SENEX-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma

Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.

Edge modes in finite-size systems with different edge terminals

We investigate the behavior of edge modes in the presence of different edge terminations and long-range(LR)hopping.Here,we mainly focus on such model crystals with two different types of structures(type I:“…-P-Q-P-Q-…”and type II:“…=P-Q=P-Q=…”),where P and Q represent crystal lines(CLs),while the symbols“-”and“=”denote the distance between the nearest neighbor(NN)CLs.Based on the lattice model Hamiltonian with LR hopping,the existence of edge modes is determined analytically by using the transfer matrix method(TMM)when different edge terminals are taken into consideration.Our findings are consistent with the numerical results obtained by the exact diagonalization method.We also notice that edge modes can exhibit different behaviors under different edge terminals.Our result is helpful in solving novel edge modes in honeycomb crystalline graphene and transition metal dichalcogenides with different edge terminals.

Activation of Transition Metal(Fe,Co and Ni)-Oxide Nanoclusters by Nitrogen Defects in Carbon Nanotube for Selective CO_(2) Reduction Reaction

The electrochemical carbon dioxide reduction reaction(CO_(2)RR),which can produce value-added chemical feedstocks,is a proton-coupled-electron process with sluggish kinetics.Thus,highly efficient,cheap catalysts are urgently required.Transition metal oxides such as CoO_(x),FeO_(x),and NiO_(x)are low-cost,low toxicity,and abundant materials for a wide range of electrochemical reactions,but are almost inert for CO_(2)RR.Here,we report for the first time that nitrogen doped carbon nanotubes(N-CNT)have a surprising activation effect on the activity and selectivity of transition metal-oxide(MO_(x)where M=Fe,Ni,and Co)nanoclusters for CO_(2)RR.MO_(x)supported on N-CNT,MO_(x)/N-CNT,achieves a CO yield of 2.6–2.8 mmol cm−2 min−1 at an overpotential of−0.55 V,which is two orders of magnitude higher than MO_(x)supported on acid treated CNTs(MO_(x)/O-CNT)and four times higher than pristine N-CNT.The faraday efficiency for electrochemical CO_(2)-to-CO conversion is as high as 90.3%at overpotential of 0.44 V.Both in-situ XAS measurements and DFT calculations disclose that MO_(x)nanoclusters can be hydrated in CO_(2)saturated KHCO_(3),and the N defects of N-CNT effectively stabilize these metal hydroxyl species under carbon dioxide reduction reaction conditions,which can split the water molecules and provide local protons to inhibit the poisoning of active sites under carbon dioxide reduction reaction conditions.

Toxoplasmosis-Associated Secondary Hemophagocytic Syndrome: A Case Report and Literature Review

Background: Toxoplasmosis is an extremely rare disease that occurs in the hosts contact with cat and dog frequently. Most human acute infections go unnoticed in immunocompetent individuals, and gradually transformed into chronic infection. However, while host immunity significantly waned, the risk of reactivation of chronic toxoplasma infection is greatly increased. Reactivation of latent toxoplasmic infection often presents with fever, leukopenia, thrombocytopenia, neurological signs and pneumonia. However, for the non-specific clinical and biological signs and its fetal outcome, toxoplasmosis is often misdiagnosed and only revealed at autopsy. Case Presenation: We report a case hospitalized for a week history of cough, anorexia and fatigue with nasal bleeding for a day. After hospitalization, broad-spectrum antibiotherapy was started without a clear diagnosis of infection. Then the patient did a lot of investigations to search the cause of infection, but there were no positive findings. However, an unexpected discovery was detected from peripheral blood smears, shows 1 - 3 μm in diameter, scattered, short and bow like microorganisms on Day 39 of hospitalization. Combined with the medical history and clinical manifestation, toxoplasmosis was diagnosed finally. Unfortunately, secondary hemophagocytic syndrome (HPS) was diagnosed only two days after targeted anti-infection therapy, and the patient died on Day 45 of hospitalization. Conclusions: Patient with unexplained long-term fever and neurological symptoms, interstitial pneumonitis or myocarditis, toxoplasmosis should be positively considered. Only early diagnosis and treatment can increase the possibility of a successful cure and avoid other secondary diseases.

