A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial-mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK-AKT-GSK3ß pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance. IMPLICATIONS: This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.

Functional characterization of archaeal homologs of human nuclear RNase P proteins Rpp21 and Rpp29 provides insights into the molecular basis of their cooperativity in catalysis.

Ribonuclease P (RNase P) is a ribonucleoprotein that catalyzes the processing of 5' leader sequences of precursor tRNAs (pre-tRNA). RNase P proteins PhoRpp21 and PhoRpp29 in the hyperthermophilic archaeon Pyrococcus horikoshii, homologs of human nuclear RNase P proteins Rpp21 and Rpp29 respectively, fold into a heterodimeric structure and synergistically function in the activation of the specificity domain (S-domain) in RNase P RNA (PhopRNA). To elucidate the molecular basis for their cooperativity, we first analyzed binding ability to PhopRNA using a pull-down assay. The result showed that PhoRpp21 is able to bind to PhopRNA in the absence of PhoRpp29, whereas PhoRpp29 alone has reduced affinity to PhopRNA, suggesting that PhoRpp21 primarily functions as a binding element for PhopRNA in the PhoRpp21-PhoRpp29 complex. Mutational analyses suggested that although individual positively charged clusters contribute little to the PhopRNA binding, Lys53, Lys54, and Lys56 at the N-terminal helix (α2) in PhoRpp21 and 10 C-terminal residues in PhoRpp29 are essential for PhopRNA activation. Moreover, deletion of a single stranded loop linking P11 and P12 helices in the PhopRNA S-domain impaired the PhoRpp21-PhoRpp29 complex binding to PhopRNA. Collectively, the present results suggest that PhoRpp21 binds the loop between P11 and P12 helices through overall positively charged clusters on the surface of the complex and serves as a scaffold for PhoRpp29 to optimize structural conformation of its N-terminal helix (α2) in PhoRpp21, as well as C-terminal residues in PhoRpp29, for RNase P activity.

Direct reimplantation as an alternative approach for treatment of anomalous aortic origin of the right coronary artery.

Anomalous aortic origin of the coronary artery (AAOCA) is a rare cardiac anomaly associated with myocardial ischemia, infarction, and even sudden death. We report 2 patients presenting with AAOCA of the right coronary artery originating from the left coronary sinus with an initial intramural course. In both patients, we performed uncomplicated direct reimplantation of the right coronary artery into the right coronary sinus. For this purpose, the right coronary artery was dissected from the transmural emersion point out of the aortic wall, subsequently as proximal as possible transected and directly reimplanted into the right coronary sinus. In both cases, the postoperative course was uneventful, and cardiac computed tomography confirmed excellent postoperative results after 1 year of follow-up. This technique is a convenient and easily performable approach, characterized by short cross-clamp times and avoidance of aortotomy, and thus is an excellent alternative strategy.

Characteristics and treatment strategies of mitral regurgitation associated with undifferentiated papillary muscle.

PURPOSE: In this report we review our experience of operations on mitral regurgitation associated with abnormal papillary muscles/chordae tendineae of the mitral valves and discussed the clinical characteristics, operative findings, and treatment strategies. METHODS: Undifferentiated papillary muscle was defined as a hypoplastic chordae tendineae with anomalous formation of papillary muscles attached to the mitral valves directly. Consecutive 87 patients undergoing surgery for mitral regurgitation at our institution were reviewed and 6 of them had undifferentiated papillary muscle. RESULTS: The underlying mechanism of regurgitation was prolapse at the center of the anterior leaflet in 3 cases and tethering, a wide area of myxomatous degeneration, and annular dilatation in one case, respectively. Five patients underwent mitral valve plasty and 1 patient received replacement. Anomalous formation of chordae tendineae was corrected by resection and suture with transplantation at the tip of the leaflet to which abnormal chordae were attached in 2 cases, while resection and suture with chordal shortening was performed in 1 case, and chordal reconstruction using artificial chordae was employed in 2 cases. There was no operative death, and postoperative echocardiography showed no residual regurgitation in any of the cases. CONCLUSIONS: Mitral regurgitation associated with undifferentiated papillary muscle resulted from prolapse or tethering and impaired flexibility of leaflets. It was possible to successfully treat the patients by mitral valve plasty unless complex congenital cardiac malformation coexisted. Detailed examinations of attached papillary muscle by echocardiography and intraoperative inspection are necessary and surgical techniques should be selected appropriately in each case.

