Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A.

Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 µM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

Mechanistic Action of Cell Cycle Arrest and Intrinsic Apoptosis via Inhibiting Akt/mTOR and Activation of p38-MAPK Signaling Pathways in Hep3B Liver Cancer Cells by Prunetrin-A Flavonoid with Therapeutic Potential.

Hepatocellular carcinoma (HCC) has a poor prognosis and a low survival rate. Drugs without side effects are desperately needed since chemotherapy has a negative effect on the host cells. Previous research has firmly established that plant-based compounds have significant bioactivities without a negative impact on the host. Flavonoids, in particular, are a class of compounds with both anti-inflammatory and anti-cancer properties. Prunetrin (PUR) is a glycosyloxyisoflavone (Prunetin 4'-O-glucoside) derived from Prunus sp., and its other form, called prunetin, showed optimistic results in an anti-cancerous study. Hence, we aimed to discover the anti-cancer ability of prunetrin in liver cancer Hep3B cells. Our cytotoxicity results showed that PUR can decrease cell viability. The colony formation assay confirms this strongly and correlates with cell cytotoxicity results. Prunetrin, in a dose-dependent manner, arrested the cell cycle in the G2/M phase and decreased the expression of cyclin proteins such as Cyclin B1, CDK1/CDC2, and CDC25c. Prunetrin treatment also promoted the strong cleavage of two important apoptotic hallmark proteins called PARP and caspase-3. It also confirms that apoptosis occurs through the mitochondrial pathway through increased expression of cleaved caspase-9 and increased levels of the pro-apoptotic protein Bak. Bak was significantly increased with the declining expression of the anti-apoptotic protein Bcl-xL. Next, it inhibits the mTOR/AKT signaling pathways, proving that prunetrin includes apoptosis and decreases cell viability by suppressing these pathways. Further, it was also observed that the activation of p38-MAPK was dose-dependent. Taken together, they provide evidence that prunetrin has an anti-cancerous ability in Hep3B liver cancer cells by arresting the cell cycle via p38 and inhibiting mTOR/AKT.

Potential Antioxidant and Anti-Inflammatory Effects of Lonicera japonica and Citri Reticulatae Pericarpium Polyphenolic Extract (LCPE).

Dermatitis is an inflammatory condition of the outer layer of the skin that causes itching, blisters, redness, swelling, and often exudation, scabs, and peeling. Among them, purulent inflammation is a symptom that often occurs on the skin and appears in the form of boils and acne. Various studies are being conducted to treat these inflammatory diseases. Accordingly, Lonicera japonica and Citri Reticulatae Pericarpium Polyphenolic Extract (LCPE), which uses herbal preparations such as Lonicera japonica, Citri Reticulatae Pericarpium, and Glycyrrhiza uralensis, has been used to suppress inflammation since ancient times, and its anti-inflammatory effect can be observed in skin keratinocytes after inducing inflammation. In this study, the major polyphenolic compounds in LCPE were quantitatively determined by analyzing the data through peak values using high-performance chromatography (HPLC-MS/MS) coupled with mass spectrometry. Additionally, bioactive compounds targeting 2,2-diphenyl-1-picrylhydrazyl (DPPH) were analyzed by ultrafiltration integrated with LC. Several compounds with the most significant effects were selected (chlorogenic acid, narirutin, and isorhamnetin). Skin keratinocytes induced by lipopolysaccharide (LPS) were treated with LCPE to show its anti-inflammatory effects. After LCPE treatment, inflammation-mediating cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were decreased. In addition, nuclear factor kappa (NF-кB) and mitogen-activated protein kinase (MAPK) were inhibited in important pathways related to inflammation. Lastly, molecular modeling was performed to determine binding scores with inflammation-related proteins using molecular docking for the selected compounds. According to these results, LCPE is effective in treating keratinocytes induced by LPS and reducing inflammation and has potential antioxidant effects, and the polyphenol components have been identified.

Flavones: The Apoptosis in Prostate Cancer of Three Flavones Selected as Therapeutic Candidate Models.

