Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Survival is poor among patients with triple-class-exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma. METHODS: In this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150×106 to 450×106 CAR-positive T cells) or one of five standard regimens. The primary end point was progression-free survival. Key secondary end points were overall response (partial response or better) and overall survival. Safety was assessed. RESULTS: A total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P<0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P<0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher. CONCLUSIONS: Ide-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports. (Funded by 2seventy bio and Celgene, a Bristol-Myers Squibb company; KarMMa-3 ClinicalTrials.gov number, NCT03651128.).

Diagnostic value of plasma-derived exosomal miR-223 for epithelial ovarian cancer.

OBJECTIVES: To evaluate the diagnostic value of plasma exosomal miR-223 and its combination with CA125 for the diagnosis of early-stage epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Exosomes derived from the plasma of 78 EOC patients, 40 patients with epithelial benign ovarian tumors, and 52 healthy participants were isolated using the ultracentrifugation method and identified by transmission electron microscopy (TEM) and western blot. RESULTS: The expression of exosomal miR-223 was significantly upregulated in the plasma of EOC patients compared to that in healthy subjects and patients with benign diseases. The combination of exosomal miR-223 and CA125 from plasma had an equivalent area under the ROC curve (AUC) to CA125 alone for discriminating between EOC and non-EOC cases, including healthy subjects and benign ovarian tumors. However, the AUC value of the combination was 0.944 (95% CI: 0.899-0.990) for differentially diagnosing early-stage EOC from healthy subjects, slightly higher than that of CA125 alone (0.928, 95% CI: 0.875-0.981), with a sensitivity and specificity of 0.9784 and 0.885, respectively. CONCLUSION: Our data suggest that plasma exosomal miR-223 can be used as a complement to CA125 to increase the diagnostic power for differentiating early-stage EOC from healthy subjects.

Physalin A Induces Apoptosis and Autophagy in Hepatocellular Carcinoma via Inhibition of PI3K/Akt Signaling Pathway.

Physalin A (PA) is a bioactive withanolide with multiple pharmacological properties and has been indicated to be cytotoxic to hepatocellular carcinoma (HCC) cell line HepG2. This study aims to explore the mechanisms underlying PA antitumor activity in HCC. HepG2 cells were exposed to various concentrations of PA. Cell counting kit-8 assay and flow cytometry were implemented for evaluating cell viability and apoptosis, respectively. Immunofluorescence staining was utilized for detecting autophagic protein LC3. Western blotting was employed for measuring levels of autophagy-, apoptosis- and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling-related proteins. A xenograft mouse model was established to verify the antitumor activity of PA in vivo. PA impaired HepG2 cell viability, and triggered apoptosis as well as autophagy. Inhibiting autophagy augmented PA-evoked HepG2 cell apoptosis. PA repressed PI3K/Akt signaling in HCC cells and activating PI3K/Akt reversed PA-triggered apoptosis and autophagy. PA treatment inhibited tumor growth in tumor-bearing mice. PA triggers HCC cell apoptosis and autophagy by inactivating PI3K/Akt signaling.

Attenuation of Epileptogenesis and Cognitive Deficits by a Selective and Potent Kv7 Channel Opener in Rodent Models of Seizures.

Targeting neuronal Kv7 channels by pharmacological activation has been proven to be an attractive therapeutic strategy for epilepsy. Here, we show that activation of Kv7 channels by an opener SCR2682 dose-dependently reduces seizure activity and severity in rodent models of epilepsy induced by a GABAa receptor antagonist pentylenetetrazole (PTZ), maximal electroshock, and a glutamate receptor agonist kainic acid (KA). Electroencephalographic recordings of rat cerebral cortex confirm that SCR2682 also decreases epileptiform discharges in KA-induced seizures. Nissl and neuronal nuclei staining further demonstrates that SCR2682 also protects neurons from injury induced by KA. In Morris water maze navigation and Y-maze tests, SCR2682 improves PTZ- and KA-induced cognitive impairment. Taken together, our findings demonstrate that pharmacological activation of Kv7 by novel opener SCR2682 may hold promise for therapy of epilepsy with cognitive impairment. SIGNIFICANCE STATEMENT: A neuronal Kv7 channel opener SCR2682 attenuates epileptogenesis and seizure-induced cognitive impairment in rodent models of seizures, thus possessing a developmental potential for effective therapy of epilepsy with cognitive impairment.

