Immunophenotypic classification regarding prognosis in peripheral T cell lymphoma, NOS, and nodal T follicular helper T cell lymphoma, angioimmunoblastic-type.

This study aimed to determine the clinicopathological predictive factors of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), and nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFH, AI-type). In this single-centered, retrospective study, medical records of 59 patients who were diagnosed with PTCL, NOS, or nTFH, AI-type from March 2007 to September 2022 were reviewed. The clinicopathological variables, including immunohistochemistry(IHC) subgroups, distinguishing TBX21 from the GATA3 subgroups were analyzed. Overall, 28 patients (75.7%) in the TBX21 group were PTCL, NOS. There were 9 (24.3%) patients in the GATA3 group. In univariable analyses, lymphoma subtype, age, and performance status were associated with progression-free survival (PFS), and overall survival (OS). In multivariable analyses, lymphoma subtype, and performance status were related to PFS and OS (P = 0.012, P < 0.001, P = 0.006, and P < 0.001, respectively). The GATA3 subgroup tended to have a worse prognosis in univariable analyses; however, it became more insignificant in multivariable when lymphoma subtype and performance status were adjusted (P = 0.065, P = 0.180, P = 0.972, and P = 0.265, respectively). The double-positive group showed variable prognoses of better PFS and worse OS. PD-1 and PD-L1 were associated with the EBV in situ hybridization (P = 0.027, and P = 0.005), and PD-1 was associated with CD30 expression (P = 0.043). This study demonstrated the potential of IHC classification to predict prognosis for PTCL, NOS, as well as nTFH AI-type, although further validation is necessary. Treatments targeting CD30, PD-1, and PD-L1 appear promising for lymphoma treatment.

Outcome of single-incision laparoscopic cholecystectomy compared to three-incision laparoscopic cholecystectomy for acute cholecystitis.

Backgrounds/Aims: While single-incision laparoscopic cholecystectomy (SILC) has advantages in cosmesis and postoperative pain, its utilization has been limited. This study raises the possibility of expanding its indication to acute cholecystitis with the novel method of solo surgery under retrospective analysis. Methods: We compared the outcomes of SILC (n = 58) to those of three-incision laparoscopic cholecystectomy (TILC; n = 117) for acute cholecystitis, being performed from March 2014 to December 2015. Results: Intraoperative results, including the operation time, did not differ significantly, except for drain catheter insertion (p = 0.004). Each group had 1 case of open conversion due to common bile duct injury. There was no significant difference in the length of hospital stay. Either group by itself was not a risk factor for complications, but in preoperative drainage for intraoperative perforation, 3 factors of intraoperative perforation, biliary complication, and history of upper abdominal operation for additional port, only American Society of Anesthesiology (ASA) scores for postoperative complication of Clavien-Dindo grades III and IV were significant risk factors. Conclusions: Our study findings showed comparative outcomes between both groups, providing evidence for the safety and feasibility of SILC for acute cholecystitis.

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized, double-blind, active-controlled, multicenter phase 3 trial.

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are -19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and -11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.

Over-Expression of p190RhoGEF Regulates the Formation of Atherosclerotic Plaques in the Aorta of ApoE-/- Mice via Macrophage Polarization.

The RhoA-specific guanine nucleotide exchange factor p190RhoGEF has been implicated in the control of cell morphology, focal adhesion formation, and cell motility. Previously, we reported that p190RhoGEF is also active in various immune cells. In this study, we examined whether over-expression of p190RhoGEF could affect atherosclerotic plaque formation in mouse aortae. For that purpose, transgenic (TG) mice over-expressing p190RhoGEF were cross-bred with atherosclerosis-prone apolipoprotein E (ApoE)-/- mice to obtain p190RhoGEF-TG mice with ApoE-/- backgrounds (TG/ApoE-/-). Aortic plaque formation was significantly increased in TG/ApoE mice-/- at 30 to 40 weeks of age compared to that in ApoE-/- mice. Serum concentrations of inflammatory cytokines (IL-6 and TNF-α) were greater in TG/ApoE-/- mice than in ApoE-/- mice at ~40 weeks of age. Furthermore, TG/ApoE-/- mice had a greater proportion of peritoneal macrophages within the M1 subset at 30 to 40 weeks of age, together with higher production of inflammatory cytokines and stronger responses to bacterial lipopolysaccharide than ApoE-/- mice. Collectively, these results highlight a crucial role of enhanced p190RhoGEF expression in atherosclerosis progression, including the activation of pro-inflammatory M1 macrophages.