Cancer is a widespread but dangerous disease that can strike anyone and is the second 1leading cause of death worldwide. Prostate cancer, in particular, is a prevalent cancer that occurs in men, and much research is being done on its treatment. Although chemical drugs are effective, they have various side effects, and accordingly, anticancer drugs using natural products are emerging. To date, many natural candidates have been discovered, and new drugs are being developed as drugs to treat prostate cancer. Representative candidate compounds that have been studied to be effective in prostate cancer include apigenin, acacetin and tangeretin of the flavone family among flavonoids. In this review, we look at the effects of these three flavones on prostate cancer cells via apoptosis in vitro and in vivo. Furthermore, in addition to the existing drugs, we suggest the three flavones and their effectiveness as natural anticancer agents, a treatment model for prostate cancer.

Immune Responses After Vaccination With Primary 2-Dose ChAdOx1 Plus a Booster of BNT162b2 or Vaccination With Primary 2-Dose BNT162b2 Plus a Booster of BNT162b2 and the Occurrence of Omicron Breakthrough Infection

Background@#Before the omicron era, health care workers were usually vaccinated with either the primary 2-dose ChAdOx1 nCoV-19 (Oxford-AstraZeneca) series plus a booster dose of BNT162b2 (Pfizer-BioNTech) (CCB group) or the primary 2-dose BNT162b2 series plus a booster dose of BNT162b2 (BBB group) in Korea. @*Methods@#The two groups were compared using quantification of the surrogate virus neutralization test for wild type severe acute respiratory syndrome coronavirus 2 (SVNT-WT), the omicron variant (SVNT-O), spike-specific IgG, and interferon-gamma (IFN-γ), as well as the omicron breakthrough infection cases. @*Results@#There were 113 participants enrolled in the CCB group and 51 enrolled in the BBB group. Before and after booster vaccination, the median SVNT-WT and SVNT-O values were lower in the CCB (SVNT-WT [before-after]: 72.02–97.61%, SVNT-O: 15.18–42.29%) group than in the BBB group (SVNT-WT: 89.19–98.11%, SVNT-O: 23.58–68.56%; all P < 0.001). Although the median IgG concentrations were different between the CCB and BBB groups after the primary series (2.677 vs. 4.700 AU/mL, respectively, P < 0.001), they were not different between the two groups after the booster vaccination (7.246 vs. 7.979 AU/mL, respectively, P = 0.108). In addition, the median IFN-γ concentration was higher in the BBB group than in the CCB group (550.5 and 387.5 mIU/mL, respectively, P = 0.014). There was also a difference in the cumulative incidence curves over time (CCB group 50.0% vs. BBB group 41.8%; P = 0.045), indicating that breakthrough infection occurred faster in the CCB group. @*Conclusion@#The cellular and humoral immune responses were low in the CCB group so that the breakthrough infection occurred faster in the CCB group than in the BBB group.

A study on changes in lung function, neutralizing antibodies, and symptoms of adult patients hospitalized with COVID-19

Background/Aims@#To identify changes in symptoms and pulmonary sequelae in patients with coronavirus disease 2019 (COVID-19). @*Methods@#Patients with COVID-19 hospitalized at seven university hospitals in Korea between February 2020 and February 2021 were enrolled, provided they had ≥ 1 outpatient follow-up visit. Between January 11 and March 9, 2021 (study period), residual symptom investigations, chest computed tomography (CT) scans, pulmonary function tests (PFT), and neutralizing antibody tests (NAb) were performed at the outpatient visit (cross-sectional design). Additionally, data from patients who already had follow-up outpatient visits before the study period were collected retrospectively. @*Results@#Investigation of residual symptoms, chest CT scans, PFT, and NAb were performed in 84, 35, 31, and 27 patients, respectively. After 6 months, chest discomfort and dyspnea persisted in 26.7% (4/15) and 33.3% (5/15) patients, respectively, and 40.0% (6/15) and 26.7% (4/15) patients experienced financial loss and emotional distress, respectively. When the ratio of later CT score to previous ones was calculated for each patient between three different time intervals (1–14, 15–60, and 61–365 days), the median values were 0.65 (the second interval to the first), 0.39 (the third to the second), and 0.20 (the third to the first), indicating that CT score decreases with time. In the high-severity group, the ratio was lower than in the low-severity group. @*Conclusions@#In COVID-19 survivors, chest CT score recovers over time, but recovery is slower in severely ill patients. Subjects complained of various ongoing symptoms and socioeconomic problems for several months after recovery.