Single-frequency violet and blue laser emission from AlGaInN photonic integrated circuit chips.

Chip-based, single-frequency and low phase-noise integrated photonic laser diodes emitting in the violet (412 nm) and blue (461 nm) regime are demonstrated. The GaN-based edge-emitting laser diodes were coupled to high-quality on-chip micro-resonators for optical feedback and mode selection resulting in laser self-injection locking with narrow emission linewidth. Multiple group III-nitride (III-N) based photonic integrated circuit chips with different waveguide designs including single-crystalline AlN, AlGaN, and GaN were developed and characterized. Single-frequency laser operation was demonstrated for all studied waveguide core materials. The best side-mode suppression ratio was determined to be ∼36 dB at 412 nm with a single-frequency laser emission linewidth of only 3.8 MHz at 461 nm. The performance metrics of this novel, to the best of our knowledge, type of laser suggest potential implementation in next-generation, portable quantum systems.

Purinergic receptors mediate endothelial dysfunction and participate in atherosclerosis.

Atherosclerosis is the main pathological basis of cardiovascular disease and involves damage to vascular endothelial cells (ECs) that results in endothelial dysfunction (ED). The vascular endothelium is the key to maintaining blood vessel health and homeostasis. ED is a complex pathological process involving inflammation, shear stress, vascular tone, adhesion of leukocytes to ECs, and platelet aggregation. The activation of P2X4, P2X7, and P2Y2 receptors regulates vascular tone in response to shear stress, while activation of the A2A, P2X4, P2X7, P2Y1, P2Y2, P2Y6, and P2Y12 receptors promotes the secretion of inflammatory cytokines. Finally, P2X1, P2Y1, and P2Y12 receptor activation regulates platelet activity. These purinergic receptors mediate ED and participate in atherosclerosis. In short, P2X4, P2X7, P2Y1, and P2Y12 receptors are potential therapeutic targets for atherosclerosis.

Effects of Cascade Reservoirs on Spatiotemporal Dynamics of the Sedimentary Bacterial Community: Co-occurrence Patterns, Assembly Mechanisms, and Potential Functions.

Dam construction as an important anthropogenic activity significantly influences ecological processes in altered freshwater bodies. However, the effects of multiple cascade dams on microbial communities have been largely overlooked. In this study, the spatiotemporal distribution, co-occurrence relationships, assembly mechanisms, and functional profiles of sedimentary bacterial communities were systematically investigated in 12 cascade reservoirs across two typical karst basins in southwest China over four seasons. A significant spatiotemporal heterogeneity was observed in bacterial abundance and diversity. Co-occurrence patterns in the Wujiang Basin exhibited greater edge counts, graph density, average degree, robustness, and reduced modularity, suggesting more intimate and stronger ecological interactions among species than in the Pearl River Basin. Furthermore, Armatimonadota and Desulfobacterota, identified as keystone species, occupied a more prominent niche than the dominant species. A notable distance-decay relationship between geographical distance and community dissimilarities was identified in the Pearl River Basin. Importantly, in the Wujiang Basin, water temperature emerged as the primary seasonal variable steering the deterministic process of bacterial communities, whereas 58.5% of the explained community variance in the neutral community model (NCM) indicated that stochastic processes governed community assembly in the Pearl River Basin. Additionally, principal component analysis (PCA) revealed more pronounced seasonal dynamics in nitrogen functional compositions than spatial variation in the Wujiang Basin. Redundancy analysis (RDA) results indicated that in the Wujiang Basin, environmental factors and in Pearl River Basin, geographical distance, reservoir age, and hydraulic retention time (HRT), respectively, influenced the abundance of nitrogen-related genes. Notably, these findings offer novel insights: building multiple cascade reservoirs could lead to a cascading decrease in biodiversity and resilience in the river-reservoir ecosystem.