A rapid structural degeneration of a porcine mitral valve.

A 73-year-old woman underwent both mitral and aortic valve replacements with porcine heart valve prostheses because of severe mitral regurgitation and severe aortic regurgitation. Ten months after surgery, maximal flow velocity of the aortic valve reached 4.6 m/sec and moderate mitral regurgitation was detected. Repeated mitral and aortic valve replacements with mechanical heart valves were performed. The excised mitral valve showed thinning of the 3 cusps, and 2 of them were perforated. There was pannus overgrowth on the flow surface of the porcine aortic valve. Histologic examination of the excised mitral valve revealed marked inflammatory changes with macrophages.

Survival and quality of life of octogenarians who underwent mechanical valve replacement at a younger age.

PURPOSE: Mechanical valve replacement is associated with complications, however, there is little information on the quality of life (QOL) of octogenarians who had undergone mechanical valve replacement at a relatively younger age. We examined survival, valve-related events, and the QOL of octogenarians who had undergone mechanical valve replacement. METHODS: A total of 56 octogenarians who underwent mechanical valve replacement between 1969 and 1997 (age at the time of surgery, 65.6 ± 6.7 years), completed a questionnaire on survival, valve-related events, and QOL (basic activities of daily living, instrumental activities of daily living, mental health). RESULTS: The mean follow-up was 12.4 ± 6.6 years, and the cumulative follow-up period was 642.4 patient-years. Six valve-related deaths (0.9%/patient-year) were registered during the follow-up. Furthermore, 11 valve-related events (1.8%/patient-year) were recorded. The mean age of the 21 survivors was 82.9 ± 1.8 years, and 19 of the survivors lived at home. Their QOL was excellent. CONCLUSION: The valve-related deaths and events in octogenarians who had previously undergone mechanical valve replacement at a younger age were within acceptable limits. The QOL was similar to that of octogenarians described in previous studies.

Systolic anterior motion after mitral valve repair: predicting factors and management.

PURPOSE: The aim of this study was to determine the mechanism of systolic anterior motion (SAM) after mitral valve (MV) repair by analyzing the clinical data of patients with MV repair. METHODS: A total of 104 MV repairs were performed for patients with isolated degenerative posterior leaflet prolapse. Eight patients (7.7%) developed SAM with severe mitral regurgitation. We compared the preoperative and intraoperative findings of the two groups (8 patients in the SAM group, 96 in the non-SAM group) and reported the clinical courses of the SAM patients. RESULTS: Preoperative left ventricular end-diastolic and end-systolic diameters were significantly smaller and the preoperative left ventricular ejection fraction was significantly greater in the SAM group than in the non-SAM group. The number of patients with a sigmoid septum and the number with anterior leaflet-septal contact (LSC) during diastole were significantly larger in the SAM group. Incidence of billowing posterior leaflet, prolapsed segments, and operative techniques were comparable for the two groups. SAM improved with correction of hemodynamic status in four patients. In four other patients secondary cardiopulmonary bypass was required to resolve SAM. SAM resolved with additional repairs in two patients, whereas the other two required MV replacement. Of the six patients in whom conservative treatment or re-repair was successful, one had recurrent SAM 3 months after surgery. CONCLUSION: The sigmoid septum and LSC may predict SAM after MV repair. A strict follow-up is imperative for patients with persistent or recurrent SAM.

'Clover technique' for tricuspid regurgitation due to pacemaker lead.

Whilst tricuspid regurgitation (TR) secondary to severe mitral regurgitation (MR) is a common problem, organic TR caused by pacemaker leads is also frequently encountered. In a 63-year-old patient who developed TR attributable to both MR and a pacemaker lead inserted 12 years previously, the regurgitation could not be controlled satisfactorily using a normal ring annuloplasty. Consequently, the 'clover technique' provided an efficient correction to the TR.

Active infective endocarditis after mitral valve repair.

A 22-year-old man was diagnosed with active mitral endocarditis 14 months after mitral valve repair. The responsible organism was methicillin-resistant Staphylococcus epidermidis. Transthoracic echocardiography showed an 8-mm patch of vegetation adhering to the anterior part of the artificial ring. Although antibiotics (piperacillin, minocycline, imipenem/cilastatin, and ampicillin) were administered, the vegetation grew to 30 mm. Reoperation was performed 35 days after the diagnosis. Before surgery, there was mild mitral regurgitation without congestive heart failure. Re-repair was performed by removing the vegetation and the artificial ring, and mattress sutures repaired the circumferential sulcus formed by the artificial ring. Teicoplanin and minocycline were administered for 6 weeks. At 20 months, infective endocarditis was absent. Residual mitral regurgitation has been consistently mild. Although active mitral endocarditis after mitral valve repair is rare, prompt reoperation should be considered if the responsible organism is drug-resistant and infection spreads to the artificial ring.