CD34^(+)CD38^(-)subpopulation without CD123 and CD44 is responsible for LSC and correlated with imbalance of immune cell subsets in AML

Acute myeloid leukemia(AML)is regarded as a stem cell disease.However,no one unique marker is expressed on leukemia stem cells(LSC)but not on leukemic blasts nor normal hematopoietic stem cells(HSC).CD34^(+)CD38^(-)with or without CD123 or CD44 subpopulations are immunophenotypically defined as putative LSC fractions in AML.Nevertheless,markers that can be effectively and simply held responsible for the intrinsical heterogeneity of LSC is still unclear.In the present study,we examined the frequency of three different LSC subtypes(CD34^(+)CD38^(-),CD34^(+)CD38^(-)CD123^(+),CD34^(+)CD38^(-)CD44^(+))in AML at diagnosis.We then validated their prognostic significance on the relevance of spectral features for diagnostic stratification,immune status,induction therapy response,treatment effect maintenance,and long^(-)term survival.In our findings,high proportions of the above three different LSC subtypes were all significantly characterized with low complete remission(CR)rate,high relapse/refractory rate,poor overall survival(OS),frequent FLT3^(-)ITD mutation,the high level of regulatory T cells(Treg)and monocytic myeloid^(-)derived suppressor cells(M^(-)MDSC).However,there was no significant statistical difference in all kinds of other clinical performance among the three different LSC groups.It was demonstrated that CD34^(+)CD38^(-)subpopulation without CD123 and CD44 might be held responsible for LSC and correlated with an imbalance of immune cell subsets in AML.

Decreased CD10-positive granulocytes for the differential diagnosis of myelodysplastic syndrome

Myelodysplastic syndromes(MDS)are highly heterogeneous myeloid neoplasms,and a large number of patients are difficult to diagnose and classify by blood and bone marrow examination.As a surface marker of granulocyte,studies have shown CD10 can be used to define the degree of granulocyte maturation in MDS patients.However,whether it can be used for differential diagnosis of MDS and other hematological diseases remains inconclusive.To explore the value of CD10 for differential diagnosis of MDS,60 newly diagnosed MDS,20 aplastic anemia(AA)patients,and 35 iron-deficient anemia(IDA)patients were selected for this study.Bone marrow(BM)specimens were processed for surface marker analysis and labeled with pre-conjugated monoclonal antibodies.Stained cells were detected by flow cytometry.Our results indicated that CD10-positive granulocytes were significantly decreased in BM of MDS patients than AA and IDA patients,and the level of CD10-positive mature granulocytes was not associated with the clinical stages of malignancy.Receiver operating characteristic(ROC)areas under the curve(AUC)of CD10-positive granulocytes was 0.86 and 0.85,respectively,in MDS patients than the IDA group and AA group with good specificity and sensitivity.Further,CD10-positive granulocytes were increased after effective treatment.In conclusion,we found the decrease in CD10-positive granulocytes has a differential diagnostic value of MDS.

Edge states enhanced by long-range hopping:An analytical study

We analyze the behavior of edge states in long-range(LR)interacting systems.In terms of lattice model Hamiltonian with the LR coupling,we determine analytically the condition of existence of edge states within the transfer matrix method(TMM).The expressions we obtain are general and hold for any choice of the LR hopping.The reason why edge states can appear is the transfer matrix in the bulk different from that in the boundary layers.Our predictions are in good agreement with numerical results by exact diagonalization.Our result is helpful in solving novel edge states in oneand two-dimensional(2D)superconductors with LR hopping and pairing.

Online Effective Identification of Glycopeptide Using Liquid Chromatography Combined with Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FTICR-MS)

The detailed glycan structural analysis of glycoprotein is amenable to glycopeptide enrichment. Here, we develop a simple, effective and economical approach to enrich glycopeptides from proteolytically digested peptide mixtures by chromatographic column packed with graphite carbon and activated charcoal (G/A-column). Glycopeptide from ovalbumin was efficiently enriched by homemade G/A-column using liquid chromatography and the structure of glycopeptide was obtained by tandem mass spectrometry using Fourier transform ion cyclotron resonance mass spectrometry. The results in this study demonstrate that G/A-column can be used to enrich N-glycolpeptides and be benefit for online identification of glycopeptide using LC-MS.

