Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce ß-Amyloid Accumulation: The Potential Mechanism Underlying Augmentation of ß-Amyloid Pathology by Type 2 Diabetes Mellitus.

The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of ß-amyloid (Aß) protein, a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aß pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aß pathology. Herein, we demonstrate that cholesterol metabolism-related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aß in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aß pathology in T2DM-affected brains, which, in turn, may increase the risk for developing AD.

Hagedorn instability in dimensionally reduced large-N gauge theories as Gregory-Laflamme and Rayleigh-Plateau instabilities.

It is expected that the Gregory-Laflamme (GL) instability in the black string in gravity is related to the Rayleigh-Plateau instability in fluid mechanics. Especially, the orders of the phase transitions associated with these instabilities depend on the number of the transverse space dimensions, and they are of first and second order below and above the critical dimension. Through the gauge-gravity correspondence, the GL instability is conjectured to be thermodynamically related to the Hagedorn instability in large-N gauge theories, and it leads to a prediction that the order of the confinement-deconfinement transition associated with the Hagedorn instability may depend on the transverse dimension. We test this conjecture in the D-dimensional bosonic D0-brane model using numerical simulation and the 1/D expansion, and confirm the expected D dependence.

Multiple pleural nodules diagnosed as IgG4-related disease: a case report.

BACKGROUND: Immunoglobulin G4 (IgG4)-related diseases are characterized by abnormal IgG4 levels, swelling, and marked infiltration and fibrosis of the lymphocytes and IgG4-positive plasma cells, causing hypertrophic lesions or nodules. The cause is currently not well understood. IgG4-related diseases involving lesions limited to the pleura are extremely rare. Herein, we report an IgG4-related disease presenting with multiple pleural nodules confirmed by thoracoscopic surgical biopsy. CASE PRESENTATION: A 74 year-old man was referred to our department for definitive diagnosis of multiple pleural nodules after 1 year of follow-up. Computed tomography of the chest revealed multiple pleural nodules, while 2-deoxy-2-( 18F)-fluorodeoxyglucose positron emission tomography imaging exhibited tracer accumulation in the nodules. A thoracoscopic surgical biopsy was performed. Histopathological examination revealed hyalinized fibrous tissue with a high degree of plasma cell-based inflammatory cell infiltration. Immunohistochemically, IgG4-positive cells were conspicuous, accounting for 70.5% of the plasma cells. The postoperative serum IgG4 concentration was 289 mg/dL. We diagnosed the patient with an IgG4-related disease with multiple pleural nodules. The postoperative course was good, and the patient is currently being followed up. CONCLUSION: IgG4-related disease should be considered in cases presenting with multiple pleural nodules.

Anterior mediastinal ectopic pancreatic cyst incidentally identified by pericarditis: a case report.

Ectopic pancreas often occurs in the gastrointestinal tract. However, the identification of a mediastinal ectopic pancreas is extremely rare. Herein, we report a case of ectopic pancreas of the anterior mediastinum, which was incidentally detected during treatment for pericarditis with widespread ST elevation on electrocardiogram. A 40-year-old woman complaining of chest pain was admitted with suspected pericarditis. A closer examination revealed a cystic mass in the anterior mediastinum, which was diagnosed as a pancreatic cyst of the anterior mediastinum on thoracoscopic tumor resection.

Venous hemangioma of the anterior mediastinum.

We report a rare case of venous hemangioma (VH) of the anterior mediastinum in a 56-year-old man admitted to our hospital because of hematemesis. Systemic examinations were performed and chest computer tomography (CT) revealed a 1.5-cm sized small nodule with contrast enhancement in the thymus. Both CT and magnetic resonance imaging (MRI) suggested a solid tumor such as a thymoma or neurogenic tumor rather than a vascular neoplasm. A partial thymectomy including this nodule by video-assisted thoracic surgery (VATS) was performed. Histological examination showed VH. There was no recurrence with no further treatment.

Hoarseness as an Initial Symptom of Thymic Carcinoma: A Case Report.