Benzodiazepines: Pharmacology Up-to-Date and Practical Issues / 신경정신의학

Benzodiazepines have been widely used as anxiolytics, sedatives, hypnotics, anticonvulsants, or central muscle relaxants since the 1960s despite significant adverse effects, the potential for misuse, and consequent overdose. Benzodiazepines exert their pharmacological action by binding to gamma-aminobutyric acid type A (GABA-A) receptors in the brain and facilitateing the inhibitory actions of the neurotransmitter GABA. Recent findings have also elucidated the effects of benzodiazepines on the allosteric modulation of GABA-A receptors, including receptor subtypes and transmembrane proteins, which is a significant step in our understanding of GABA pharmacology. In clinical practice, the use of benzodiazepines to treat psychiatric disorders has been limited due to the challenges associated with the long-term use, namely the risks of abuse, misuse, and overdose, as well as withdrawal effects. Furthermore, the approval of selective serotonin reuptake inhibitors for anxiety disorders has led to their extensive use as a first-line pharmacological option and they have also been promoted in various practice guidelines for the treatment of anxiety disorders. However, although recent systematic reviews and meta-analyses have shown that benzodiazepines are useful and effective drugs for the treatment of various neuropsychiatric disorders, including anxiety, debates over the clinical use of benzodiazepines continue. More than 60 years after the introduction of benzodiazepines in clinical practice, it is necessary to revisit the controversies associated with benzodiazepine use and to update the discussion current approach to practice with thethrough an understanding of the new data on their pharmacological actions and to identify appropriate indications according to the new diagnostic systems of psychiatric disorders through an extensive literature review.

Practical Issues With Clonazepam Use / 신경정신의학

Clonazepam, a 7-nitrobenzodiazepine, has been used for the treatment of various neuropsychiatric disorders such as seizures, sleep disorders, panic disorders, anxiety, and movement disorders. However, clonazepam is officially approved as a therapeutic drug only for epilepsy and panic disorders in Korea. This raises ethical issues in clinical practice, as clonazepam is prescribed off-label for most neuropsychiatric disorders in many other countries as well. The misuse and abuse of clonazepam as a recreational drug have also been commonly reported in global literature. In this review, as a therapeutic drug as the authors aim to highlight the pharmacological aspects, clinical effects, and potential addictive risks of clonazepam use, by reviewing the current literature on clonazepam to increase its clinical use by accurately understanding and identifying its psychopharmacological benefits and characteristics. However, establishing the risk/benefit ratio of clonazepam for use in specific clinical situations is difficult because of the lack of adequate updated data. Therefore, the use of clonazepam needs to be approached from the point of view of personalized drug treatment rather than following fixed guidelines which would not reflect the current real-world clinical practices.

Effects of Long-acting Injectable 3-Monthly Paliperidone Palmitate on the Clinical and Social Performance of Patients with Schizophrenia

Objective@#To investigate the effects of long-acting injectable 3-monthly paliperidone palmitate on the clinical and social functioning of patients with schizophrenia. @*Methods@#This study enrolled patients with schizophrenia receiving long-acting injectable 1-monthly paliperidone palmitate for at least 4 months and who subsequently received 3-monthly paliperidone palmitate. Accordingly, 418 patients were followed up for 24 weeks. Their clinical symptoms and social functioning were measured using the Clinical Global Impression-Severity of Illness and Personal and Social Performance scales. @*Results@#The Personal and Social Performance total score was significantly higher after 3-monthly paliperidone palmitate treatment than at baseline (baseline vs. week 24: 54.3 ± 18.0 vs. 61.0 ± 14.5 [mean ± standard deviation]; p ＜ 0.001; Wilcoxon signed-rank test); the proportion of patients in the mildly ill group (scores 71−100) also increased significantly (baseline vs. week 24: 16.5% vs. 20.6%; p＜ 0.001; McNemar-Bowker test). The mean Clinical Global Impression-Severity of Illness score decreased significantly (baseline vs. week 24: 3.7 ± 1.0 vs. 3.4 ± 0.9; p＜ 0.001; Wilcoxon signed-rank test), as did the proportion of patients in the severely ill group (baseline vs. week 24: 4.1% vs. 2.1%; p ＜ 0.001; McNemar-Bowker test). @*Conclusion@#Continuous 3-monthly paliperidone palmitate treatment significantly enhances the personal and social performance of patients with schizophrenia and reduces the proportion of those with severe illness. These findings suggest that long-acting injectable antipsychotic administration at intervals longer than 1 month might improve the social functioning of and promote return to activities of daily living in patients with schizophrenia.