Prognostic significance of BLK expression in R-CHOP treated diffuse large B-cell lymphoma.

BACKGROUND: The aim of the present study was to evaluate the prognostic significance of B-cell lymphocyte kinase (BLK) expression for survival outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP. METHODS: We retrospectively analyzed the medical records of 89 patients from two tertiary referral hospitals. The expression of BLK, SYK, and CDK1 were evaluated in a semiquantitative method using an H-score, and the proportions of BCL2 and C-MYC were evaluated. RESULTS: A total of 89 patients received R-CHOP chemotherapy as a first-line chemotherapy. The expression rates of BLK in tumor cells was 39.2% (n = 34). BLK expression status was not significantly associated with clinical variables; however, BLK expression in tumor cells was significantly associated with the expression of both C-MYC and BCL2 (p = .003). With a median follow-up of 60.4 months, patients with BLK expression had significantly lower 5-year progression-free survival (PFS) and overall survival rates (49.8% and 60.9%, respectively) than patients without BLK expression (77.3% and 86.7%, respectively). In multivariate analysis for PFS, BLK positivity was an independent poor prognostic factor (hazard ratio, 2.208; p = .040). CONCLUSIONS: Here, we describe the clinicopathological features and survival outcome according to expression of BLK in DLBCL. Approximately 39% of DLBCL patients showed BLK positivity, which was associated as a predictive marker for poor prognosis in patients who received R-CHOP chemotherapy.

Clinicopathologic Characteristics Associated with Prognosis in Ocular Extranodal Marginal Zone B Cell Lymphoma.

Background and Objectives: Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) type is the most common subtype of the ocular adnexal lymphoma. Despite its excellent prognosis, some patients experience partial remission or progressive disease. We aimed to evaluate clinicopathologic differences in the treatment responder group by comparing complete remission (CR) and non-complete remission (non-CR). Materials and Methods: This study retrospectively reviewed 48 patients who were diagnosed with ocular adnexal MALT lymphoma at Ulsan University Hospital between March 2002 and August 2018. Patients who were followed up for less than 6 months were excluded. Histologic and clinical features were analyzed. The patients were divided into two groups: CR and non-CR. Results: Among the 48 patients, 33 achieved CR and 15 achieved non-CR during the median follow-up period of 40.00 months (range, 7-109 months). In univariable analysis, more patients tend to undergo treatment in the CR group, and post-radiotherapy (post-RT) SUVmax, PET and serum lactate dehydrogenase (LDH) levels were higher in the non-CR group (p = 0.043, p = 0.016, and p = 0.042, respectively). In a multivariable analysis, only application of treatment, including radiotherapy or chemotherapy with immunotherapy, was related to CR (odd ratio 7.301, 95% confidence interval 1.273-41.862, p = 0.026). In subgroup analysis according to the site of involvement, none of the variables were significant except for the post-RT SUVmax of PET and level of serum LDH in the non-conjunctiva group (p = 0.026, and p = 0.037, respectively). Seven (14.6%) patients had a recurrence, and those with a recurring site other than the primary site had a higher Ki-67 labeling index, although it was not statistically significant (9.56% vs. 18.00%, p = 0.095). Conclusions: Although belonging to the early stages, the non-CR rate was high in patients with high serum LDH levels, and recurred patients had higher Ki-67. Thus, considering active treatment is recommended in this group of patients.

TNF-α Induces Mitophagy in Rheumatoid Arthritis Synovial Fibroblasts, and Mitophagy Inhibition Alleviates Synovitis in Collagen Antibody-Induced Arthritis.

Mitophagy is a selective form of autophagy that removes damaged mitochondria. Increasing evidence indicates that dysregulated mitophagy is implicated in numerous autoimmune diseases, but the role of mitophagy in rheumatoid arthritis (RA) has not yet been reported. The aim of the present study was to determine the roles of mitophagy in patient-derived RA synovial fibroblasts (RASFs) and in the collagen antibody-induced arthritis mouse model. We measured the mitophagy marker PTEN-induced putative kinase 1 (PINK1) in RASFs treated with tumor necrosis factor-α (TNF-α) using Western blotting and immunofluorescence. Arthritis was induced in PINK1-/- mice by intraperitoneal injection of an anti-type II collagen antibody cocktail and lipopolysaccharide. RA severity was assessed by histopathology. PINK1 expression and damaged mitochondria increased in TNF-α treated RASFs via increased intracellular levels of reactive oxygen species. PINK1 knockdown RASFs decreased cellular migration and invasion functions. In addition, PINK1-/- mice with arthritis exhibited markedly reduced swelling and inflammation relative to wild-type mice with arthritis. Taken together, these findings suggest that regulation of PINK1 expression in RA could represent a potential therapeutic and diagnostic target for RA.

Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, in Mouse Macrophages Negatively Affects M1 Polarization and Inflammatory Responses.

A RhoA-specific guanine nucleotide exchange factor, p190RhoGEF, was first cloned and identified in neuronal cells. In immune cells, we first reported the role of p190RhoGEF in B cells: expression of p190RhoGEF increased after CD40 stimulation and was required for CD40-mediated B cell activation and differentiation. We also showed that over-expression of p190RhoGEF negatively affected dendritic cell function in response to bacterial lipopolysaccharide (LPS). In this study, we examined the role of p190RhoGEF in macrophages using p190RhoGEF over-expressing transgenic (TG) mice. We found macrophages from TG mice to be more round than those from control mice, with enriched polymerized actin at the edge attached to the glass. TG macrophages also responded less to LPS: production of reactive oxygen species, phagocytosis, chemokine-dependent migration, and pro-inflammatory cytokine secretion were all reduced compared with the responses of macrophages from littermate (LTM) control mice. Furthermore, the classical M1 subset population was observed less in the peritoneal macrophages of TG mice than the LTM control mice during LPS-elicited peritoneal inflammation. When the activity of RhoA was inhibited in TG macrophages, their morphology and LPS responses became similar to those of the LTM macrophages. These results suggest that over-expression of p190RhoGEF in macrophages could reduce M1 polarization and inflammatory responses by regulating the actin cytoskeleton.

Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration.

Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.

TGF-ß/IL-7 Chimeric Switch Receptor-Expressing CAR-T Cells Inhibit Recurrence of CD19-Positive B Cell Lymphoma.

Chimeric antigen receptor (CAR)-T cells are effective in the treatment of hematologic malignancies but have shown limited efficacy against solid tumors. Here, we demonstrated an approach to inhibit recurrence of B cell lymphoma by co-expressing both a human anti-CD19-specific single-chain variable fragment (scFv) CAR (CD19 CAR) and a TGF-ß/IL-7 chimeric switch receptor (tTRII-I7R) in T cells (CD19 CAR-tTRII-I7R-T cells). The tTRII-I7R was designed to convert immunosuppressive TGF-ß signaling into immune-activating IL-7 signaling. The effect of TGF-ß on CD19 CAR-tTRII-I7R-T cells was assessed by western blotting. Target-specific killing by CD19 CAR-tTRII-I7R-T cells was evaluated by Eu-TDA assay. Daudi tumor-bearing NSG (NOD/SCID/IL2Rγ-/-) mice were treated with CD19 CAR-tTRII-I7R-T cells to analyze the in vivo anti-tumor effect. In vitro, CD19 CAR-tTRII-I7R-T cells had a lower level of phosphorylated SMAD2 and a higher level of target-specific cytotoxicity than controls in the presence of rhTGF-ß1. In the animal model, the overall survival and recurrence-free survival of mice that received CD19 CAR-tTRII-I7R-T cells were significantly longer than in control mice. These findings strongly suggest that CD19 CAR-tTRII-I7R-T cell therapy provides a new strategy for long-lasting, TGF-ß-resistant anti-tumor effects against B cell lymphoma, which may lead ultimately to increased clinical efficacy.

Translesional Fractional Flow Reserve is Related to Plaque Components in Coronary Artery Disease: A Study Combining Pressure Wire and NIRS-IVUS Analysis.