A 65-year-old man was referred to our hospital for evaluation of hoarseness and deteriorating voice. Computed tomography revealed an area of poor contrast enhancement in soft tissue (size, 30 mm) in the inferior pole of the thyroid gland, extending to the upper margin of the sternum. No infiltration of blood vessels or bones, and no significant swelling of neck lymph nodes, was observed. These findings suggested a diagnosis of thymoma, thymic carcinoma, or thyroid tumor. Surgery was performed via median sternotomy, and complete thymectomy and tumor excision accompanied by partial thyroidectomy were performed. Histopathological examination revealed atypical polygonal tumor cells in a sheet-like arrangement, which formed a solid proliferative focus, and squamous cell carcinoma with infiltrative growth was diagnosed. Postoperatively, radiotherapy (60 Gy) was administered to the superior mediastinum. The patient is alive 22 months after surgery, without recurrence.

Single-port video-assisted thoracic surgery for early lung cancer: initial experience in Japan.

BACKGROUND: Single-port video-assisted thoracic surgery (SPVATS) emerged several years ago as a new, minimally invasive surgery for diseases in the field of respiratory surgery, and is increasingly becoming a subject of interest for some thoracic surgeons in Europe and Asia. However, the adoption rate of this procedure in the United States and Japan remains low. We herein reviewed our experience of SPVATS for early lung cancer in our center, and evaluated the safety and minimal invasiveness of this technique. METHODS: We retrospectively analyzed patients who had undergone SPVATS for pathological stage I lung cancer in Nippon Medical School Chiba Hokusoh Hospital between September 2012 and October 2015. In SPVATS, an approximately 4-cm incision was made at the 4(th) or 5(th) intercostal space between the anterior and posterior axillary lines. A rib spreader was not used at the incision site, and surgical manipulation was performed very carefully in order to avoid contact between surgical instruments and the intercostal nerves. The same surgeon performed surgery on all patients, and analyzed laboratory data before and after surgery. RESULTS: Eighty-four patients underwent anatomical lung resection for postoperative pathological stage I lung cancer. The mean wound length was 4.2 cm. Eighty-four patients underwent lobectomy and segmentectomy, respectively. The mean preoperative forced expiratory volume in 1 second (FEV1%) was 1.85%±0.36%. Our patients consisted of 49 men (58.3%) and 35 women (41.7%), with 64, 18, 1, and 1 having adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, and small-cell lung cancer, respectively. The mean operative time was 175±21 min, operative blood loss 92±18 mL, and duration of drain placement 1.9±0.6 days. The duration of the postoperative hospital stay was 7.1±1.7 days, numeric rating scale (NRS) 1 week after surgery 2.8±0.6, and occurrence rate of allodynia 1 month after surgery 10.7%. No patient developed serious complications, and no deaths occurred within 30 days of surgery. Two patients (2.4%) were converted to open thoracotomy. CONCLUSIONS: SPVATS is a safe and feasible technique, and is promising for next-generation thoracoscopic surgery. It may also reduce postoperative wound pain and contribute to improvements in the activities of daily living of patients.

Single-incision thoracoscopic surgery and conventional video-assisted thoracoscopic surgery: a retrospective comparative study of perioperative clinical outcomes†.

OBJECTIVES: To assess the feasibility, safety and postoperative wound pain of single-incision thoracoscopic surgery (SITS) for Stage I lung cancer in patients who had previously undergone surgery compared with conventional video-assisted thoracoscopic surgery (c-VATS). METHODS: Lobectomy by SITS (60) and c-VATS (20) was performed for Stage I lung cancer between 2011 and 2014. In SITS, an ∼ 5-cm small incision was placed at the fourth or fifth intercostal space from the anterior to posterior axillary line. C-VATS was performed via three or four ports using trocars only. The evaluation items were general operative outcomes, pain stress using the Numeric Rating scale (NRS) on postoperative days 3, 7 and 30, and some pathological symptoms related to the neuropathic wound pain through the operative course. The number of days of use of analgesic agents was also evaluated for 1 month after surgery. RESULTS: SITS showed similar perioperative outcomes (postoperative hospital stay, blood loss, surgical time, drainage duration, creatine phosphokinase (CPKmax), creactive protein (CRPmax) and frequency of postoperative complications) to those of c-VATS. Additionally, the average NRS in SITS decreased on postoperative days 7 and 30 (Day 7: 2.4 ± 0.4 vs 4.2 ± 0.3, P = 0.041, Day 30: 1.7 ± 0.4 vs 3.3 ± 0.3, P = 0.038) and the number of days analgesic agents were administered was also reduced (SITS: 8.1 ± 0.9 vs c-VATS 13.1 ± 1.2 days, P = 0.045). The frequency of allodynia, hyperalgesia, hypaesthesia and numbness was significantly reduced in the SITS group. CONCLUSIONS: Although conclusive evidence has not yet been obtained, SITS is more minimally invasive in regard to postoperative wound pain compared with c-VATS. This procedure should be considered as a treatment option for early-stage lung cancer.