Evaluation of Isometric Shoulder Muscle Contraction during Awakening after Arthroscopic Rotator Cuff Repair / 대한스포츠의학회지

Purpose@#Most rotator cuff repairs are performed under general anesthesia, and the shoulder muscles undergo exertion during the patient’s awakening. These may lead to subsequent retear. The purpose of this study is to evaluate the characteristics of shoulder muscle contraction during awakening from general anesthesia after rotator cuff repair. @*Methods@#Twenty patients underwent arthroscopic rotator cuff repair. Surface electromyography was used to investigate the amplitude of shoulder (upper trapezius [UT] and biceps brachii [BB]) and body (rectus femoris, RF) muscles during awakening in the operating room and resting in the postanesthesia care unit (PACU). @*Results@#The mean maximum voluntary isometric contraction (MVIC) of the UT, BB, and RF during awakening were 28.00%, 27.84%, and 35.65%, and the mean durations of activation were 3.98, 2.50, and 2.71 seconds. In the PACU, the mean MVIC of the UT, BB, and RF were 27.18%, 25.03%, and 27.20%, and the mean durations were 2.72, 0.26, and 0.67 seconds. No correlation between muscle contraction and postoperative pain was identified. @*Conclusion@#Less than 10% of the involuntary muscle contractions of the UT and BB measured in this study exceeded 20% of the MVIC and the contractions lasted less than 4 seconds. As the percentage of the MVIC of the rotator cuff is typically lower than that of the UT and BB, strong contractions of the rotator cuff muscle with detrimental effects occur at a low frequency and short duration. Therefore, retear due to muscle contraction during awakening is unlikely.

Development of a New Liquid Type Rapid Urease Test Kit (Helicotest ® ): Comparison with Other Commercial Kits / 대한소화기학회지

Background/Aims@#A quick and accurate diagnosis of Helicobacter pylori (H. pylori) infections is vital for effectively managing many upper gastrointestinal tract diseases. Many diagnostic methods have been developed for rapid and accurate diagnosis, including invasive and non-invasive methods, but each tool has some limitations. Among the invasive diagnostic methods, the rapid urease test (RUT) is a relatively time-saving and accurate method, but a variation in the reaction time range causes inconvenience and inefficiency in the clinical field. This study developed a liquid-type medium, Helicotest ® , to enable faster detection. This study examined the reaction time of a new liquid-type RUT kit with other commercial kits. @*Methods@#Two H. pylori strains were cultured (H. pylori ATCC 700392 and 43504), and the urease activity of H. pylori was measured using a urease activity assay kit (MAK120, Sigma Aldrich). Four RUT kits were used to compare the time of H. pylori detection, including Helicotest ® (Won Medical, Bucheon, Korea), Hp kit (Chong Kun Dang, Seoul, Korea), CLO kit (Halyard, Alpharetta, GA, USA), and ASAN Helicobacter Test ® (ASAN, Seoul, Korea). @*Results@#The detection of H. pylori was possible in bacterial amounts less than 10 μL. The color change was detected from five minutes with bacterial densities of 5 μL and 10 μL for both strains, whereas 30 minutes and one hour were required for 0.5 μL and a 1 μL bacterial density of ATCC 43504 and 700392 strains, respectively. @*Conclusions@#Compared to other RUT kits, Helicotest ® showed the fastest reaction. Therefore, faster diagnosis in clinical practice is expected.