A rare case of infective endocarditis complicated by Trichosporon asahii fungemia treated by surgery.

The patient was a 58-year-old male. He consulted our hospital because of weight loss and fever. Computed tomography (CT) revealed renal infarction. Nine days after admission, CT showed hemorrhagic cerebral infarction in the right frontal lobe. A blood culture revealed streptococcus oralis, and echocardiography revealed vegetation in the mitral and aortic valves, suggesting infective endocarditis (IE). Fever (39 degrees C or higher) was noted 23 days after admission. A blood culture revealed Trichosporon asahii (T. asahii), suggesting T. asahii fungemia. An intravenous drip of fluconazole at 400 mg/day was initiated, and two-valve replacement was performed 34 days after admission. Following surgery, the patient became negative for beta-D glucan and was discharged 85 days after admission. We report the present case of IE complicated by T. asahii fungemia, which is rare in patients other than malignant blood disease or tumor patients, showing a poor prognosis in which survival was achieved by surgery.

Surgical repair for a coronary-pulmonary artery fistula with a saccular aneurysm of the coronary artery.

The patient, a 69-year-old woman, had been diagnosed with a heart murmur. A chest X-ray at a local clinic had shown an abnormal shadow. Since CT revealed a 3-cm-diameter mass close to the pulmonary artery, we performed a coronary angiography and diagnosed her as having a coronary artery aneurysm associated with a coronary-pulmonary artery fistula. We incised the aneurysm under cardiac arrest, the wall of which had three openings that were suture closed from the inside and outside. The coronary-pulmonary artery fistula was suture closed. A postoperative angiography confirmed the disappearance of the coronary artery aneurysm and the abnormal blood vessels. The patient had an uneventful postoperative course and was discharged on postoperative day 15. We report a rare case of coronary-pulmonary artery fistula with a coronary artery aneurysm for which surgery was followed by an uneventful postoperative course.

Triple-valve treatment for prosthetic valve endocarditis occurring 20 years after implantation of a Carpentier-Edwards pericardial bioprosthesis in the aortic valve.

A 68-year-old woman had undergone aortic valve replacement and open commissurotomy 20 years previously. At the beginning of 2008, fever, cold, and heart failure symptoms were noted. On blood culture, Streptococcus oralis was detected three times. Surgery was performed under a diagnoses of prosthetic valve endocarditis in the aortic valve, mitral stenosis and insufficiency, and tricuspid insufficiency. Techniques consisted of additional aortic valve replacement, mitral valve replacement, and tricuspid annuloplasty. Vegetation was macroscopically and pathologically observed in the extirpated Carpentier-Edwards pericardial bioprosthesis that had been placed in the aortic valve. There was no postoperative recurrent inflammatory response. The patient was discharged 32 days after surgery.

The efficacy of human atrial natriuretic peptide in patients with renal dysfunction undergoing cardiac surgery.

OBJECTIVES: The purpose of this study was to investigate the efficacy of carperitide (human atrial natriuretic peptide [h-ANP]) in perioperative management in patients with renal dysfunction, especially its kidney-protecting effects. PATIENTS AND METHODS: The subjects were 18 patients who underwent elective cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative serum creatinine (Cr) level of 1.2 mg/dl or more. The subjects were prospectively assigned to 2 groups: an h-ANP-treated group (Group H, n = 10) and a non-h-ANP-treated group (Group N, n = 8). At the beginning of surgery, h-ANP administration was initiated and continued for 5 days or more. The central dose was 0.02 microg/kg/min. The primary end point included the serum Cr level and creatinine clearance (Ccr). RESULTS: In Group H, Cr level significantly decreased after surgery compared to the preoperative level. The Ccr values were significantly higher 2 and 3 days after surgery than the preoperative values. And the intraoperative urine volume significantly increased. In Group H, an increase in urinary N-acetyl-beta-D-glucosaminidase (NAG) level the day after surgery was significantly inhibited in comparison with Group N. CONCLUSION: The results of this study suggest that in patients with renal dysfunction before cardiac surgery, continuous low-dose h-ANP therapy maintains renal function, preventing its deterioration.