Primary pulmonary mucosa-associated lymphoid tissue lymphoma combined with idiopathic thrombocytopenic purpura and amyloidoma in the lung.

Three abnormal shadows were detected in the right lung on chest X-ray films and computed tomography in a 75-year-old woman during follow-up for idiopathic thrombocytopenic purpura. Because a definitive diagnosis was not obtained through general examinations, exploratory thoracotomy was performed for diagnosis and treatment. The main lesion in the right middle lobe was diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma according to histopathological findings, cytogenic studies and reverse transcriptase-polymerase chain reaction analysis, and nodular lesions in S(3) and S(7) were diagnosed with Congo-red staining as local deposition of amyloid. The patient had no recurrence of the MALT lymphoma of the lung or other organs for 4 years after surgery. To our knowledge, this is the first reported case of primary pulmonary MALT lymphoma combined with idiopathic thrombocytopenic purpura/lung amyloidoma.

Eph/ephrin reverse signalling induces axonal retraction through RhoA/ROCK pathway.

Eph/ephrin signalling plays essential roles in various tissue developments, such as axon guidance, angiogenesis and tissue separation. Interaction between Ephs and ephrins upon cell-cell contact results in forward (towards Eph-expressing cells) and reverse (towards ephrin-expressing cells) signalling. Although the molecular mechanisms downstream of Eph/ephrin forward signalling have been extensively studied, the functions and intracellular molecular mechanisms of Eph/ephrin reverse signalling are not fully understood. Rho GTPases are key regulators of the actin cytoskeleton to regulate cell morphology. In this study, we revealed that stimulation with the extracellular domain of EphB2 to activate Eph/ephrin reverse signalling induced axonal retraction in hippocampal neurons. The reduction of axonal length and branching by Eph/ephrin reverse signalling was blocked by inhibition of RhoA or Rho-associated coiled-coil-containing protein kinase (ROCK). These results suggest that Eph/ephrin reverse signalling negatively regulates axonal outgrowth and branching through RhoA/ROCK pathway in hippocampal neurons.

Covering the staple line with a polyglycolic acid sheet after bullectomy for primary spontaneous pneumothorax prevents postoperative recurrent pneumothorax.

BACKGROUND: Postoperative recurrent pneumothorax (PORP) can arise after surgery for primary spontaneous pneumothorax (PSP) that is recurrent or involves prolonged air leakage. In this study, which included 265 patients (279 cases) with PSP who underwent surgery at our department, the percentage of patients that did not experience PORP was compared between a group that underwent bullectomy alone (group A) and a group in which the staple line and the surrounding visceral pleura were covered with a PGA sheet after bullectomy (group B) in order to study the utility of PGA sheets for preventing PORP. METHODS: Among the patients with PSP who underwent surgery, the cases of 92 patients (98 cases) from Group A and 173 patients (181 cases) from Group B were reviewed retrospectively. The incidence rates of PORP in these two groups were statistically analyzed in addition to the associations between PORP and age, gender, the affected side, height, body weight, height/weight ratio, smoking habits, or the surgical procedure. RESULTS: In total, 96.7% of the patients in group B did not suffer PORP, which was significantly higher than the equivalent figure for group A (83.7%, log-rank test: P=0.0003). Moreover, among the examined parameters, only covering the staple line with a PGA sheet was found to be an independent prognostic factor (Cox regression: P=0.0003; HR =0.212; 95% CI, 0.082-0.547). CONCLUSIONS: It was revealed that when bullectomy is performed in patients with PSP, wide coverage of the staple line and the surrounding visceral pleura with a PGA sheet significantly reduces the risk of PORP.