OBJECTIVES: It remains unclear whether atherosclerotic plaque structure or composition is related to translesional biomechanical stresses in coronary artery disease. The aim of this study was to evaluate the association between translesional pressure parameters (using a pressure wire) and plaque characteristics (using a combined near-infrared spectroscopy [NIRS] and intravascular ultrasound [IVUS] imaging catheter). METHODS: Fractional flow reserve (FFR), delta (Δ) FFR, and Δ pressure were obtained during adenosine-induced maximum hyperemic status. Lipid core burden index (LCBI) and maximum LCBI within 2 mm (maxLCBI2mm) and tomographic anatomy were evaluated by NIRS-IVUS. RESULTS: Sixty-six lesions from 57 patients were analyzed (57 lesions for FFR, 45 lesions for ΔFFR). There was a negative correlation between FFR and maxLCBI2mm (r=-0.264; P=.049) and a positive correlation between ΔFFR and maxLCBI2mm (r=0.299; P=.049). ΔFFR of lesions with maxLCBI2mm ≥500 was significantly higher than maxLCBI2mm <500 (0.159 ± 0.085 vs 0.104 ± 0.075, respectively; P=.04). By receiver-operating characteristic curve analysis, ΔFFR ≥0.1 was a predictor for maxLCBI2mm ≥500 (area under curve, 0.707; 95% confidence interval, 0.552-0.862; P=.03). On multivariate analysis, ΔFFR was the only predictor of maxLCBI2mm (ß=0.347; P=.03). CONCLUSION: ΔFFR across a coronary artery lesion is related to lipid core burden assessed using NIRS-IVUS and might be a meaningful predictor of high-risk plaque (plaque with high lipid content).

Functional Ambivalence of Dendritic Cells: Tolerogenicity and Immunogenicity.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and inducers of T cell-mediated immunity. Although DCs play a central role in promoting adaptive immune responses against growing tumors, they also establish and maintain peripheral tolerance. DC activity depends on the method of induction and/or the presence of immunosuppressive agents. Tolerogenic dendritic cells (tDCs) induce immune tolerance by activating CD4+CD25+Foxp3+ regulatory T (Treg) cells and/or by producing cytokines that inhibit T cell activation. These findings suggest that tDCs may be an effective treatment for autoimmune diseases, inflammatory diseases, and infertility.

Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products.

BACKGROUND: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. METHODS: to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein-ligand binding free energy function improved by introducing an adequate dehydration energy term. RESULTS: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. CONCLUSIONS: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.

Primary hepatic extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), is one of the specific type of low-grade B-cell lymphoma not infrequently found worldwide. It typically involves mucosal sites such as stomach and conjunctiva; however, primary hepatic MALT lymphoma has been extremely rarely reported. We describe a case of hepatic MALT lymphoma in a 70-year-old male patient who underwent left hepatectomy due to the incidentally detected liver masses at a medical checkup. The resected specimen revealed multinodular masses consisting of small-to-intermediate-sized lymphoid cells with serpentine pattern and focal lymphoepithelial lesions. The tumor cells were diffusely positive for CD20 and Bcl-2 but negative for CD3, CD10, CD5, CD23, CD43, and cyclinD1. The Ki-67 labeling index was 10% and immunoglobulin heavy chain gene rearrangement study confirmed monoclonal proliferation. In this paper, we discuss several unique clinicopathologic characteristics which will be helpful to the differential diagnosis of hepatic MALT lymphoma.

The Effect of the Tumor Microenvironment and Tumor-Derived Metabolites on Dendritic Cell Function.

Dendritic cells (DCs) have a critical effect on the outcome of adaptive immune responses against growing tumors. Recent studies on the metabolism on DCs provide new insights on the functioning of these critical controllers of innate and adaptive immunity. DCs within the tumor microenvironment (TME) often exist in an inactive state, which is thought to limit the adaptive immune response elicited by the growing tumor. Tumor-derived factors in the TME are known to suppress DC activation and result in functional alterations in DC phenotype. We are now beginning to appreciate that many of these factors can also induce changes in immune cell metabolism. In this review, we discuss the functional alternation of DC phenotype by tumor metabolites.

Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway.

Dendritic cells (DCs) are the most potent professional antigen presenting cells and inducers of T cell-mediated immunity. However, few specific markers of mature DCs (mDC) have been reported. A previous microarray analysis revealed expression of mDC-specific genes and identified Rsad2 (radical S-adenosyl methionine domain containing 2) as a candidate specific marker for DC maturation. Mouse bone marrow-derived DCs were transfected with Rsad2 siRNA and examined by flow cytometry, ELISA, western, and confocal microscopy. C57BL/6 mice received intravenously B16F10 cells to establish a pulmonary metastasis model. Tumor-bearing mice then received subcutaneously two injections of mDCs or Rsad2 knockdown DCs. The cytotoxic T lymphocyte (CTL) population was examined from splenocytes of DC-vaccinated mice by flow cytometry. Rsad2 was induced at high levels in LPS-stimulated mDCs and mDC function was markedly attenuated under conditions of Rsad2 knockdown. Moreover, Rsad2 was necessary for mDC maturation via the IRF7-mediated signaling pathway. The importance of Rsad2 was confirmed in an Rsad2 knockdown lung metastasis mouse model in which mDCs lost their antitumor efficacy. Data on the CTL population further supported the results as above. Taken together, Rsad2 was an obvious and specific marker necessary for DC maturation and these findings will be clearly helpful for further understanding of DC biology.