A case of Takotsubo cardiomyopathy complicated by ventricular septal perforation.

The patient was a 73-year-old female who developed chest pain and dyspnea 16 days after her husband passed away. ST segment elevation was detected on V2-5 by electrocardiography and emergency coronary arteriography was done for suspected acute myocardial infarction. No coronary arterial stenosis was present and ventricular septal perforation and takotsubo cardiomyopathy were diagnosed by left ventriculography. The perforation was closed and the patient was discharged 23 days after surgery. This patient had a very rare case of takotsubo cardiomyopathy, which was complicated by ventricular septal perforation and was saved by surgical treatment.

Comparison of the effects of aortic valve replacement using 19-mm Carpentier-Edwards Perimount bioprosthesis and 19-mm Medtronic Mosaic bioprosthesis.

OBJECTIVE: Short (< or =3 months)- and middle (> or =4 months)-term results of aortic valve replacement (AVR) using 19-mm Carpentier-Edwards Perimount (CEP) bioprosthetic valves and 19-mm Medtronic Mosaic (MM) bioprosthetic valves in patients with small aortic annulus were compared. PATIENTS AND METHODS: At our facility, AVR was performed using bioprostheses in 110 patients from April 1999 to March 2006. Of these patients, 40 were treated using 19-mm CEP (Group C), and 9 using 19-mm MM (Group M). Evaluation by inquiry, physical examination, and echocardiography was performed before, a short term after, and a middle term after surgery, and the effects of AVR were compared. RESULTS: The New York Heart Association (NYHA) functional class grade showed improvements in both groups. The aortic valve peak pressure gradient was 29.8 +/- 10.1 mmHg in Group C and 53.8 +/- 17.3 mmHg in Group M, being higher in Group M, a middle term after surgery. However, the left ventricular mass index (LVMI) showed improvements in both groups compared with the values before surgery, and the left ventricular ejection fraction (LVEF) was maintained. During the middle term after surgery, the frequency of cardiac events showed no significant difference between the two groups. CONCLUSIONS: In the patients treated with 19-mm MM, the aortic valve peak pressure gradient was higher than in those treated with 19-mm CEP, but acceptable improvements in the LVMI, maintenance of the LVEF, and avoidance of cardiac events were observed in both groups.

Mitral valve repair in patients with infective endocarditis.

BACKGROUND: The goal of the present study was to investigate the feasibility of mitral valvle repair in patients with infective endocarditis (IE). METHODS AND RESULTS: Twenty-one patients who had undergone mitral valve surgery for IE were reviewed. Valve repair was performed in 8 patients with active and in 6 patients with healed endocarditis: 6 of these 14 patients were New York Heart Association (NYHA) functional class III or IV preoperatively. Valve replacement was performed in 5 patients with active endocarditis and in 2 with healed endocarditis: 6 of these 7 patients were NYHA functional class III or IV preoperatively. Repair techniques included annuloplasty (n=13), resection-suture (n=13), chordal transfer (n=2), and closure of the perforation (n=3). In the valve replacement group, 6 patients required concomitant aortic valve replacement. In the valve repair group, 1 patient died and 1 patient required reoperation for recurrent mitral regurgitation. Postoperative echocardiography demonstrated no (n=8) or mild (n=4) mitral regurgitation at the last follow-up examination. In the valve replacement group, 1 patient died and 1 patient required reoperation because of a paravalvular leak. No cases of recurrent infection occurred in either group. CONCLUSIONS: Mitral valve repair in patients with IE is feasible and has low morbidity.

Combined aortic and mitral valve repair in active infective endocarditis.

We describe a case of successful combined repair of the aortic and mitral valves for an indication of active infective endocarditis involving both valves. Mitral valve repair was achieved by vegetation debridement, fixation of the anterior mitral commissure, resection and suturing of the posterior mitral leaflet, and posterior annuloplasty with autologous pericardium. Aortic valve repair was achieved by vegetectomy and commissural plication. Postoperative clinical course was without signs of recurrent infection, and echocardiogram demonstrated mitral valve competence with trivial aortic regurgitation. We concluded that simultaneous valve repair is a viable option in the context of active endocarditis.

Risk factors of posterior pericardial annuloplasty for isolated posterior leaflet prolapse.

BACKGROUND: Posterior autologous pericardial annuloplasty is an option in mitral valve repair. However, the durability of posterior pericardial annuloplasty remains controversial. METHODS: From June 1999 to July 2004, 49 patients (18 male and 31 female; mean age, 64 +/- 12 years) with isolated posterior leaflet prolapse received posterior autologous pericardial annuloplasty. Transthoracic echocardiographic examination before the operation, at the time of discharge, and then annually was performed and analyzed. RESULTS: There was no incidence of in-hospital or late death. Only 1 patient (2.1%) required reoperation. In terms of recurrent mitral regurgitation, 31 patients (64.6%) exhibited grade 0 mitral regurgitation, 7 patients (14.6%) exhibited grade 1, and 9 patients (18.8%) exhibited grade 2, whereas only 1 patient (2.0%) exhibited more than grade 3. In terms of predicting postoperative recurrence of significant mitral regurgitation (> or =grade 2), multivariate Cox analysis demonstrated that marked left atrial dilatation and high fractional shortening were independent risk factors. In 8 of 10 patients significant mitral regurgitation recurred after discharge. In terms of left atrial dimension, no significant reduction was observed in the postdischarge recurrent group, and there was a significant difference of left atrial dimension between the postdischarge recurrent group and the nonrecurrent group at the time of discharge. CONCLUSIONS: The merits of mitral valve repair using posterior autologous pericardial annuloplasty are attractive. However, its use should be limited in selected patients with isolated posterior leaflet disease, nonenlarged atria, and non-high fractional shortening to maintain the durability of the mitral valve repair.

Thrombus removal with a temporary vena caval filter in patients with acute proximal deep vein thrombosis.

Between September 1999 and January 2001 we performed thrombus removal with the use of a temporary vena caval filter in 11 patients who had acute iliofemoral venous thrombosis. To facilitate thrombus removal, 5 patients initially received catheter-directed thrombolytic therapy (thrombolysis group), and the other 6 received surgical thrombectomy (thrombectomy group). Residual thrombus was confirmed after initial catheter-directed thrombolysis in all patients in the thrombolysis group, and thrombolysis was continued in the ward. Bleeding complications subsequently occurred in 2 patients. In the thrombectomy group, 1 patient had residual thrombus just below the temporary filter, and a permanent vena caval filter was deployed for removal. Another patient had a residual thrombus in the superficial femoral vein, and rethrombectomy was performed. One patient in the thrombectomy group died of pneumonia. All other patients were discharged. There were no deaths from pulmonary thromboembolism in this series. Post-thrombotic syndrome occurred in 2 of the 5 patients in the thrombolysis group (40%) and in 3 of the 6 patients (50%) in the thrombectomy group. We conclude that a temporary vena caval filter is useful for the management of acute proximal deep vein thrombosis, especially when aggressive treatment is required.

Biocompatibility of poly2methoxyethylacrylate coating for cardiopulmonary bypass.

The systemic inflammatory response to cardiopulmonary bypass (CPB) may contribute to the development of postoperative complications. Heparin-coated circuits and poly2methoxyethylacrylate (PMEA)-coated circuits have been developed to reduce the risk of such complications. We compared the biocompatibility of these circuits. Twelve patients scheduled to undergo elective coronary artery bypass grafting (CABG) with CPB were assigned to CPB with a PMEA-coated circuit (PMEA-coated group, n=6) or a heparin-coated circuit (heparin-coated group, n=6). The plasma concentrations of the following inflammatory markers were measured before CPB and just after, 4 hours after, and 24 hours after the termination of CPB: cytokines (interleukin [IL]-6, IL-8, IL-10), complement factor (C3a), polymorphonuclear elastase (PMNE), and coagulofibrinolytic factors (thrombin-antithrombin III complex [TAT], D-dimer). Postoperative clinical response was evaluated on the basis of respiratory index, blood loss, and the postoperative and preoperative body-weight percent ratio. There were no significant differences between the groups in the plasma concentrations of IL-6, IL-10, C3a, PMNE, TAT, or D-dimer. Plasma IL-8 concentrations were below the assay detection limits at all time points in both groups. Clinical variables did not differ significantly between the groups. In conclusion, PMEA-coated CPB circuits are as biocompatible as heparin-coated CPB circuits and prevent postoperative organ dysfunction in patients undergoing elective CABG with CPB.