed by Ni-NTA-MNP, and the released segments remained in solution to emit strong fluorescence. The method was used to determine protease of caspase-3 with a low detection limit (4 pg/mL). By changing the peptide sequence and signal reporters, the proposal could be used to develop novel homogeneous biosensors for the detection of other proteases.

Hepatocyte SREBP signaling mediates clock communication within the liver.

Rhythmic intraorgan communication coordinates environmental signals and the cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific KO of core components of the molecular clock Rev-erbα and -ß (Reverb-hDKO) alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in nonparenchymal cells (NPCs) of the liver. Here, we report that in fatty liver caused by diet-induced obesity (DIO), hepatocyte SREBP cleavage-activating protein (SCAP) was required for Reverb-hDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in liver macrophages (LMs). Integrative analyses of isolated hepatocytes and LMs revealed that SCAP-dependent lipidomic changes in REV-ERB-depleted hepatocytes led to the enhancement of LM metabolic rhythms. Hepatocytic loss of REV-ERBα and ß (REV-ERBs) also attenuated LM rhythms via SCAP-independent polypeptide secretion. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in fatty liver disease caused by DIO.

LncRNA H19 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-181/PDCD4 Axis.

Chronic obstructive pulmonary disease (COPD) kills more than 3 million people worldwide every year. Despite progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to ameliorate disease progression or affect mortality. Exercise plays a positive role in the prevention and treatment of diaphragm dysfunction in COPD, and the changes in diaphragm structure and function induced by exercise are closely related to the regulation of oxidative stress. But the mechanism remains unclear. So the aim of this study was to reveal the therapeutic mechanism of exercise to COPD using both in vivo and in vitro experiments. In this study, cigarette smoke (CS) induced COPD mice model, treadmill aerobic training for COPD mice were constructed and cigarette smoke extract (CSE) induced bronchial epithelial cells (BECs) model were used for COPD study. Bioinformatics analysis, luciferase reporting analysis, and RT-qPCR detection were used to clarify the interacted relationship among lncRNA, miRNA, and mRNA. ROS, inflammatory cytokines expression, and EMT relative protein α-SMA were detected using immunofluorescence and ELISA detection. The result shows that exercise ameliorates COPD induced lung injury by inhibit ROS, inflammation, and epithelial-mesenchymal transition (EMT) relative protein α-SMA expression. RT-qPCR detection shows that lnc-H19 expression was increased in lung tissues of COPD mice. Exercise decreased COPD induced lnc-H19 expression. Downregulation lnc-H19 inhibits COPD mediated lung injury. Bioinformatics analysis and luciferase reporting analysis confirmed that miR-181 and PDCD4 were downstream targets of lnc-H19. Upregulation of PDCD4 or downregulation of miR-181 reversed the protective effect of si-lnc-H19 to BECs after exposure to CSE. In conclusion, lncRNA H19 contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-181/PDCD4 Axis.