Deep learning for colorectal cancer detection in contrast-enhanced CT without bowel preparation: a retrospective, multicentre study.

BACKGROUND: Contrast-enhanced CT scans provide a means to detect unsuspected colorectal cancer. However, colorectal cancers in contrast-enhanced CT without bowel preparation may elude detection by radiologists. We aimed to develop a deep learning (DL) model for accurate detection of colorectal cancer, and evaluate whether it could improve the detection performance of radiologists. METHODS: We developed a DL model using a manually annotated dataset (1196 cancer vs 1034 normal). The DL model was tested using an internal test set (98 vs 115), two external test sets (202 vs 265 in 1, and 252 vs 481 in 2), and a real-world test set (53 vs 1524). We compared the detection performance of the DL model with radiologists, and evaluated its capacity to enhance radiologists' detection performance. FINDINGS: In the four test sets, the DL model had the area under the receiver operating characteristic curves (AUCs) ranging between 0.957 and 0.994. In both the internal test set and external test set 1, the DL model yielded higher accuracy than that of radiologists (97.2% vs 86.0%, p < 0.0001; 94.9% vs 85.3%, p < 0.0001), and significantly improved the accuracy of radiologists (93.4% vs 86.0%, p < 0.0001; 93.6% vs 85.3%, p < 0.0001). In the real-world test set, the DL model delivered sensitivity comparable to that of radiologists who had been informed about clinical indications for most cancer cases (94.3% vs 96.2%, p > 0.99), and it detected 2 cases that had been missed by radiologists. INTERPRETATION: The developed DL model can accurately detect colorectal cancer and improve radiologists' detection performance, showing its potential as an effective computer-aided detection tool. FUNDING: This study was supported by National Science Fund for Distinguished Young Scholars of China (No. 81925023); Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20345); National Natural Science Foundation of China (No. 82072090 and No. 82371954); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011); High-level Hospital Construction Project (No. DFJHBF202105).

Study on the detection rate, genetic polymorphism, viral load, persistent infection capacity, and pathogenicity of human papillomavirus type 81.

Human papillomavirus (HPV) type 81 has recently become one of the most common low-risk HPV types; however, literature focusing on it is limited. This study aimed to analyze the reasons for the increased detection rate of HPV81 and investigate its evolving pathogenicity. We analyzed the detection rates and trends of HPV81 in 229 061 exfoliated cervical cell samples collected from 2014 to 2023; collected samples of HPV81 single infections from two different time periods; and analyzed the allele frequencies, positive selection, viral load, persistent infection capacity, and pathogenicity of E6 and E7 genotypes. We found that the detection rate of HPV81 ranked first among the low-risk types in exfoliated cervical cells and exhibited a significantly increasing trend (p < 0.001). The frequency of the E6 prototype allele of HPV81 (n = 317) was significantly increased (p = 0.018) and demonstrated the strongest adaptive capacity. The viral load and persistent infection capacity of the E6 prototype were significantly higher than those of the mutants, thus serving as key drivers for increasing the detection rate of HPV81 and enhancing its pathogenicity. The viral load was positively correlated with persistent infection capacity and pathogenicity. Persistent infection was a crucial factor in the pathogenicity of HPV81. Successful adaptive evolution of HPV81 is accompanied by enhanced pathogenicity.

Effects of Dietary Selenium Yeast Supplementation on Lactation Performance, Antioxidant Status, and Immune Responses in Lactating Donkeys.

Donkey milk is a traditional medicinal food with various biological activities. However, its production is very low, and lactating donkeys often experience oxidative stress, leading to a further decline in milk yield. In this study, we supplemented the diets of lactating donkeys with yeast selenium (SY) to investigate its effects on lactation performance, antioxidant status, and immune responses, and we expected to determine the optimum additive level of SY in the diet. For this study, 28 healthy lactating Dezhou donkeys with days in milk (DIM, 39.93 ± 7.02 d), estimated milk yield (EMY, 3.60 ± 0.84 kg/d), and parity (2.82 ± 0.48) were selected and randomly divided into 4 groups of 7 donkeys in each: Group SY-0 (control), Group SY-0.15, Group SY-0.3, and Group SY-0.5, with selenium supplementation of 0, 0.15, 0.3, and 0.5 mg of Se/kg DM (in form of SY) to the basal diet, respectively. The results showed a dose-dependent increase in milk yield, milk component yield, milk protein production efficiency, milk production efficiency, the activities of glutathione peroxidases (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC), as well as the content of serum interleukin-10 (IL-10), white blood cells (WBC), lymphocytes (LYM), red blood cells (RBC), hematocrit, plasma selenium, and milk selenium. Conversely, it presented a dose-dependent decrease in the activity of nitric oxide synthase (iNOS) and the contents of malondialdehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interferon-γ (IFN-γ). In conclusion, the results confirmed that dietary supplementation with SY can improve lactation performance, antioxidant status, and immune responses in lactating donkeys, and the recommended dose of SY was 0.3 mg/kg.