Role of CD5 molecular-like on hepatocellular carcinoma

Background: CD5L (CD5 molecular-like) plays an important role in lipid metabolism and immune regulation. This study aimed to investigate the roles of CD5L on liver hepatocellular carcinoma (LIHC). Methods: We analyzed the CD5L mRNA expression and its potential prognostic value based on The Cancer Genome Atlas and Gene Expression Omnibus databases. Immunohistochemical analysis was used to investigate the CD5L levels in LIHC tissues. Serum CD5L levels in LIHC were detected by enzyme-linked immunosorbent assay. Cell Counting Kit-8 (CCK-8) assay was used to investigate the effect of CD5L treatment on HepG2 and QSG-7701 cell proliferation. CD5L expression correlated genes were exhumed based on the LinkedOmics. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for CD5L associated genes were performed. The correlation between CD5L and tumor immune infiltration was analyzed by using Tumor Immune Estimation Resource (TIMER) 2.0. Results: CD5L mRNA and protein levels were significantly decreased in LIHC tumor tissue compared with non-tumor control tissues. Moreover, serum CD5L levels were significantly lower in LIHC patients than that in healthy subjects. Gene Expression Profiling Interactive Analysis 2 and Kaplan-Meier plotter analysis showed that a high-CD5L expression was correlated with favorable overall survival in LIHC patients, except the LIHC patients with hepatitis virus. CCK-8 results showed that CD5L treatment significantly decreased HepG2 cell proliferation in a concentration-dependent manner, and CD5L treatment had no effect on the proliferation of non-tumor hepatocyte line QSG-7701. CD5L associated genes were enriched in the immune response biological process, and CD5L expression levels were positively correlated with the immune infiltrates of CD8 ^(+) T cell and M1 macrophage cells but negatively correlated with CD4 ^(+) T cells and M0 macrophage cell infiltration. Conclusions: Exogenous CD5L inhibits cell proliferation of hepatocellular carcinoma. CD5L may act as a role of prognostic marker.

Evaluation of the immunogenicity and protective efficacy of a Chlamydia muridarum protein OmcB and its C segment in BALB/c mice

To the Editor:Chlamydia trachomatis(Ct)is an obligate intracellular bacterium that can infect the human urogenital system and cause cervicitis,salpingitis,and pelvic inflammatory diseases.Ct infections can be easily treated using antibiotics.However,drug resistance and infection persistence pose significant challenges to the diagnosis and treatment of Ct.^([1])Therefore,developing effective vaccines is the most convenient and reliable option for controlling Ct infection.

Outcomes of allograft from donor kidney microthrombi and secondary recipient thrombotic microangiopathy: should we consider loosening the belt?

There is currently a huge worldwide demand for donor kidneys for organ transplantation.Consequently,numerous marginal donor kidneys,such as kidneys with microthrombi,are used to save patients'lives.While some studies have shown an association between the presence of microthrombi in donor kidneys and an increased risk for delayed graft function(DGF)(McCall et al.,2003;Gao et al.,2019),other studies have demonstrated that microthrombi negatively impact the rate of DGF(Batra et al.,2016;Hansen et al.,2018),but not graft survival rate(McCall et al.,2003;Batra et al.,2016;Gao et al.,2019).In contrast,Hansen et al.(2018)concluded that fibrin thrombi were not only associated with reduced graft function six months posttransplantation but also with increased graft loss within the first year of transplantation.On the other hand,Batra et al.(2016)found no significant differences in the DGF rate or one-year graft function between recipients in diffuse and focal microthrombi groups.To date,however,the overall influence of donor kidney microthrombi and the degree of influence on prognosis remain controversial,necessitating further research.

Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy

BK polyomavirus-associated nephropathy(BKPyVAN)is a common cause of allograft failure.However,differentiation between BKPyVAN and type I T cell-mediated rejection(TCMR)is challenging when simian virus 40(SV40)staining is negative,because of the similarities in histopathology.This study investigated whether donor-derived cell-free DNA(ddcfDNA)can be used to differentiate BKPyVAN.Target region capture sequencing was applied to detect the ddcfDNAs of 12 recipients with stable graft function,22 with type I TCMR,21 with proven BKPy VAN,and 5 with possible Py VAN.We found that urinary ddcfDNA levels were upregulated in recipients with graft injury,whereas plasma ddcfDNA levels were comparable for all groups.The median urinary concentrations and fractions of ddcfDNA in proven BKPyVAN recipients were significantly higher than those in type I TCMR recipients(10.4 vs.6.1 ng/mL,P<0.001 and 68.4%vs.55.3%,P=0.013,respectively).Urinary ddcfDNA fractions(not concentrations)were higher in the BKPyVAN-pure subgroup than in the BKPyVAN-rejection-like subgroup(81.30%vs.56.64%,P=0.025).With a cut-off value of 7.81 ng/m L,urinary ddcf DNA concentrations distinguished proven BKPyVAN from type I TCMR(area under the curve(AUC)=0.848,95%confidence interval(95%CI):0.734 to 0.963).These findings suggest that urinary ddcf DNA is a non-invasive biomarker which can reliably differentiate BKPy VAN from type I TCMR.