Circulating Extracellular-Vesicle-Incorporated MicroRNAs as Potential Biomarkers for Ischemic Stroke in Patients With Cancer / 대한뇌졸중학회지

Background@#and Purpose This study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke. @*Methods@#This cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort. @*Results@#This study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692–0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077–0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels. @*Conclusion@#Stroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

The Role of Artificial Intelligence in Gastric Cancer: Surgical and Therapeutic Perspectives:A Comprehensive Review

Stomach cancer has a high annual mortality rate worldwide necessitating early detection and accurate treatment. Even experienced specialists can make erroneous judgments based on several factors. Artificial intelligence (AI) technologies are being developed rapidly to assist in this field. Here, we aimed to determine how AI technology is used in gastric cancer diagnosis and analyze how it helps patients and surgeons. Early detection and correct treatment of early gastric cancer (EGC) can greatly increase survival rates. To determine this, it is important to accurately determine the diagnosis and depth of the lesion and the presence or absence of metastasis to the lymph nodes, and suggest an appropriate treatment method. The deep learning algorithm, which has learned gastric lesion endoscopyimages, morphological characteristics, and patient clinical information, detects gastric lesions with high accuracy, sensitivity, and specificity, and predicts morphological characteristics. Through this, AI assists the judgment of specialists to help select the correct treatment method among endoscopic procedures and radical resections and helps to predict the resection margins of lesions.Additionally, AI technology has increased the diagnostic rate of both relatively inexperienced and skilled endoscopic diagnosticians. However, there were limitations in the data used for learning, such as the amount of quantitatively insufficient data, retrospective study design, single-center design, and cases of non-various lesions. Nevertheless, this assisted endoscopic diagnosis technology that incorporates deep learning technology is sufficiently practical and future-oriented and can play an important role in suggesting accurate treatment plans to surgeons for resection of lesions in the treatment of EGC.

Stroke-Specific Predictors of Major Bleeding in Anticoagulated Patients With Stroke and Atrial Fibrillation: A Nationwide Multicenter Registry-Based Study

Background@#and Purpose The congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack (CHA2DS2-VASc) and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol (HAS-BLED) scores have been validated in estimating the risks of ischemic stroke and major bleeding, respectively, in patients with atrial fibrillation (AF). This study investigated stroke-specific predictors of major bleeding in patients with stroke and AF who were taking oral anticoagulants (OACs). @*Methods@#Subjects were selected from patients enrolled in the Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) nationwide multicenter registry between 2013 and 2015. Patients were excluded if they were not taking OACs, had no brain imaging data, or had intracranial bleeding directly related to the index stroke. Major bleeding was defined according to International Society of Thrombosis and Haemostasis criteria. Cox regression analyses were performed to assess the associations between clinical variables and major bleeding and Kaplan-Meier estimates were performed to analyze event-free survival. @*Results@#Of a total of 3,213 patients, 1,414 subjects (mean age of 72.6 years, 52.5% males) were enrolled in this study. Major bleeding was reported in 34 patients during the median follow-up period of 1.73 years. Multivariable analysis demonstrated that initial National Institutes of Health Stroke Scale scores (hazard ratio [HR] 1.07, p=0.006), hypertension (HR 3.18, p=0.030), persistent AF type (HR 2.51, p=0.016), and initial hemoglobin level (HR 0.74, p=0.001) were independently associated with major bleeding risk. Except for hypertension, these associations remained significant after adjusting for the HAS-BLED score. Intracranial atherosclerosis presented a trend of association without statistical significance (HR 2.21, p=0.050). @*Conclusions@#This study found that major bleeding risk was independently associated with stroke-specific factors in anticoagulated patients with stroke and AF. This has the clinical implication that baseline characteristics of patients with stroke and AF should be considered in secondary prevention, which would bring the net clinical benefit of balancing recurrent stroke prevention with minimal bleeding complications.