Effects of dietary energy level on antioxidant capability, immune function and rectal microbiota in late gestation donkeys.

Introduction: This study investigated the effects of dietary energy level on the antioxidant capability, immune function, and rectal microbiota in donkey jennets during the last 60 days of gestation. Methods: Fifteen pregnant DeZhou donkeys with age of 6.0 ± 0.1 years, body weight of 292 ± 33 kg, parity of 2.7 ± 0.1 parities and similar expected date of confinement (74 ± 4 days) were randomly allocated to three groups and feed three diets: high energy (10.92 MJ/kg, H), medium energy (10.49 MJ/kg, M), and low energy (9.94 MJ/kg, L). Results and Discussion: The serum activity of catalase (CAT), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) in group M was significantly higher, whereas the concentrations of malondialdehyde (MDA), interleukin 1 (IL-1), IL-2, and IL-6 were lower than those recorded for groups H and L (p ≤ 0.05). The dietary energy level significantly affected rectal microbial community structure in the jennet donkeys 35 days and 7 days before the parturition (p ≤ 0.05). The abundances of norank_f_norank_o_Coriobacteriales genus was significantly higher (p ≤ 0.05) in group H, and the abundances of norank_f_norank_o_Mollicutes_RF39 and the Candidatus_Saccharimonas were higher in group L (p ≤ 0.05). The abundance of Fibrobacter in group M was significantly increased (p ≤ 0.05). The abundance of norank_f_norank_o_Coriobacteriales was positively correlated with average daily gain (ADG) and tumor necrosis factor-α (TNF-α) concentrations (p ≤ 0.05). The abundance of norank_f_norank_o_Mollicutes_RF39 was positively correlated with IL-2 and IL-6 concentrations. The abundance of Candidatus_Saccharimonas was positively correlated with CAT, T-SOD and GSH-Px activities (p ≤ 0.05). The abundance of Fibrobacter was positively correlated with CAT and T-SOD activities (p ≤ 0.05), but negatively correlated with IL-2 concentration (p ≤ 0.05). In conclusion, an appropriate dietary with an energy content of 10.49 MJ/kg for jennet donkeys during late gestation increased the prenatal antioxidant capacity, reduced inflammatory cytokines, and promoted fetal growth, and these changes were related to diet-induced changes in rectal microbiota compositions.

Intestinal Microbiota Community and Blood Fatty Acid Profiles of Albas Cashmere Goats Fed with Flaxseed Oil and Whole Flaxseed.

The present study investigated the effects of flaxseed oil or flaxseed grain on the intestinal microbiota and blood fatty acid profiles of Albas cashmere goats. Sixty kid goats were allocated to three treatments and fed for 90 days with a control treatment, comprising a basal diet (CON, total-mixed ration with flaxseed meal), or experimental treatments, comprising a basal diet with added flaxseed oil (LNO) and a basal diet with added heated flaxseed grain (HLS). On day 90, two goats were randomly selected from each pen (eight goats per treatment) for euthanizing; then, five of the eight goats were randomly selected, and we collected their intestinal (duodenum, jejunum, ileum, cecum, and colon) digesta for analysis of the bacteria community. The results indicated that Firmicutes are the most predominant phylum in different segments of the intestinal digesta. Compared with the CON group, the relative abundance of duodenal Firmicutes, jejunal Saccharibacteria, and Verrucomicrobia significantly decreased in the LNO and HLS groups (p < 0.05), but there was no significant difference between the LNO and HLS groups. Compared with the CON and HLS groups, the RA of duodenal and jejunal Proteobacteria remarkably increased in the LNO group (p < 0.05), and there was no significant difference between the CON and HLS groups. Compared with the CON and LNO groups, the RA of Actinobacteria remarkably increased in the small intestine of the HLS group (p < 0.05), but there was no significant difference between the CON and LNO groups in the duodenum and ileum. The results of linear discriminant analysis (LDA) effect size (LEfSe) analysis showed that the HLS group was characterized by a higher RA of the [Eubacterium]_coprostanoligenes_group in the small intestine and the LNO group was represented by a higher RA of the Lachnospiraceae_NK3A20_group in the cecum and colon, while the CON group was represented by a higher RA of Solobacterium, Pseudoramibacter, and Acetitomaculum in the small intestine and a higher RA of norank_o__Bradymonadales, the Prevotellaceae_Ga6A1_group, and Ruminiclostridium_1 in the cecum and colon. In conclusion, the addition of flaxseed oil and grain rich in c18:3n3 to the diet could reduce the microbial diversity of the small intestinal segments and the microbial diversity and richness of the cecum and colon in Albas cashmere goats. And flaxseed grain is more efficient than flaxseed oil in protecting intestinal health and promoting the absorption of c18:3n3.

The effects of supplementation of noni (Morinda citrifolia L.) fruit polysaccharides-rich extract on antioxidant status and immune function in cashmere goats.

This experiment was designed to examine the effects of a dietary supplementation of polysaccharides-rich noni (Morinda citrifolia L.) fruit extract (NFP) on the anti-oxidant enzyme activities, cytokines level, and expression of corresponding genes in blood of cashmere goats. Twelve castrated, 2-yr-old male cashmere goats (45.44 ± 3.30 kg of BW ± SD) were used in a 2 × 2 crossover design: the basal diet with or without (CON) supplementation of NFP at 4 g per kg DM (0.4%). Each period lasted for 29 d, including 1 wk for diet transition, 20 d for adaptation, and the last 2 d for sampling. The results showed that NFP supplementation increased (P < 0.05) the levels of nitric oxide, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and the activities of catalase (CAT), glutathione peroxidase (GPx), thioredoxin reductase (TrxR), and total superoxide dismutase (T-SOD) in serum. The expressions of CAT, GPx4, TrxR, SOD1, IL-6, and TNF-α genes were upregulated (P < 0.05), whereas the levels of malondialdehyde (P = 0.015) and reactive oxygen species (P = 0.051) in serum were reduced. The body weight gain of goats was increased (P = 0.006) with a nonsignificant increase of feed intake with NFP supplementation. In conclusion, dietary NFP supplementation enhanced the antioxidant status and immune function in blood of cashmere goats.

Due to the limited pasture supply and the seasonal imbalance of nutrients in grazed pastures in China, cashmere goats are commonly raised in a confined yard-feeding system, which may result in oxidative stress from a lack of green pastures. Noni (Morinda citrifolia L.) fruit polysaccharides contain various biological compounds that function as anti-inflammatory, antitumor, and to enhance immune responses, hence likely to relieve oxidative stress in animals. Previous researches in our laboratory have shown that polysaccharides-rich extract from noni fruit (NFP) enhanced rumen fermentation in cashmere goats. This experiment was designed to evaluate the effect of NFP supplementation on serum antioxidant status and immune function in cashmere goats. The results showed that dietary supplementation of 0.40% NFP enhanced the immune signaling molecule levels and antioxidant enzyme activities by upregulating the expression of related genes in blood and reduced the levels of lipid peroxides and free radicals in serum, while mature goats improved body weight. Therefore, NFP could be a viable source of antioxidants for cashmere goats.

Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.

The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms. Different adverse genetic factors often rely on common pathways. KMT2A rearrangement, DEK-NUP214 fusion, and NPM1 mutation are associated with the upregulation of HOX genes. The dominant tyrosine kinase activity of the mutant FLT3 or BCR-ABL1 fusion proteins is transduced by the AKT-mTOR, MAPK-ERK, and STAT5 pathways. Concurrent mutations of ASXL1 and RUNX1 are associated with activated AKT. Both TP53 mutation and mis-expressed MECOM are related to impaired apoptosis. Clinical data suggest that adverse genetic factors can be found in at least one in eight AML patients and appear to accumulate in relapsed/refractory cases. TP53 mutation is associated with particularly poor prognosis. Molecular-targeted therapies focusing on specific genomic abnormalities, such as FLT3, KMT2A, and TP53, have been developed and have demonstrated promising results.

IL-6 Generated from Human Hematopoietic Stem and Progenitor Cells through TLR4 Signaling Promotes Emergency Granulopoiesis by Regulating Transcription Factor Expression.

Emergency granulopoiesis, also known as demand-adapted granulopoiesis, is defined as the response of an organism to systemic bacterial infections, and it results in neutrophil mobilization from reservoir pools and increased myelopoiesis in the bone marrow. Indirect and direct initiating mechanisms of emergency granulopoiesis have been hypothesized. However, the detailed mechanism of hyperactive myelopoiesis in the bone marrow, which leads to granulocyte left shift, remains unknown. In this study, we report that TLR4 is expressed on granulo-monocytic progenitors, as well as mobilized human peripheral blood CD34+ cells, which account for 0.2% of monocytes in peripheral blood, and ∼ 10% in bone marrow. LPS, a component of Gram-negative bacteria that results in a systemic bacterial infection, induces the differentiation of peripheral blood CD34+ cells into myelocytes and monocytes in vitro via the TLR4 signaling pathway. Moreover, CD34+ cells directly responded to LPS stimulation by activating the MAPK and NF-κB signaling pathways, and they produced IL-6 that promotes emergency granulopoiesis by phosphorylating C/EBPα and C/EBPß, and this effect was suppressed by the action of an IL-6 receptor inhibitor. This work supports the finding that TLR is expressed on human hematopoietic stem and progenitor cells, and it provides evidence that human hematopoietic stem and progenitor cells can directly sense pathogens and produce cytokines exerting autocrine and/or paracrine effects, thereby promoting differentiation.

Brentuximab vedotin maintenance after autologous stem cell transplantation for refractory gray zone lymphoma with long-term remission.

Gray zone lymphoma (GZL) is a rare type of B-cell lymphoma characterized by features of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (cHL). The prognosis of GZL is poorer than that of cHL and mediastinal large B-cell lymphoma. However, an optimal treatment strategy for relapsed/refractory (R/R) GZL has not been established in the clinical setting. The current study reported an excellent clinical response in a patient with R/R CD30-positive GZL who received brentuximab vedotin (BV) maintenance after autologous stem cell transplantation (ASCT). Although the patient was resistant to prior treatments, BV maintenance after ASCT achieved long-term remission. Hence, BV was determined to be a safe and effective therapeutic option for CD30-positive R/R GZL.

Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports.

BACKGROUND: The outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR-ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response. CASE PRESENTATION: Patient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR. CONCLUSION: In our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

Scutellarin is Highly Likely to be Responsible for Drug-Drug Interactions Mediated by Hepatic Organic Anion-Transporting Polypeptide1B3.

PURPOSE: Scutellarin, a flavonoid derived from the plant Erigeron breviscapus, is currently widely used to treat cerebrovascular diseases, liver-related diseases, and hyperlipidemia in china and other East Asian countries. This study was to investigate the effect of scutellarin on the uptake of rosuvastatin in HEK293T cells expressing human organic anion transporting polypeptide 1B3 (hOATP1B3) and rat OATP1B2 (rOATP1B2), respectively, and the effect of scutellarin on the pharmacokinetics of rosuvastatin in rats. METHODS: The newly established HEK293T cells expressing hOATP1B3 and rOATP1B2 were used to examine the effects of scutellarin and positive controls on in vitro rosuvastatin transport. After co-feeding with scutellarin, the rosuvastatin area under the plasma concentration-time curve (AUC0-24h), the peak plasma drug concentration (Cmax), elimination half-life (t1/2), time to reach Cmax (tmax), clearance (CL) and apparent clearance (CL/F) of rosuvastatin were determined in rats. RESULTS: Scutellarin inhibited hOATP1B3- and rOATP1B2-mediated rosuvastatin uptake (IC50: 45.54 ± 6.67 µM and 27.58 ± 3.97 µM) in vitro in a concentration-dependent manner. After co-feeding with scutellarin, the AUC0-24h and Cmax of rosuvastatin in rats increased to 27.4% and 37.7%, respectively. The t1/2 and tmax of rosuvastatin showed no significant change. Moreover, scutellarin caused 29.2% and 28.1% decrease in the CL and CL/F of rosuvastatin. CONCLUSION: Scutellarin may inhibit the hOATP1B3- and rOATP1B2-mediated transport of rosuvastatin in vitro, and exerts a moderate inhibitory effect on the pharmacokinetics of rosuvastatin in rats. Scutellarin is highly likely to participate in drug-drug interactions, as mediated by OATP1B3 in humans.

Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells.

In this report, we investigated the hepatocytic uptake of rosuvastatin when administered with scutellarin (a Chinese herbal medicine) in rats and the role of organic anion transporting polypeptide 1B1 (OATP1B1) plays in the uptake. Forty-eight rats were randomly divided into two groups according to the medicine administered: rosuvastatin alone and rosuvastatin in combination with a series concentration of scutellarin. Rosuvastatin concentrations in blood and liver were measured using the liquid chromatography-tandem mass spectrometry (LC-MS) method. The uptake was also measured in rat primary hepatocytes and OATP1B1 transfected human embryonic kidney 293 T (HEK293T) cells. The uptake was investigated under the optimal intake conditions. The rosuvastatin Cmax and AUC0-∞ in rat plasma increased 55% and 61%, respectively in the combination treatment group; and the liver scutellarin concentrations decreased 32%, 34%, and 33% at 1 h, 2 h, and 6 h, respectively. All scutellarin dosages (20, 50, and 100 µM) inhibited the uptake of rosuvastatin in rat primary hepatocytes (4.71%, 22.73%, and 45.89%). Scutellarin of 10 µM significantly inhibited the in vitro uptake of rosuvastatin in OATP1B1-HEK293T cells (P < 0.05), with an IC50 of 60.53 ± 5.74 µM. Scutellarin increases the plasma concentration of rosuvastatin and inhibits the uptake in rat primary hepatocytes and OATP1B1-HEK293T cells, suggesting a drug interaction between scutellarin and rosuvastatin and OATP1B1 as a potential mechanism.

The protective effect of selenium on the lipopolysaccharide-induced oxidative stress and depressed gene expression related to milk protein synthesis in bovine mammary epithelial cells.

The objective of this study was to determine the effects of selenium (Se) on antioxidative function and the synthesis of milk protein in bovine mammary epithelial cells (BMECs). Two experiments were conducted using a single-factor completely randomized design study. In part I, BMECs were randomly divided into seven groups: control (without Se) and six Se treatments (10, 20, 50, 100, 150, and 200 nmol/L). In part II, based on the results of part I, we used lipopolysaccharide (LPS) as the induced stress source to analyze the protective effect of Se on LPS-induced oxidative damage and the influence on milk protein synthesis of BMECs. BMECs were randomly divided into eight groups: control (without Se and LPS), LPS treatment (only LPS), and six Se treatments with LPS (LS10 to LS200). Treatment of BMECs with Se was found to significantly improve cell proliferation and antioxidant function. LPS could induce oxidative damage which significantly inhibited cell proliferation and antioxidant function in BMECs. Se had a protective effect on the oxidative damage of BMECs induced by LPS. Additionally, our results indicated that LPS damage downregulated the gene expression of milk protein synthesis. Se effectively relieved the inhibition due to LPS-induced oxidative damage on the synthesis of milk protein, and Se concentrations of 50 to 200 nmol/L showed the best effect. In conclusion, Se at concentrations of 50 to 100 nmol/L is better for antioxidant function but had no effect on milk protein synthesis in healthy BMECs. Se ameliorated the damage caused by LPS-induced by improving levels of antioxidant markers and upregulating milk protein synthesis and the expression of genes associated with milk protein in BMECs.

Immunoglobulin Light Chain Amyloidosis with Severe Liver Dysfunction Accompanied by Factor X Deficiency.

Severe hepatic failure is rarely a cause of death in patients with immunoglobulin light chain (AL) amyloidosis. We herein report a case of AL amyloidosis involving a bleeding tendency due to factor X deficiency and marked hepatic involvement of amyloidosis. The patient died due to severe liver dysfunction two weeks after admission. The diagnosis was confirmed histologically by AL-λ amyloidosis, with the liver and spleen as the main lesions, on an autopsy. As treatment-related toxicity is strong in advanced cases, appropriate treatments are required to improve the prognosis of AL amyloidosis with severe liver dysfunction.

ATP produced by anaerobic glycolysis is essential for enucleation of human erythroblasts.

More than 2million human erythroblasts extrude their nuclei every second in bone marrow under hypoxic conditions (<7% O2). Enucleation requires specific signal transduction pathways and the local assembly of contractile actomyosin rings. However, the energy source driving these events has not yet been identified. We examined whether different O2 environments (hypoxic [5% O2] and normoxic [21% O2] conditions) affected human CD34+ cell erythroblast differentiation. We also investigated the regulatory mechanisms underlying energy production in erythroblasts during terminal differentiation under 5% or 21% O2 conditions. The results obtained revealed that the enucleation ratio and intracellular levels of adenosine triphosphate (ATP), lactate dehydrogenase (LDH) M3H, and hypoxia-inducible factor 1α in erythroblasts during terminal differentiation were higher under the 5% O2 condition than under the 21% O2 condition. We also found that the enzymatic inhibition of glyceraldehyde 3-phosphate dehydrogenase and LDH, key enzymes in anaerobic glycolysis, blocked the proliferation of colony-forming units-erythroid and enucleation of erythroblasts, and also reduced ATP levels in erythroblasts under both hypoxic and normoxic conditions. Under both conditions, phosphorylation of the Ser232, Ser293, and Ser300 residues in pyruvate dehydrogenase (inactive state of the enzyme) in erythroblasts was involved in regulating the pathway governing energy metabolism during erythroid terminal differentiation. This reaction may be mediated by pyruvate dehydrogenase kinase (PDK) 4, the major PDK isozyme expressed in erythroblasts undergoing enucleation. Collectively, these results suggest that ATP produced by anaerobic glycolysis is the main source of energy for human erythroblast enucleation in the hypoxic bone marrow environment.

Relationship between clinical course of nivolumab-related myositis and immune status in a patient with Hodgkin's lymphoma after allogeneic hematopoietic stem cell transplantation.

Although programmed cell death (PD)-1 blockade induces immune-related adverse events (irAEs), little is known about the safety of PD-1 blockade after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we describe immune system changes during nivolumab-related myositis in a patient with Hodgkin's lymphoma after allogeneic HSCT; to our knowledge, this is the first such report in the literature. At the onset of myositis, the patient lost lower limb mobility against gravity, and had an activated immune profile with increased cytotoxic CD107a and granzyme B expression, as well as pro-inflammatory cytokines, interferon-γ, tumor necrosis factor-α, interleukin-2 in T and NK cells compared to healthy donor. Pulse steroid therapy decreased creatine kinase levels and induced PD-1 expression and regulatory T cells, but did not improve myositis; previously activated markers remained high. Four-week corticosteroid therapy decreased previously activated markers and the myositis improved. These findings provide new insights into nivolumab-induced irAE pathogenesis and suggest possible optimal treatments for irAEs.

Mechanism Underlying the Protective Effect of Selenium on NO-Induced Oxidative Damage in Bovine Mammary Epithelial Cells.

This experiment was conducted to investigate the effects and mechanism of selenium (Se) on antioxidant and immune function of bovine mammary epithelial cells (BMEC) damaged by nitric oxide (NO). The third-generation BMEC was randomly divided into eight treatments with six replicates. The BMEC in the control group was cultured in the medium without Se and diethylenetriamine/NO (DETA/NO) for 30 h. For the DETA/NO group and Se protection group BMEC were exposed to different concentrations of Se (0, 10, 20, 50, 100, 150, and 200 nmol/L) for 24 h, followed by treatment with DETA/NO (1000 µmol/L) for 6 h. Compared with the control group, DETA/NO decreased proliferation rate and activity of thioredoxin reductase (TrxR; P < 0.05). Additionally, DETA/NO decreased the gene expression of both nuclear factor-E2-related factor 2 (Nrf2) and TrxR, as well as the protein expression level of TrxR. However, the activity, and expression levels of inducible nitric oxide synthase (iNOS), as well as the concentration and gene expression level of interleukin-1ß (IL-1ß) and the concentration of NO significantly increased (P < 0.05). The gene expression levels of indexes related to the mitogen-activated protein kinase (MAPK) signaling pathway showed similar changes. Treatment of BMEC with Se significantly reversed DETA/NO-induced changes in a linear or quadratic dose-dependent manner (P < 0.05), with greatest benefit at 50 nmol/L. These data suggests that Se improves the antioxidant function of BMEC, and protects cells from DETA/NO-induced oxidative damage, primarily by enhancing the activity of TrxR and decreasing the concentration of NO through modulation of Nrf2 and MAPK signaling pathways.