Embryo development, pregnancy and live birth outcomes following IVF treatment were not compromised during the COVID-19 pandemic.

PURPOSE: To evaluate whether outcomes of in vitro fertilization (IVF) are affected during the coronavirus disease-19 (COVID-19) pandemic. METHODS: This was a single-center, retrospective study. Embryo development, pregnancy, and live birth outcomes were compared between COVID-19 and pre-COVID-19 groups. Blood samples from patients during the COVID-19 pandemic were tested for COVID-19. RESULTS: After 1:1 random matching, 403 cycles for each group were included in the study. The rates of fertilization, normal fertilization, and blastocyst formation were higher in the COVID-19 group than in the pre-COVID-19 group. No difference was observed in the rates of day 3 good-quality embryos and good-quality blastocysts between the groups. A multivariate analysis showed that the live birth rate in the COVID-19 group was higher than that in the pre-COVID-19 group (51.4% vs. 41.4%, P = 0.010). In fresh cleavage-stage embryo and blastocyst transfer cycles, there were no differences between the groups in terms of pregnancy, obstetric, and perinatal outcomes. In the freeze-all cycles, the live birth rate was higher during the COVID-19 pandemic (58.0% vs. 34.5%, P = 0.006) than during the pre-COVID-19 period following frozen cleavage stage embryo transfer. The rate of gestational diabetes during the COVID-19 pandemic was higher than that during the pre-COVID-19 period (20.3% vs. 2.4%, P = 0.008) following frozen blastocyst transfer. All the serological results of the patients during the COVID-19 pandemic were negative. CONCLUSION: Our results indicate that embryo development, pregnancy, and live birth outcomes in uninfected patients were not compromised during the COVID-19 pandemic at our center.

Elevation of Arginase-II in Podocytes Contributes to Age-Associated Albuminuria in Male Mice.

One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of an age-associated increase in arginase-II (Arg-II) in proximal tubules of both male and female mice. However, it is unclear whether Arg-II is also involved in aging glomeruli. The current study investigates the role of the sex-specific elevation of Arg-II in podocytes in age-associated increased albuminuria. Young (3-4 months) and old (20-22 months) male and female mice of wt and arginase-II knockout (arg-ii-/-) were used. Albuminuria was employed as a readout of glomerular function. Cellular localization and expression of Arg-II in glomeruli were analyzed using an immunofluorescence confocal microscope. A more pronounced age-associated increase in albuminuria was found in male than in female mice. An age-associated induction of Arg-II in glomeruli and podocytes (as demonstrated by co-localization of Arg-II with the podocyte marker synaptopodin) was also observed in males but not in females. Ablation of the arg-ii gene in mice significantly reduces age-associated albuminuria in males. Also, age-associated decreases in podocyte density and glomerulus hypertrophy are significantly prevented in male arg-ii-/- but not in female mice. However, age-associated glomerulosclerosis is not affected by arg-ii ablation in both sexes. These results demonstrate a role of Arg-II in sex-specific podocyte injury in aging. They may explain the sex-specific differences in the development of renal disease in humans during aging.

Paracrine Effects of Renal Proximal Tubular Epithelial Cells on Podocyte Injury under Hypoxic Conditions Are Mediated by Arginase-II and TGF-ß1.

Hypoxia is an important risk for renal disease. The mitochondrial enzyme arginase-II (Arg-II) is expressed and/or induced by hypoxia in proximal tubular epithelial cells (PTECs) and in podocytes, leading to cellular damage. Because PTECs are vulnerable to hypoxia and located in proximity to podocytes, we examined the role of Arg-II in the crosstalk of PTECs under hypoxic conditions with podocytes. A human PTEC cell line (HK2) and a human podocyte cell line (AB8/13) were cultured. Arg-ii gene was ablated by CRISPR/Case9 in both cell types. HK2 cells were exposed to normoxia (21% O2) or hypoxia (1% O2) for 48 h. Conditioned medium (CM) was collected and transferred to the podocytes. Podocyte injuries were then analyzed. Hypoxic (not normoxic) HK2-CM caused cytoskeletal derangement, cell apoptosis, and increased Arg-II levels in differentiated podocytes. These effects were absent when arg-ii in HK2 was ablated. The detrimental effects of the hypoxic HK2-CM were prevented by TGF-ß1 type-I receptor blocker SB431542. Indeed, TGF-ß1 levels in hypoxic HK2-CM (but not arg-ii-/--HK2-CM) were increased. Furthermore, the detrimental effects of TGF-ß1 on podocytes were prevented in arg-ii-/--podocytes. This study demonstrates crosstalk between PTECs and podocytes through the Arg-II-TGF-ß1 cascade, which may contribute to hypoxia-induced podocyte damage.

Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate.

Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP. Robust glycemic control and graft survival were achieved for the planned study period of >90 days. Our observations suggest the intrapleural space provides an attractive locale for islet transplantation due to its higher oxygen tension, ability to accommodate large transplant tissue volumes, and a lack of IBMIR-mediated islet damage. Our preliminary results reveal the promise of the intrapleural space as an alternative site for clinical islet transplantation in the treatment of type 1 diabetes.

Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma.

BACKGROUND: Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS: In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS: Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS: We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).

Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol-Associated Hepatitis.

BACKGROUND AND AIMS: We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol-associated hepatitis (AH) pathogenesis and their prognostic significance. APPROACH AND RESULTS: Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell-cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 (RRM2), cyclin D1 (CCND1), cyclin D2 (CCND2), MYC proto-oncogene (MYC), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3'-UTR (untranslated region) luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3'-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End-Stage Liver Disease (MELD), and serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted mortality. CONCLUSIONS: Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and up-regulating genes responsible for DNA synthesis and cell-cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients.

Stress-Responsive Gene FK506-Binding Protein 51 Mediates Alcohol-Induced Liver Injury Through the Hippo Pathway and Chemokine (C-X-C Motif) Ligand 1 Signaling.

BACKGROUND AND AIMS: Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. APPROACH AND RESULTS: We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. CONCLUSIONS: We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.

The Apelin-Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis.

BACKGROUND AND AIMS: Apelin (APLN) is the endogenous ligand of its G protein-coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN-APJ axis regulates ductular reaction and liver fibrosis during cholestasis. APPROACH AND RESULTS: We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild-type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1 week. WT and APLN-/- mice underwent BDL or sham surgery for 1 week. Multidrug resistance gene 2 knockout (Mdr2-/- ) mice were treated with ML221 for 1 week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN-APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN-treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2-/- mice. ML221 treatment or APLN-/- reduced BDL-induced and Mdr2-/- -induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro, APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal-regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N-acetyl-cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN-induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC. CONCLUSIONS: The APLN-APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK-dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN-APJ axis may be important for managing cholangiopathies.

Differential Effect of Dietary Supplementation with a Soybean Oil Enriched in Oleic Acid versus Linoleic Acid on Plasma Lipids and Atherosclerosis in LDLR-Deficient Mice.

Both monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) play important roles in lipid metabolism, and diets enriched with either of these two fatty acids are associated with decreased cardiovascular risk. Conventional soybean oil (CSO), a common food ingredient, predominantly contains linoleic acid (LA; C18:2), a n-6 PUFA. Recently, a modified soybean oil (MSO) enriched in oleic acid (C18:1), a n-9 MUFA, has been developed, because of its improved chemical stability to oxidation. However, the effect of the different dietary soybean oils on cardiovascular disease remains unknown. To test whether diets rich in CSO versus MSO would attenuate atherosclerosis development, LDL receptor knock-out (LDLR-KO) mice were fed a Western diet enriched in saturated fatty acids (control), or a Western diet supplemented with 5% (w/w) LA-rich CSO or high-oleic MSO for 12 weeks. Both soybean oils contained a similar amount of linolenic acid (C18:3 n-3). The CSO diet decreased plasma lipid levels and the cholesterol content of VLDL and LDL by approximately 18% (p < 0.05), likely from increased hepatic levels of PUFA, which favorably regulated genes involved in cholesterol metabolism. The MSO diet, but not the CSO diet, suppressed atherosclerotic plaque size compared to the Western control diet (Control Western diet: 6.5 ± 0.9%; CSO diet: 6.4 ± 0.7%; MSO diet: 4.0 ± 0.5%) (p < 0.05), independent of plasma lipid level changes. The MSO diet also decreased the ratio of n-6/n-3 PUFA in the liver (Control Western diet: 4.5 ± 0.2; CSO diet: 6.1 ± 0.2; MSO diet: 2.9 ± 0.2) (p < 0.05), which correlated with favorable hepatic gene expression changes in lipid metabolism and markers of systemic inflammation. In conclusion, supplementation of the Western diet with MSO, but not CSO, reduced atherosclerosis development in LDLR-KO mice independent of changes in plasma lipids.

