Synergistic suppression of the PI3K inhibitor CAL-101 with bortezomib on mantle cell lymphoma growth

Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B(NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups. Results: CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment. Conclusion: Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline(updated version)

The novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the cause of a rapidly spreading illness,coronavirus disease 2019(COVID-19),affecting more than seventeen million people around the world.Diagnosis and treatment guidelines for clinicians caring for patients are needed.In the early stage,we have issued"A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus(2019-nCoV)infected pneumonia(standard version)";now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline.We formed a working group of clinical experts and methodologists.The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas:chemoprophylaxis,diagnosis,treatments,and discharge management.We searched the literature for direct evidence on the management of COVID-19,and assessed its certainty generated recommendations using the Grading of Recommendations,Assessment,Development and Evaluation(GRADE)approach.Recommendations were either strong or weak,or in the form of ungraded consensus-based statement.Finally,we issued 34 statements.Among them,6 were strong recommendations for,14 were weak recommendations for,3 were weak recommendations against and 11 were ungraded consensus-based statement.They covered topics of chemoprophylaxis(including agents and Traditional Chinese Medicine(TCM)agents),diagnosis(including clinical manifestations,reverse transcription-polymerase chain reaction(RT-PCR),respiratory tract specimens,IgM and IgG antibody tests,chest computed tomography,chest X-ray,and CT features of asymptomatic infections),treatments(including lopinavirritonavir,umifenovir,favipiravir,interferon,remdesivir,combination of antiviral drugs,hydroxychloroquine/chloroquine,interleukin-6 inhibitors,interleukin-1 inhibitors,glucocorticoid,qingfei paidu decoction,lianhua qingwen granules/capsules,convalescent plasma,lung transplantation,invasive or noninvasive ventilation,and extracorporeal membrane oxygenation(ECMO)),and discharge management(including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge).We also created two figures of these recommendations for the implementation purpose.We hope these recommendations can help support healthcare workers caring for COVID-19 patients.

Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a subgroup analysis of the CHANCE- 2 trial

Objectives Evidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited,especially those elder than 80 years.This study aimed to explore the efficacy and safety of dual antiplatelet therapy(DAPT)in old-old patients compared with younger patients in the ticagrelor or Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events-II(CHANCE-2)trial.Methods CHANCE-2 was a randomised,double-blind,placebo-controlled trial in China involving patients with high-risk transient ischaemic attack or minor stroke with CYP2C19 loss-of-function alleles.In our substudy,all enrolled patients were stratified by age:old-old(≥80 years),young-old(65–80 years)and younger(<65 years).The primary outcomes were stroke recurrence and moderate to severe bleeding within 90 days,respectively.Results Of all the 6412 patients,406(6.3%)were old-old,2755(43.0%)were young-old and 3251(50.7%)were younger.Old-old patients were associated with higher composite vascular events(HR 1.41,95%CI 1.00 to 1.98,p=0.048),disabling stroke(OR 2.43,95%CI 1.52 to 3.88,p=0.0002),severe or moderate bleeding(HR 8.40,95%CI 1.95 to 36.21,p=0.004)and mortality(HR 7.56,95%CI 2.23 to 25.70,p=0.001)within 90 days.Ticagrelor-aspirin group was associated with lower risks of stroke recurrence within 90 days in younger patients(HR 0.68,95%CI 0.51 to 0.91,p=0.008),which was no differences in old-old patients.Conclusion Elderly patients aged over 80 in CHANCE-2 trial had higher risks of composite vascular events,disabling stroke,severe or moderate bleeding and mortality within 90 days.Genotype-guided DAPT might not be as effective in old-old patients as in younger ones.Trial registration number NCT04078737.

The Third China National Stroke Registry (CNSR-Ⅲ) for patients with acute ischaemic stroke or transient ischaemic attack: design, rationale and baseline patient characteristics

Background and purpose Stroke is the leading cause of mortality and disability in China.Precise aetiological classification,imaging and biological markers may predict the prognosis of stroke.The Third China National Stroke Registry(CNSR-Ⅲ),a nationwide registry of ischaemic stroke or transient ischaemic attack(TIA)in China based on aetiology,imaging and biology markers,will be considered to clarify the pathogenesis and prognostic factors of ischaemic stroke.Methods Between August 2015 and March 2018,the CNSR-Ⅲrecruited consecutive patients with ischaemic stroke or TIA from 201 hospitals that cover 22 provinces and four municipalities in China.Clinical data were collected prospectively using an electronic data capture system by face-to-face interviews.Patients were followed for clinical outcomes at 3 months,6 months and 1-5 year annually.Brain imaging,including brain MRI and CT,were completed at baseline.Blood samples were collected and biomarkers were tested at baseline.Results A total of 15166 stroke patients were enrolled,among which 31.7%patients were women with the average age of 62.2±11.3 years.Ischaemic stroke was predominant(93.3%,n=14146)and 1020(6.7%)TIAs were enrolled.Conclusions CNSR-Ⅲis a large scale nationwide registry in China.Data from this prospective registry may provide opportunity to evaluate imaging and biomarker prognostic determinants of stroke.

Differential effect of ethanol intoxication on peripheral markers of cerebral injury in murine blunt traumatic brain injury

Background:Blood-based biomarkers have proven to be a reliable measure of the severity and outcome of traumatic brain injury(TBI)in both murine models and patients.In particular,neuronspecific enolase(NSE),neurofilament light(NFL)and S100 beta(S100B)have been investigated in the clinical setting post-injury.Ethanol intoxication(EI)remains a significant comorbidity in TBI,with 30–40%of patients having a positive blood alcohol concentration post-TBI.The effect of ethanol on blood-based biomarkers for the prognosis and diagnosis of TBI remains unclear.In this study,we investigated the effect of EI on NSE,NFL and S100B and their correlation with blood–brain barrier integrity in a murine model of TBI.Methods:We used ultra-sensitive single-molecule array technology and enzyme-linked immunosorbent assay methods to measure NFL,NSE,S100B and claudin-5 concentrations in plasma 3 hours post-TBI.Results:We showed that NFL,NSE and S100B were increased at 3 hours post-TBI.Interestingly,ethanol blood concentrations showed an inverse correlation with NSE but not with NFL or S100B.Claudin-5 levels were increased post-injury but no difference was detected compared to ethanol pretreatment.The increase in claudin-5 post-TBI was correlated with NFL but not with NSE or S100B.Conclusions:Ethanol induces an effect on biomarker release in the bloodstream that is different from TBI not influenced by alcohol.This could be the basis of investigations into humans.