Feasibility of Ultrashort Echo Time T2* Mapping in Comparison With T2 Mapping for Quantitative Evaluation of Meniscal Degeneration

Purpose@#This study aimed to assess the feasibility of ultrashort echo time (UTE)-T2* mapping in comparison with T2 mapping for quantitative evaluation of meniscal degeneration. @*Materials and Methods@#This study included 208 menisci of 99 patients (59 women and 40 men, median age 52 years old [16–80 years]) who underwent knee MRI with both standard T2 mapping and UTE-T2* mapping sequences. A radiologist reviewed the images and graded meniscal degeneration according to the morphologic criteria on T2-weighted and proton density-weighted sequences. Manually drawn regions of interest were placed along the outline and hyperintensity subregion within the meniscus, and in the same location on midsagittal images of each T2 and UTE-T2* sequence. Meniscal T2 and T2* values (T2m and T2*m) as well as T2 and T2* values of hyperintensity subregions (T2h, T2*h) were calculated. @*Results@#There was a strong correlation between T2m, T2*m, T2h, and T2*h, and morphological grades (correlation coefficient 0.793–0.943, 95% CI). On morphologic analysis, 50, 52, 50, and 56 menisci were graded as 0, 1, 2, and 3, respectively. T2m, T2*m, T2h, and T2*h were found to be significantly different in all the grades and tended to be higher in the more degraded meniscus (p < 0.001 for both). Mean T2m was 10.78 ± 2.91 ms, 15.81 ± 2.99 ms, 20.26 ± 3.19 ms, and 30.80 ± 7.38 ms and mean T2*m was 7.10 ± 1.12 ms, 9.64 ± 1.27 ms, 12.01 ± 1.58 ms, and 18.98 ± 4.67 ms for grades 0, 1, 2, and 3, respectively. Mean T2h was 20.05 ± 3.67 ms, 24.39 ± 4.73 ms, and 38.92 ± 9.49 ms and mean T2*h was 10.94 ± 1.65 ms, 13.67 ± 2.41 ms, and 22.36 ± 5.20 ms for grades 1, 2, and 3, respectively. @*Conclusion@#UTE-T2* mapping was feasible for quantitative evaluation of meniscal degeneration in patients. With a few improvements UTE-T2* mapping is a potential substitute for the standard T2 mapping, with improved efficacy.

Transient postoperative inferior subluxation of the shoulder after surgical stabilization of recurrent anterior dislocation in a patient with myasthenia gravis: a case report

The authors present a case of transient postoperative inferior subluxation of the shoulder after arthroscopic surgical stabilization for recurrent anterior dislocation. The patient was a 61-year-old woman with myasthenia gravis (MG). The first anterior shoulder dislocation occurred because of a fall to the ground. Despite a successful closed reduction, two more dislocations occurred in 3 weeks. Magnetic resonance imaging revealed an anterior labroligamentous periosteal sleeve avulsion (ALPSA) lesion, an engaging Hill-Sachs lesion, and large tears of the supraspinatus and infraspinatus tendons. The patient underwent arthroscopic rotator cuff repair and ALPSA repair with a remplissage procedure. Intraoperatively, no tendency for instability was found; however, a widened glenohumeral joint space and inferior subluxation of the humeral head without functional compromise was observed on the day after surgery and disappeared spontaneously on radiographs 2 weeks later. To the authors’ knowledge, this is the first report documenting the occurrence of transient postoperative inferior subluxation of the shoulder in a patient with MG.

Current Research on the Influence of Statin Treatment on Rotator Cuff Healing

Rotator cuff tears are a condition characterized by damage to the muscles and tendons that connect the scapula and humerus, which are responsible for shoulder rotation and arm lifting. Metabolic factors such as diabetes, thyroid disease, high cholesterol, vitamin D deficiency, obesity, and smoking have been associated with an increased risk of rotator cuff tears. Interestingly, patients with hyperlipidemia, a condition characterized by high levels of cholesterol and other fats in the blood, have been found to have a higher incidence of rotator cuff tears and breakdown of tendon matrix. As a result, statin therapy, which is commonly used to lower cholesterol levels in hyperlipidemia, has been explored as a potential treatment to improve clinical outcomes in rotator cuff tears. However, the results of preclinical and clinical studies on the effects of statins on tendon healing in rotator cuff tears are limited and not well-defined. Moreover, since hyperlipidemia and rotator cuff tears are more prevalent in older individuals, a literature review on the efficacy and safety of statin therapy in this population is needed.