Degradome sequencing-based identification of phasiRNAs biogenesis pathways in Oryza sativa.

BACKGROUND: The microRNAs(miRNA)-derived secondary phased small interfering RNAs (phasiRNAs) participate in post-transcriptional gene silencing and play important roles in various bio-processes in plants. In rice, two miRNAs, miR2118 and miR2275, were mainly responsible for triggering of 21-nt and 24-nt phasiRNAs biogenesis, respectively. However, relative fewer phasiRNA biogenesis pathways have been discovered in rice compared to other plant species, which limits the comprehensive understanding of phasiRNA biogenesis and the miRNA-derived regulatory network. RESULTS: In this study, we performed a systematical searching for phasiRNA biogenesis pathways in rice. As a result, five novel 21-nt phasiRNA biogenesis pathways and five novel 24-nt phasiRNA biogenesis pathways were identified. Further investigation of their regulatory function revealed that eleven novel phasiRNAs in 21-nt length recognized forty-one target genes. Most of these genes were involved in the growth and development of rice. In addition, five novel 24-nt phasiRNAs targeted to the promoter of an OsCKI1 gene and thereafter resulted in higher level of methylation in panicle, which implied their regulatory function in transcription of OsCKI1,which acted as a regulator of rice development. CONCLUSIONS: These results substantially extended the information of phasiRNA biogenesis pathways and their regulatory function in rice.

Knockout of the Tachykinin Receptor 1 in the Mdr2-/- (Abcb4-/-) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis.

Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2-/- (alias Abcb4-/-) mice through enhanced transforming growth factor-ß1 (TGF-ß1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-ß1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-ß1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R-/ (alias Tacr1-/-) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R-/-; (ii) Mdr2-/-; and (iii) NK1R-/-/Mdr2-/- (Tacr1-/-/Abcb4-/-) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R-/-/Mdr2-/- mice compared with Mdr2-/- mice. Elevated expression of miR-31 was observed in Mdr2-/- mice, which was reduced in NK1R-/-/Mdr2-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma.

Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization- and sequencing-based methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis.

COVID-19-Associated dyslipidemia: Implications for mechanism of impaired resolution and novel therapeutic approaches.

The current coronavirus disease 2019 (COVID-19) pandemic presents a global challenge for managing acutely ill patients and complications from viral infection. Systemic inflammation accompanied by a "cytokine storm," hemostasis alterations and severe vasculitis have all been reported to occur with COVID-19, and emerging evidence suggests that dysregulation of lipid transport may contribute to some of these complications. Here, we aim to summarize the current understanding of the potential mechanisms related to COVID-19 dyslipidemia and propose possible adjunctive type therapeutic approaches that modulate lipids and lipoproteins. Specifically, we hypothesize that changes in the quantity and composition of high-density lipoprotein (HDL) that occurs with COVID-19 can significantly decrease the anti-inflammatory and anti-oxidative functions of HDL and could contribute to pulmonary inflammation. Furthermore, we propose that lipoproteins with oxidized phospholipids and fatty acids could lead to virus-associated organ damage via overactivation of innate immune scavenger receptors. Restoring lipoprotein function with ApoA-I raising agents or blocking relevant scavenger receptors with neutralizing antibodies could, therefore, be of value in the treatment of COVID-19. Finally, we discuss the role of omega-3 fatty acids transported by lipoproteins in generating specialized proresolving mediators and how together with anti-inflammatory drugs, they could decrease inflammation and thrombotic complications associated with COVID-19.