Abundant extrasynaptic expression of α3ß4-containing nicotinic acetylcholine receptors in the medial habenula-interpeduncular nucleus pathway in mice.

Nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb)-interpeduncular nucleus (IPN) pathway play critical roles in nicotine-related behaviors. This pathway is particularly enriched in nAChR α3 and ß4 subunits, both of which are genetically linked to nicotine dependence. However, the cellular and subcellular expression of endogenous α3ß4-containing nAChRs remains largely unknown because specific antibodies and appropriate detection methods were unavailable. Here, we successfully uncovered the expression of endogenous nAChRs containing α3 and ß4 subunits in the MHb-IPN pathway using novel specific antibodies and a fixative glyoxal that enables simultaneous detection of synaptic and extrasynaptic molecules. Immunofluorescence and immunoelectron microscopy revealed that both subunits were predominantly localized to the extrasynaptic cell surface of somatodendritic and axonal compartments of MHb neurons but not at their synaptic junctions. Immunolabeling for α3 and ß4 subunits disappeared in α5ß4-knockout brains, which we used as negative controls. The enriched and diffuse extrasynaptic expression along the MHb-IPN pathway suggests that α3ß4-containing nAChRs may enhance the excitability of MHb neurons and neurotransmitter release from their presynaptic terminals in the IPN. The revealed distribution pattern provides a molecular and anatomical basis for understanding the functional role of α3ß4-containing nAChRs in the crucial pathway of nicotine dependence.

Association between the Angle of the Left Subclavian Artery and Procedural Time for Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome.

Background: The effect of left subclavian artery tortuosity during percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) remains unclear. Methods: Of 245 ACS patients (from November 2019 and May 2021), 79 who underwent PCI via a left radial approach (LRA) were included. We measured the angle of the left subclavian artery in the coronal view on CT imaging as an indicator of the tortuosity and investigated the association between that angle and the clinical variables and procedural time. Results: Patients with a left subclavian artery angle of a median of <70 degrees (severe tortuosity) were older (75.4 ± 11.7 vs. 62.9 ± 12.3 years, P < 0.001) and had a higher prevalence of female sex (42.1% vs. 14.6%, P=0.007), hypertension (94.7% vs. 75.6%, P=0.02), and subclavian artery calcification (73.7% vs. 34.2%, P < 0.001) than those with that ≥70 degrees. The left subclavian artery angle correlated negatively with the sheath cannulation to the first balloon time (ρ = -0.51, P < 0.001) and total procedural time (ρ = -0.32, P=0.004). A multiple linear regression analysis revealed that the natural log transformation of the sheath insertion to first balloon time was associated with a subclavian artery angle of <70 degrees (ß = 0.45, P < 0.001). Conclusion: Our study showed that lower left subclavian artery angles as a marker of the tortuosity via the LRA were strongly associated with a longer sheath insertion to balloon time and subsequent entire procedure time during the PCI.

Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas.

Adult T-cell leukemia/lymphoma (ATLL) is one of the aggressive peripheral T-cell neoplasms with a poor prognosis. Accumulating evidence demonstrates that escape from adaptive immunity is a hallmark of ATLL pathogenesis. However, the mechanisms by which ATLL cells evade natural killer (NK)-cell-mediated immunity have been poorly understood. Here we show that CD48 expression in ATLL cells determines the sensitivity for NK-cell-mediated cytotoxicity against ATLL cells. We performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening using 2 ATLL-derived cell lines and discovered CD48 as one of the best-enriched genes whose knockout conferred resistance to YT1-NK cell line-mediated cytotoxicity. The ability of CD48-knockout ATLL cells to evade NK-cell effector function was confirmed using human primary NK cells with reduced interferon-γ (IFNγ) induction and degranulation. We found that primary ATLL cells had reduced CD48 expression along with disease progression. Furthermore, other subgroups among aggressive peripheral T-cell lymphomas (PTCLs) also expressed lower concentrations of CD48 than normal T cells, suggesting that CD48 is a key molecule in malignant T-cell evasion of NK-cell surveillance. Thus, this study demonstrates that CD48 expression is likely critical for malignant T-cell lymphoma cell regulation of NK-cell-mediated immunity and provides a rationale for future evaluation of CD48 as a molecular biomarker in NK-cell-associated immunotherapies.

Protective effect of the Impella on the left ventricular function after acute broad anterior wall ST elevation myocardial infarctions with cardiogenic shock: cardiovascular magnetic resonance imaging strain analysis.

BACKGROUND: The clinical efficacy of the Impella for high-risk percutaneous coronary intervention (PCI) and cardiogenic shock remains under debate. We thus sought to investigate the protective effects on the heart with the Impella's early use pre-PCI using cardiac magnetic resonance imaging (CMRI). METHODS: We retrospectively evaluated the difference in the subacute phase CMR imaging results (19 ± 9 days after admission) between patients undergoing an Impella (n = 7) or not (non-Impella group: n = 18 [12 intra-aortic balloon pumps (1 plus veno-arterial extracorporeal membrane oxygenation) and 6 no mechanical circulation systems]) in broad anterior ST-elevation myocardial infarction (STEMI) cases. A mechanical circulation system was implanted pre-PCI. RESULTS: No differences were found in the door-to-balloon time, peak creatine kinase, and hospital admission days between the Impella and non-Impella groups; however, the CMRI-derived left ventricular ejection fraction was significantly greater (45 ± 13% vs. 34 ± 7.6%, P = 0.034) and end-diastolic and systolic volumes smaller in the Impella group (149 ± 29 vs. 187 ± 41 mL, P = 0.006: 80 ± 29 vs. 121 ± 40 mL, P = 0.012). Although the global longitudinal peak strain did not differ, the global radial (GRS) and circumferential peak strain (GCS) were significantly higher in the IMPELLA than non-IMPELLA group. Greater systolic and diastolic strain rates (SRs) in the Impella than non-Impella group were observed in non-infarcted rather than infarcted areas. CONCLUSIONS: Early implantation of an Impella before PCIs for STEMIs sub-acutely prevented cardiac dysfunction through preserving the GRS, GCS, and systolic and diastolic SRs in the remote myocardium. This study provided mechanistic insight into understanding the usefulness of the Impella to prevent future heart failure.

Prognostic Significance of a Combination of Cardiogenic Shock and the Critical Culprit Lesion Location in ST-Elevation Myocardial Infarctions.

Both cardiogenic shock (CS) and critical culprit lesion locations (CCLLs), defined as the left main trunk and proximal left anterior descending coronary artery, are associated with worse outcomes in ST-elevation myocardial infarctions (STEMIs). We aimed to examine how the combination of CS and/or CCLLs affected the prognosis in Japanese STEMI patients in the primary percutaneous coronary intervention era (PPCI-era). The subjects included 624 STEMI patients admitted to our hospital between January 2013 and April 2020. They were divided into four groups according to the combination of CS and CCLLs: CS (-) CCLL (-) group [n = 405], CS (-) CCLL (+) group [n = 150], CS (+) CCLL (-) group [n = 25], and CS (+) CCLL (+) group [n = 44]. The cumulative incidences of all-cause death at 30 days and 1 year were 3.5% and 6.4% in the CS (-) CCLL (-), 3.3% and 5.6% in the CS (-) CCLL (+), 32.0% and 32.0% in the CS (+) CCLL (-), and 50.0% and 65.9% in the CS (+) CCLL (+) group, respectively. After a multivariate adjustment, the CS (+) CCLL (+) group was independently associated with all-cause death (hazard ratio: 17.00, 95% confidence interval: 7.12-40.59 versus the CS (-) CCLL (-) group). In the CS (+) CCLL (+) group, compared to years 2013-2017, the IMPELLA begun to be used (44.4% versus 0%), and intra-aortic balloon pumps significantly decreased (44.4% versus 92.3%) during years 2018-2020, while the medications upon discharge did not significantly differ. The 30-day mortality was numerically lower during years 2018-2020 than years 2013-2017 (Log-rank test, P = 0.092). In conclusion, the prognosis of STEMIs varies greatly depending on the combination of CS and CCLLs, and in particular, patients with both CS and CCLLs had the poorest prognosis during the modern PPCI-era.

Impact of the COVID-19 outbreak on hospitalizations and outcomes in patients with acute myocardial infarction in a Japanese Single Center.

There are a few Japanese data regarding the incidence and outcomes of acute myocardial infarction (AMI) after the coronavirus disease 2019 (COVID-19) outbreak. We retrospectively reviewed the data of AMI patients admitted to the Nihon University Itabashi Hospital after a COVID-19 outbreak in 2020 (COVID-19 period) and the same period from 2017 to 2019 (control period). The patients' characteristics, time course of admission, diagnosis, and treatment of AMI, and 30-day mortality were compared between the two period-groups for both ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI), respectively. The AMI inpatients decreased by 5.7% after the COVID-19 outbreak. There were no differences among most patient backgrounds between the two-period groups. For NSTEMI, the time from the symptom onset to admission was significantly longer, and that from the AMI diagnosis to the catheter examination tended to be longer during the COVID-19 period than the control period, but not for STEMI. The 30-day mortality was significantly higher during the COVID-19 period for NSTEMI (23.1% vs. 1.9%, P = 0.004), but not for STEMI (9.4% vs. 8.3%, P = 0.77). In conclusion, hospitalizations for AMI decreased after the COVID-19 outbreak. Acute cardiac care for STEMI and the associated outcome did not change, but NSTEMI outcome worsened after the COVID-19 outbreak, which may have been associated with delayed medical treatment due to the indirect impact of the COVID-19 pandemic.

Absence of coronary angioscopy-derived in-stent thrombi is associated with major bleeding events in acute myocardial infarction.

BACKGROUND AND AIMS: The optimal duration of dual antiplatelet therapy for acute myocardial infarction is controversial because the bleeding risk outweighs the thromboembolic risk. We hypothesized that an in-stent thrombus (IS-thrombus) detected by coronary angioscopy (CAS) after stent implantation would be associated with high bleeding risk. METHODS: This study included 208 patients who underwent CAS at 2 weeks after stent implantation for an acute myocardial infarction. The study was approved by the ethics committee at the Nihon University Itabashi Hospital (reference number RK-200714-10). RESULTS: In 84 patients, in whom no IS-thrombus was identified in the culprit vessel using CAS, the major bleeding event rate was significantly higher than that in patients with IS-thrombi (n = 124). However, no difference was detected in major adverse cardiovascular events (MACE; stroke, hospitalization for a non-fatal myocardial infarction/unstable angina, target lesion revascularization, and cardiovascular death). After adjustments by the propensity score based on patient characteristics, the absence of IS-thrombi remained an independent predictor of major bleeding events (hazard ratio 4.73, 95% confidence interval 2.04-11.00, p < 0.001). CONCLUSIONS: The absence of CAS-detected IS-thrombi in the subacute phase was independently associated with future major bleeding events, but not with MACE. These findings may help optimize the duration of dual antiplatelet therapy.

Anticoagulant therapy with dual antiplatelet for left ventricular thrombus following acute myocardial infarction.

Two men aged 71 and 62 years were admitted for ST elevation myocardial infarction and percutaneous coronary intervention was performed to the occlusion of left anterior descending artery. Echocardiogram showed an akinetic or a dyskinetic movement of left ventricular anterior wall with mural thrombus on admission in Case 1 and 10 days from admission in Case 2. A direct oral anticoagulant (DOAC) in addition to dual antiplatelet therapy (DAPT) in both patients was started successfully for the resolution of left ventricular thrombus 3 weeks after the initiation of DOAC in Case 1, and 2 weeks after the initiation of DOAC in Case 2. However, the dose of DOAC was decreased and aspirin was stopped in Case 1 with HAS-BLED score five due to colon polyp bleeding, and there was no bleeding complication in Case 2 with HAS-BLED score two during this triple therapy. The duration of triple therapy was 2 months in Case 1 and 6 months in Case 2, and of DOAC therapy was total 6 months in both cases. .

Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells.

[Figure: see text] Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan-Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.