Whole-exome sequencing analysis reveals co-segregation of a COL20A1 missense mutation in a Pakistani family with striate palmoplantar keratoderma.

Palmoplantar keratoderma (PPK) is a rare group of excessive skin disorder characterized by thickness over the palms and soles. The striate palmoplantar keratoderma (PPKS) is a form in which hyperkeratotic lesions are restricted to the pressure regions extending longitudinally in the length of each finger to the palm. Dominantly inherited mutations in genes including desmoglein 1, desmoplakin and keratin 1 have been suggested as genetic causes of PPKS. In this study, we investigated a three-generation Pakistani family segregating PPKS phenotype in autosomal dominant fashion to identify genetic cause in this family. We have performed whole-exome and Sanger sequencing followed by in silico bioinformatics analysis to pinpoint candidate mutation associated with PPK. Revealed a novel heterozygous mutation (NM_020882.2, COL20A1 c. 392C > G; p.Ser131Cys) in the loop region close to fibronectin type III-1 domain of the c ollagen 20 α1. This variant was not found in our in-house 219 ethnically matched Pakistani unaffected controls and showed minor allele frequency of 3.4 × 10-5 in Exome Aggregation Consortium database containing exome data of 59,464 worldwide individuals. It was assigned as "pathogenic" by in silico prediction tools. Previously, association of mutation in the COL14A1, one of the paralogous gene of COL20A1, with PPK was reported in the study with a Chinese family. Our study proposes COL20A1 gene as another potential candidate gene for PPKS which expand the spectrum of collagen proteins in the pathogenicity of PPK.

Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design.

Dysregulation of anaplastic lymphoma kinase (ALK) has been detected in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion. Secondary mutations opposing activity of the first-generation ALK inhibitor crizotinib came into existence, requiring mutation-targeting drug discovery for the powerful second-line treatment. In this study, we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M, discovered by the fragment-growing strategy. The protonation of 4-aminoquinoline core could interrupt the ability the N atom of quinoline to act as a hydrogen bond acceptor; therefore, the pKa and calculated ionization pH values of relevant pyridine-based core moieties were carefully analyzed. The replacement of amine linkage with ether resulted in single-digit nanomolar range inhibitors. The inhibitors exhibited significant antiproliferative effects on H2228 CR crizotinib-resistant cells by decreasing PI3K/AKT and MAPK signaling. This work constitutes the first example for systematic investigation of the effect of ionization pH on activity in this system.

Late-acquired incomplete stent apposition after everolimus-eluting stent versus sirolimus-eluting stent implantation in patients with non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction.

AIMS: Our aim was to evaluate the incidence and clinical outcomes of late-acquired incomplete stent apposition (LAISA) after implantation of first- and second-generation drug-eluting stents in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Late-Acquired incomplete stent aPPOsition after everolimus-eluting stent versus sirolimus-eluting Stent ImplanTatION in pAtients with non ST-segment elevation Myocardial Infarction and ST-segment elevation myocardial infarction (APPOSITION-AMI) was a prospective, randomised study comparing LAISA after everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) implantation in AMI patients. Intravascular ultrasound examination was serially performed post-procedurally and at eight-month follow-up in 195 AMI patients (205 native coronary lesions: 100 EES; 105 SES). LAISA was observed in 6.0% and 16.2% of EES- vs. SES-treated lesions (p=0.021), respectively. In 64.7% of SES-treated lesions, LAISA was caused by positive remodelling, whereas thrombus dissolution or plaque reduction was observed in 66.7% of EES-treated lesions. Among patients with LAISA, MACE developed in one (4.5%) in the SES group with no ST in either group up to one year. CONCLUSIONS: The incidence of LAISA was lower in AMI patients treated with EES as compared to SES, mainly secondary to positive remodelling in SES- but not EES-treated lesions. Patients with LAISA in both groups showed a very low MACE incidence at one-year follow-up.