Treated chronic hepatitis B is a good prognostic factor of diffuse large B-cell lymphoma

Background/Aims@#Chronic hepatitis B (CHB) is a risk factor for non-Hodgkin lymphoma (NHL). Our recent study suggested that antiviral treatment may reduce the incidence of NHL in CHB patients. This study compared the prognoses of hepatitis B virus (HBV)-associated diffuse large B-cell lymphoma (DLBCL) patients receiving antiviral treatment and HBV-unassociated DLBCL patients. @*Methods@#This study comprised 928 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at two referral centers in Korea. All patients with CHB received antiviral treatment. Time-to-progression (TTP) and overall survival (OS) were the primary and secondary endpoints, respectively. @*Results@#Among the 928 patients in this study, 82 were hepatitis B surface antigen (HBsAg)-positive (the CHB group) and 846 were HBsAg-negative (the non-CHB group). The median follow-up time was 50.5 months (interquartile range [IQR]=25.6–69.7 months). Multivariable analyses showed longer TTP in the CHB group than the non-CHB group both before inverse probability of treatment weighting (IPTW; adjusted hazard ratio [aHR]=0.49, 95% confidence interval [CI]=0.29–0.82, p=0.007) and after IPTW (aHR=0.42, 95% CI=0.26–0.70, p<0.001). The CHB group also had a longer OS than the non-CHB group both before IPTW (HR=0.55, 95% CI=0.33–0.92, log-rank p=0.02) and after IPTW (HR=0.53, 95% CI=0.32–0.99, log-rank p=0.02). Although liver-related deaths did not occur in the non-CHB group, two deaths occurred in the CHB group due to hepatocellular carcinoma and acute liver failure, respectively. @*Conclusions@#Our findings indicate that HBV-associated DLBCL patients receiving antiviral treatment have significantly longer TTP and OS after R-CHOP treatment than HBV-unassociated DLBCL patients.

Apigetrin Promotes TNFα-Induced Apoptosis, Necroptosis, G2/M Phase Cell Cycle Arrest, and ROS Generation through Inhibition of NF-κB Pathway in Hep3B Liver Cancer Cells.

Apigetrin (7-(ß-D-glucopyranosyloxy)-4',5-dihydroxyflavone), a glycoside bioactive dietary flavonoid derived from Taraxacum officinale and Teucrium gnaphalodes, is known to possess anticancer, antioxidant, and anti-inflammatory effects on numerous cancers. In the present study, we examined the effect of apigetrin in Hep3B hepatocellular cancer cell line (HCC). Apigetrin inhibited cell growth and proliferation of Hep3B cells, as confirmed by MTT and colony formation assay. We used apigetrin at concentrations of 0, 50, and 100 µM for later experiments. Of these concentrations, 100 µM of apigetrin showed a significant effect on cell inhibition. In apigetrin-treated Hep3B cells, cell cycle arrest occurred at the G2/M phase. Apoptosis and necroptosis of Hep3B cells treated with apigetrin were confirmed by Annexin V/propidium iodide (PI) staining and flow cytometry results. Morphological observation through 4',6-diamidino-2-phenylindole (DAPI) staining showed intense blue fluorescence representing chromatin condensation. Hematoxylin staining showed necroptotic features such as formation of vacuoles and swelling of organelles. Apigetrin increased reactive oxygen species (ROS) levels in cells, based on fluorescence imaging. Furthermore, the underlying mechanism involved in the apoptosis and necroptosis was elucidated through western blotting. Apigetrin up-regulated TNFα, but down-regulated phosphorylation of p-p65, and IκB. Apigetrin inhibited the expression of Bcl-xl but increased Bax levels. Up-regulation of cleaved PARP and cleaved caspase 3 confirmed the induction of apoptosis in apigetrin-treated Hep3B cells. Additionally, necroptosis markers RIP3, p-RIP3, and p-MLKL were significantly elevated by apigetrin dose-dependently, suggesting necroptotic cell death. Taken together, our findings strongly imply that apigetrin can induce apoptosis and necroptosis of Hep3B hepatocellular cancer cells. Thus, apigetrin as a natural compound might have potential for treating liver cancer.

Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.

Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals.