Choledocholithiasis caused by anatomical variation of cystic duct: A case report

Laparoscopic cholecystectomy(LC)has gradually become the first choice for the treatment of cholecystolithiasis in recent years.Iatrogenic bile duct injury(IBDI)is an important clinical problem in LC.The anatomical variation of the cystic duct increases the probability of IBDI and the difficulty of operation.We present a case of a 44-year-old male with a anatomical variation of the cystic duct complicated with cholecystolithiasis and choledocholithiasis,who successfully underwent choledocholithotomy,choledochoscopic exploration and T-tube drainage surgery.The patient recovered well and was discharged home on postoperative day 10.The T-tube was removed at 1 month postoperatively after cholangiography examination of no choledocholithiasis left.

ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage.Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease(IBD).Oral administration is the most common route for intestinal diseases.In this study,a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment,which can interrupt the pathological process of IBD,resulting in the significantly improved efficacy of existing treatments.Based on the specific pH values and high reactive oxygen species(ROS)levels in inflammatory sites of IBD,an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed,and confirmed in vitro and in vivo.The anti-inflammatory drug dexamethasone acetate(Dex)and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions(TJs).The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis.In brief,a drug delivery system and a therapeutic strategy for IBD are successfully developed.

Self-oriented central-tumor delivery of legumain-cleavable vehicles governed by circulating monocyte/macrophage for precise tumor enrichment and immune activation

Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.

Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia(T-ALL)is one of the most dangerous hematological malignancies,with high tumor heterogeneity and poor prognosis.More than 60%of T-ALL patients carry NOTCH1 gene mutations,leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways.We found that chidamide,an HDAC inhibitor,exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity.In particular,chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1(NICD1)as well as MYC,partly through their ubiquitination and degradation by the proteasome pathway.We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease(MRD)in patients and is well tolerated.Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients,including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia:targeted immunotherapy for acute lymphoblastic leukemia

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.However,several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight,and thus its clinical use is limited.Furthermore,multiple trials have shown that approximately 30%of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells.Here,we design and characterize two novel antibodies,A-319 and A-2019.Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures,and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function.Our in vitro,ex vivo,and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells,enhancing T-cell function,mediating B-cell depletion,and eventually inhibiting tumor growth in Raji xenograft models.The two molecules are complementary in terms of efficacy and specificity profile.The activity of A-319 demonstrated superior to that of A-2019,whereas A-2019 has an additional capability to target CD20 in cells missing CD19,suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

Spermine increases bactericidal activity of silver-nanoparticles against clinical methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus(MRSA) has emerged worldwide as a major multidrugresistant pathogen that causes notable morbidity and mortality. Fast emerging of MRSA prevalence requires special attention for strengthening the inventory of antimicrobial compounds. Silver nanoparticles(AgNPs) have been widely used to treat multi-drug resistant pathogens due to the unique antibacterial properties, meanwhile spermine has been proven to exert outstanding inhibition effect to S.aureus with not yet fully understood mechanisms. The aim of this study was to investigate the synergistic effect of AgNPs and spermine as well as to determine the antibacterial activity of their combination against MRSA strains. Several clinical MRSA isolates and ATCC BAA-1026 were used to determine minimum inhibitory concentration(MIC) and fractional inhibitory concentration indices(FICI) of AgNPs and spermine, and a synergistic effect was observed. This phenomenon was further confirmed by growth curve and time-killing assays, showed that spermine could be used as an adjuvant for AgNPs in the treatment of MRSA infections.