When idiopathic multicentric Castleman disease meets COVID-19: a multicenter retrospective study from China.

Idiopathic multicentric Castleman disease (iMCD) is a rare and cytokine storm-driven inflammatory disorder. The exact cause of iMCD is still unknown, although several hypotheses have been proposed. However, regardless of the underlying cause, the ultimate result is the activation of the inflammatory pathway, which can lead to damage in multiple organs. Currently, there have been several reports highlighting the intricate link between coronavirus disease 2019 (COVID-19) and iMCD. To better understand the impact of COVID-19-induced immune storm on iMCD, we conducted a multicenter retrospective study in three hospitals in China. A total of 28 patients with iMCD were included, among whom 25 had confirmed COVID-19 infection, and we presented 4 cases that showed different disease progression after the infection of COVID-19, including 2 who did not receive any treatment for Castleman disease before. Our findings underscore the necessity of carefully monitoring iMCD patients with COVID-19 and promptly intervening to address any changes in their condition. Besides, this study also summarized the shared cytokines between COVID-19 and iMCD. Recent studies have shown promising results in treating severe COVID-19 and iMCD using tocilizumab, an interleukin-6 receptor antagonist. Therefore, it suggests that other potential cytokine storm therapy targets that have been effective in COVID-19 may also be explored for the treatment of iMCD.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

Optimization Therapy by Coupling Intermittent Androgen Suppression with Impulsive Chemotherapy for a Prostate Cancer Model.

Intermittent androgen suppression in the prostate cancer is often relapsed by the increasing of prostate specific antigen level during the on-treatment. Historically, chemotherapy has had a limited role in the treatment of prostate cancer. However, new agents are showing promise in patients with advanced disease. Intermittent androgen suppression plus chemotherapy in pulsed pattern has become an indispensable clinical scheme for prostate cancer, which is presented to describe the transformation mechanism for three kinds of cancer cells in this paper. The model is then extended to include the residual effect of chemotherapy which suppresses the cancer cells production, thereby preventing the relapse. The optimal controls represent the efficiencies of both intermittent androgen suppression and chemotherapy in suppressing relapse of prostate cancer. Based on an optimal algorithm, numerical simulations are implemented not only to show the optimal durations of on- and off-treatment and chemotherapy dosages but also to present the effectiveness of different strategies in inhibiting the relapse for three types of patients. Results reveal that the optimal intermittent androgen suppression scheme with alterable treatment cycles is pivotal for type I and II patients, in part because it can greatly reduce the on-treatment time and degrade the level of prostate specific antigen. Furthermore, optimal hybrid schedule even averts the relapse of prostate cancer for type II and III patients. Finally, comparing the prostate specific antigen under intermittent androgen suppression schedule with residual effect of chemotherapy to one without residual effect of chemotherapy demonstrates the validity of both our model and algorithms in lessening the prostate specific antigen and decreasing the chemotherapy dosages.

A Novel Fused SiO2 and h-BN Modified Quartz Fiber/Benzoxazine Resin Ceramizable Composite with Excellent Flexural Strength and Ablation Resistance.

Hypersonic vehicles encounter hostile service environments of thermal/mechanical/chemical coupling, so thermal protection materials are crucial and essential. Ceramizable composites have recently attracted intensive interest due to their ability to provide large-area thermal protection for hypersonic vehicles. In this work, a novel ceramizable composite of quartz fiber/benzoxazine resin modified with fused SiO2 and h-BN was fabricated using a prepreg compression molding technique. The effects of the fused SiO2 and h-BN contents on the thermal, mechanical, and ablative properties of the ceramizable composite were systematically investigated. The ceramizable composite with an optimized amount of fused SiO2 and h-BN exhibited superb thermal stability, with a peak degradation temperature and residue yield at 1400 °C of 533.2 °C and 71.5%, respectively. Moreover, the modified ceramizable composite exhibited excellent load-bearing capacity with a flexural strength of 402.2 MPa and superior ablation resistance with a linear ablation rate of 0.0147 mm/s at a heat flux of 4.2 MW/m2, which was significantly better than the pristine quartz fiber/benzoxazine resin composite. In addition, possible ablation mechanisms were revealed based on the microstructure analysis, phase transformation, chemical bonding states, and the degree of graphitization of the ceramized products. The readily oxidized pyrolytic carbon (PyC) and the SiO2 with a relatively low melting point were converted in situ into refractory carbide. Thus, a robust thermal protective barrier with SiC as the skeleton and borosilicate glass as the matrix protected the composite from severe thermochemical erosion and thermomechanical denudation.

Rituximab-bortezomib-dexamethasone induce high response rates in iMCD in clinical practice.

Treatment options for idiopathic multicentric Castleman disease (iMCD) are currently limited, especially for patients who do not respond or are resistant to interleukin-6 inhibitors. For the first time, we innovatively designed a protocol using rituximab-bortezomib-dexamethasone (RVD) as first-line consolidation therapy in patients newly diagnosed with iMCD. Furthermore, we adopted a no-maintenance treatment strategy to simplify post-remission care. Five patients with iMCD were enrolled (including one with TAFRO syndrome) and underwent the RVD regimen, all of whom achieved partial response (PR) or better. After four cycles of RVD, three (60%) patients achieved PR, while one (20%) achieved a complete response. These five patients, who achieved PR or better, discontinued treatment but remained stable for a median follow-up of 11 months, with a duration of response of 7, 7, 10, 12 and 13 months, respectively. None of the patients experienced grade ≥3 adverse events during the observation period. Collectively, these findings demonstrated that the RVD regimen may be a promising treatment option for patients with iMCD. It was a safe and effective approach that resulted in lasting responses without the need for ongoing maintenance therapy.

Effects of Sterile Males and Fertility of Infected Mosquitoes on Mosquito-Borne Disease Dynamics.

By studying an infection-age structured model, we consider the effects of releasing sterile males and the fertility of infected mosquitoes on the mosquito-borne diseases transmission including the extinction of mosquitoes, the elimination and persistence of diseases. Firstly, equivalent integral equations are established to prove the well-posedness of solutions. Then, the main results of disease dynamics are given. By taking chikungunya as a numerical simulation example, an optimal releasing threshold is given according to our presupposed control standard. When the fertility disturbance of infected mosquitoes is small, the high releasing amount plays a main role on the control of the disease; however, when the fertility disturbance is large, the initial distributions and the fertility of infected mosquitoes are the key factors to control the disease. Mathematically, the fertility of infected mosquitoes makes the system have complex dynamics with multiple positive equilibria and bistability.

Effect of Iron Ion on Corrosion Behavior of Inconel 625 in High-Temperature Water.

The corrosion behavior of an ultralow iron nickel-based alloy Inconel 625 under high-temperature water has been evaluated. The results show that surface oxidation and pitting were the principal corrosion mechanisms of Inconel 625 during the initial immersion period. The surface layer of the oxide film is first Ni-enriched and then Fe-enriched as immersion time increases. The iron ions dissolved from the autoclave could lead to the formation of NiFe2O4 and have a great influence on the oxidation behavior of Inconel 625. The oxides nucleated by solid-state reactions with selective dissolution of Fe and Ni and then grew up through precipitation of cations from solution.

NPY alterations induced by chronic morphine exposure affect the maintenance and reinstatement of morphine conditioned place preference.

Opioid addiction is a brain disease that severely harms society and personal health. Although the tremendous numbers of patients worldwide and emerged negative events, effective treatments for opioid addiction are still lacking. Neuropeptide Y (NPY) is one of the main orexigenic peptides that play vital roles in food intake and energy metabolism. However, increasing evidence indicates that NPY may have great potential in mediating reward effects and drug dependence. In the present study, we assessed the expression changes of NPY in the nucleus accumbens at different timepoints following morphine conditioned place preference (CPP) and investigated the functional importance of potential NPY changes. Our results showed that NPY expression significantly decreased in the nucleus accumbens shell (AcbSh) immediately after chronic morphine exposure. Subsequently, it increased rapidly at first and then gradually returned to normal levels. Further data indicated that these NPY changes were involved in morphine reward memory, demonstrated by a reduction in the extinction period after blocking of the Y5 receptor by L-152,804 in the AcbSh and a prolonged duration of the extinction period following the application of NPY. More importantly, the additional results revealed that L-152,804 also remarkably suppressed the reinstatement of morphine CPP. Together, our results indicate that a complicated plasticity of the NPY pathway in AcbSh occurs following morphine CPP, and this plasticity plays an important role in modulating morphine reward memory. These findings may enhance our understanding of the role of the NPY system in opioid addiction and indicate a promising target for opioid addiction treatment.

The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia.

IKZF1 belongs to the IKAROS family of transcription factors, and its deletion/mutation frequently affects acute lymphoblastic leukemia. In acute myeloid leukemia, IKZF1 deletion has been demonstrated recurrent, but whether IKZF1 mutation also exists in AML remained largely unknown. Herein, we analyzed the IKZF1 mutation in AML. In our cohort, the frequency of IKZF1 mutation was 2.6% (5/193), and 5 frameshift/nonsense mutations as well as 2 missense mutations were identified in total. Molecularly, IKZF1 mutation was absent in fusion gene-positive AML, but it was demonstrated as the significant concomitant genetic alteration with SF3B1 or bi-allele CEBPA mutation in AML. Clinically, two IKZF1, PTPN11 and SF3B1-mutated AML patients exhibited one aggressive clinical course and showed primary resistant to chemotherapy. Furthermore, we confirmed the recurrent IKZF1 mutation in AML with cBioPortal tool from OHSU, TCGA and TARGET studies. Interestingly, OHSU study also showed that SF3B1 mutation was the significant concomitant genetic alteration with IKZF1 mutation, indicating their strong synergy in leukemogenesis. In conclusion, IKZF1 mutation recurrently affected AML.

Abivertinib synergistically strengthens the anti-leukemia activity of venetoclax in acute myeloid leukemia in a BTK-dependent manner.

B-cell lymphoma 2 (BCL-2), a crucial member of the anti-apoptotic BCL-2 family, is frequently dysregulated in cancer and plays an important role in acute myeloid leukemia (AML). Venetoclax is a highly selective BCL-2 inhibitor that has been approved by the FDA for treating elderly AML patients. However, the emergence of resistance after long-term treatment emphasizes the need for a deeper understanding of the potential mechanisms of resistance and effective rescue methods. By using RNA-seq analysis in two human AML cohorts made up of three patients with complete remission and three patients without remission after venetoclax treatment, we identified that upregulation of BTK enabled AML blast resistance to venetoclax. Interestingly, we found that abivertinib, an oral BTK inhibitor, could synergize with venetoclax to inhibit the proliferation of primary AML cells and cell lines. It is worth noting that the combination of the two effectively enhanced the sensitivity of two AML patients (AML#3 and AML#12) to venetoclax. In this study, we demonstrated that combined use of the two drugs can synergistically inhibit the colony-forming capacity of AML cells, arrest the AML cell cycle in the G0/G1 phase, and inhibit the BCL-2 anti-apoptotic family protein, activating the caspase family to induce apoptosis. Mechanistically, knockdown of BTK in AML cell lines impaired the synergistic effect of the two drugs. In vivo study showed similar results as those seen in vitro. Abivertinib in combination with venetoclax could significantly prolong the survival time and reduce the tumor burden of MV4-11-NSG mice compared with those of control and single-agent groups. Our in vitro and in vivo studies have shown that the combination of abivertinib and venetoclax may benefit AML patients, especially in patients resistant to venetoclax or those that relapse. New clinical trials will be planned.

Effects of exopolysaccharide derived from Pantoea alhagi NX-11 on drought resistance of rice and its efficient fermentation preparation.

Exopolysaccharide (EPS) plays an important role in plant growth-promoting bacteria (PGPB)-mediated enhancement of plant abiotic stress resistance. In this study, it is found that EPS from Pantoea alhagi NX-11 foliar sprayed at 20, 50, and 100 ppm could significantly enhance drought resistance of rice seedlings. The fresh weight and relative water content of EPS sprayed were increased. In addition, malondialdehyde content reduced while total chlorophyll, proline and soluble sugar content, prominent enhanced. Meanwhile, the antioxidant enzymes, CAT, POD and SOD, were also significantly increased. The drought resistance of rice was most pronounced at the 50 ppm EPS dose. For the sake of commercializing the gram-negative EPS-producing PGPB which were difficult to preserve, it is vital to improve the EPS yield. First, the carbon source, nitrogen source and inorganic salt were optimized. Subsequently, the effect of three oxygen vectors, which could increase the efficiency of oxygen mass transfer, on EPS yield was studied by response surface methodology. The maximum EPS yield (19.27 g/L) was obtained, which is 51.7% higher than the initial yield of 12.7 g/L. Overall, it may provide a new way for the industrialization of PGPB to increase the yield of EPS.

Plasma exosome-derived microRNA-532 as a novel predictor for acute myeloid leukemia.

BACKGROUND: The interest in plasma biomarkers has increased recently. Plasma exosome-derived microRNA-532 is aberrantly expressed in a variety of human cancers and has the prognostic value in many solid tumors. However, the prognostic impact of the expression value on AML remains unclear. OBJECTIVE: The aim of this study is to investigate the prognostic value of exosome-derived microRNA-532 in AML patients. METHODS: We performed the real-time PCR to quantify exosome-derived microRNA-532 in plasma of 198 AML patients. To assess the prognostic value, we performed Cox regression analyses in the context of well-established clinical and molecular markers. Cellular metabolic profile was conducted to help us understand the biological insight of its expression. RESULTS: The expression level was not associated with white blood cell counts, age, FAB subtypes, cytogenetic risk groups and genes of FLT3-ITD, NPM1, CEBPA and DNMT3A mutations. Interestingly, high expressers had a favorable overall survival in the univariate analysis. This prognostic value was testified in the multivariate analysis. Moreover, up-regulation of miR-532 was negatively associated with cellular energy like fructose and glutamine. CONCLUSION: We found plasma exosome-derived microRNA-532 can be used as a novel survival predictor for acute myeloid leukemia.

miR-221-3p Delivered by BMMSC-Derived Microvesicles Promotes the Development of Acute Myelocytic Leukemia.

Objective: The study aims to investigate the effects of miR-221-3p in bone marrow mesenchymal stem cell (BMMSC)-derived microvesicles (MVs) on cell cycle, proliferation and invasion of acute myelocytic leukemia (AML). Methods: Bioinformatics was used to predict differentially expressed miRNAs (DEmiRNAs) in AML. The morphology of BMMSC-derived MVs was observed under an electron microscope, and the positional relation of MVs and OCI-AML2 cells was observed by a fluorescence microscope. MTT, Transwell, and flow cytometry assays were used to analyze the effects of MVs on OCI-AML2 cells. The targeted relationship between miR-221-3p and CDKN1C was detected by dual luciferase assay. Results: It was verified that miR-221-3p promoted the proliferation, invasion and migration of OCI-AML2 cells, and induced the cell cycle arrest in G1/S phase as well as inhibited cell apoptosis. Further studies showed that MVs promoted the proliferation, migration and invasion of AML, and induced the cell cycle arrest in G1/S phase through miR-221-3p. It was confirmed that miR-221-3p can directly target CDKN1C to regulate cell cycle, proliferation and invasion of AML. Conclusion: miR-221-3p in BMMSC-derived MVs regulated AML cell cycle, cell proliferation and invasion through targeting CDKN1C. miR-221-3p and CDKN1C were considered to be potential targets and biomarkers for the treatment of AML in clinic.

[Empathy for pain: A novel bio-psychosocial-behavioral laboratory animal model].

Empathy, a basic prosocial behavior, is referred to as an ability to understand and share others' emotional state. Generally, empathy is also a social-behavioral basis of altruism. In contrast, impairment of empathy development may be associated with autism, narcissism, alexithymia, personality disorder, schizophrenia and depression. Thus, study of the brain mechanisms of empathy has great importance to not only scientific and clinical advances but also social harmony. However, research on empathy has long been avoided due to the fact that it has been considered as a distinct feature of human beings from animals, leading to paucity of knowledge in the field. In 2006, a Canadian group from McGill University found that a mouse in pain could be shared by its paired cagemate, but not a paired stranger, showing decreased pain threshold and increased pain responses through emotional contagion while they were socially interacting. In 2014, we further found that a rat in pain could also be shared by its paired cagemate 30 min after social interaction, showing long-term decreased pain threshold and increased pain responses, suggesting persistence of empathy for pain (empathic memory). We also mapped out that the medial prefrontal cortex, including the anterior cingulate cortex, prelimbic cortex and infralimbic cortex, is involved in empathy for pain in rats, suggesting that a neural network may be associated with development of pain empathy in the CNS. In the present brief review, we give a brief outline of the advances and challenges in study of empathy for pain in humans and animals, and try to provide a novel bio-psychosocial-behavioral model for study of pain and its emotional comorbidity using laboratory animals.

Colorectal cancer mortality in Inner Mongolia between 2008 and 2012.

AIM: To determine the extent of colorectal cancer (CRC) mortality and the association between demographic characteristics and CRC mortality in Inner Mongolia. METHODS: Data were collected from the Death Registry System, maintained by the Inner Mongolia Centers for Disease Control and Prevention, from 2008 to 2012. Deaths were classified according to the International Classification of Disease, 10(th) Revision. Years of life lost, average years of life lost (AYLL), and mortality were calculated over the five years between 2008 and 2012. A conditional logistic regression model was used to analyze the association between marital status, occupational status, education level, area of residence, and the risk of CRC. RESULTS: The AYLL of CRC was 17.39 years. The average mortality of CRC was 5.6/100000. People living in urban areas and having a higher education level had a significantly higher risk of CRC (OR = 1.74 and 95%CI: 1.29-2.35, P < 0.001 and OR = 2.39, 95%CI: 1.76-3.25, P < 0.001, respectively). People who were employed had a lower risk of CRC (OR = 0.64, 95%CI: 0.48-0.86, P = 0.003). The mortality of CRC was positively correlated with the education level (P < 0.001). No statistically significant association was observed between marital status and CRC risk (P = 0.259). CONCLUSION: Living in urban areas, higher education level and unemployment are associated with CRC mortality in Inner Mongolia.

The impact of predation on the coexistence and competitive exclusion of pathogens in prey.

A two-strain epidemic model with saturating contact rate under a generalist predator is proposed. For a generalist predator which feeds on many types of prey, we assume that the predator can discriminate among susceptible and infected with each strain prey. First, mathematical analysis of the model with regard to invariance of nonnegativity, boundedness of solutions, nature of equilibria, persistence and global stability are analyzed. Second, the two strains will competitively exclude each other in the absence of predation with the strain with the larger reproduction number persisting. If predation is discriminate, then depending on the predation level, a dominant strain may occur. Thus, for some predation levels, the strain one may persist while for other predation levels strain two may persist. Furthermore, coexistence line and coexistent asymptotic-periodic solution are obtained when coexistence occur while heteroclinic is obtained when the two strains competitively exclude each other. Finally, the impact of predation is mentioned along with numerical results to provide some support to the analytical findings.

Depression symptoms among caregivers of children in HIV-affected families in rural China.

The objectives of this study were to examine symptoms of depression among caregivers of rural AIDS orphans (i.e., children who had lost one or both of their parents to HIV/AIDS) and vulnerable children (i.e., children who were living with HIV-infected alive parents), and to explore factors associated with the presence of symptoms of depression among caregivers. Cross-sectional data were collected from 160 adult caregivers (parents, relatives, or other adults) from a rural area in China where many residents were infected with HIV through unhygienic blood collection. The sample included 120 caregivers from households caring for AIDS orphans and vulnerable children (OVC) and 40 from households without OVC. The Center for Epidemiological Studies Depression Scale (CES-D) was used to assess the symptoms of depression among the caregivers. Multiple regression analysis was performed to assess the associations of depressive symptoms with various individual and family factors among caregivers. The mean score of CES-D for the entire sample was 19.18 (17.84 for men and 20.44 for women). The univariate analysis indicated that the score of CES-D was significantly higher among caregivers with lower education, fewer household items/assets, from families with adult or pediatric HIV infection. Controlling for age, gender, and caregivers' education, multiple regression analysis revealed significant associations between symptoms of depression and reduced family socioeconomic status (SES), adult or pediatric HIV infection in family. Our results indicated an elevated level of depression symptoms among caregivers of OVC and underscored the needs for psychological support and intervention for their caregivers, especially for those with lower family SES, from families with an adult or pediatric HIV infection.

School performance and school behavior of children affected by AIDS in China.

It is generally recognized that the AIDS epidemic will have a negative effect on the orphans' school education. However, few studies have been carried out to examine the school performance and school behavior of AIDS orphans and vulnerable children (children living with HIV-infected parents). Using both self-report and teacher evaluation data of 1625 children from rural central China, we examined the impact of parental HIV/AIDS on children's school performances (academic marks, educational expectation, and student leadership) and school behaviors (e.g., aggression, shy/anxious and assertive social skills). Results indicate that AIDS orphans and vulnerable children had disadvantages in school performances in comparison to their peers from the same community who did not experience AIDS-related death and illness in their family (comparison children). AIDS orphans had the lowest academic marks based on the reports of both children and teachers. Educational expectation was significantly lower among AIDS orphans and vulnerable children than comparison children from teacher's perspective. AIDS orphans were significantly more likely to demonstrate aggressive, impulsive and anxious behaviors than non-orphans. Moreover, orphans have more learning difficulties. Vulnerable children were also at a disadvantage on most measures. The data suggest that a greater attention is needed to the school performance and behavior of children affected by AIDS. The findings also indicate that AIDS relief and assistance program for children should go beyond the school attendance and make efforts to improve their school performance and education aspiration.