Prognostic significance of PIK3CA and SOX2 in Asian patients with lung squamous cell carcinoma.

The recent development of human genome studies has demonstrated the possibility of alteration of several genes as oncogenic driver mutations of lung squamous cell carcinoma (SQCC). FGFR1, PIK3CA and SOX2 genes have been recognized as candidate driver genes of SQCC. The aim of the present study was to evaluate FGFR1, PIK3CA and SOX2 protein expression in SQCC and determine whether the expression of these can be used as prognostic biomarkers. We evaluated the relationships between FGFR1, PIK3CA and SOX2 expression by immunohistochemical analysis and overall survival in lung SQCC patients with stage I-III that originated from China, United States and Japan. FGFR1-positive, PIK3CA-negative and SOX2-positive staining each showed trends toward better survival, although the differences were not statistically significant in a Chinese cohort of 57 patients. Patients with PIK3CA-negative and SOX2-positive staining (PIK3CA(-)/SOX2(+)) showed better prognosis compared with those with PIK3CA-positive or SOX2-negative staining in the Chinese cohort (p=0.04). The robustness of PIK3CA(-)/SOX2(+) classification as having prognostic significance was validated in an independent set of 66 Japanese cohort patients (p=0.007). Japanese SQCC patients with stage I were evaluated separately and PIK3CA(-)/SOX2(+) cases had significantly better survival than the group with PIK3CA-positive or SOX2-negative status (p=0.03). In univariate and multivariable Cox proportional hazards models of Asian stage I patients, the PIK3CA(-)/SOX2(+) classification was statistically significantly associated with survival and was an independent prognostic factor. Classification by PIK3CA and SOX2 protein expression is useful for predicting the prognosis of Asian patients with lung SQCC with stage I.

Identification of pathological and normal parathyroid tissue by fluorescent labeling with 5-aminolevulinic acid during endocrine neck surgery.

BACKGROUND: When performing parathyroid or thyroid surgery, surgeons must distinguish parathyroid tissue from the surrounding thyroid tissue, to preserve healthy parathyroid tissue while excising diseased thyroid tissue or to completely remove pathological parathyroid lesions. Here, we explored the feasibility of labeling the parathyroid glands for easy identification by administering 5-aminolevulinic acid (5-ALA) orally to patients undergoing endocrine neck surgery, because 5-ALA accumulates in the parathyroid and has a fluorescent metabolite, protoporphyrin IX. METHODS: Twenty-nine patients about to undergo endocrine (parathyroid or thyroid gland) neck surgery were orally given 5-ALA, a nontoxic substance that occurs naturally in the human body and has no known major side effects. During surgery, we used blue light to excite protoporphyrin IX, the fluorescent metabolite of 5-ALA, and viewed the resulting bright red fluorescence through an optical filter. RESULTS: In the majority of the patients, the parathyroid glands were defined by a clear fluorescence. In 23 patients with pathological parathyroid tissue, the fluorescence enabled us to identify and completely remove diseased parathyroid tissue. In 3 patients with thyroid disease, we were able to easily remove diseased thyroid tissue, and an accidentally removed parathyroid gland was autotransplanted during surgery. CONCLUSIONS: In all but a few cases, 5-ALA clearly labeled parathyroid tissue, allowing for its clean removal or preservation according to the purpose of the surgery. This simple, benign technique is extremely useful for identifying parathyroid tissue, whether pathological or normal, during endocrine neck surgery.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha.

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.

Mature teratoma of the posterior mediastinum: report of a case.

Mediastinal teratoma generally arises in the anterior mediastinum. Posterior mediastinal teratomas have been rarely reported to date, especially in adults. We report a case of posterior mediastinal teratoma in a 57-year-old woman. The pre-operative diagnostic work-up revealed a posterior mediastinal tumor with calcification and fluid components. The tumor, adhering to the descending aorta, was radically removed through video-assisted thoracic surgery. Histological examination was concluded for a mature teratoma with cystic change. The imaging features of posterior mediastinal teratomas are identical to those in the anterior mediastinum, except for their location. To be different from anterior mediastinal teratomas, benign teratomas in the posterior mediastinum are often involved with a major surrounding structure, including aorta, chest wall, and esophagus. When a posterior mediastinal tumor has the typical features of a mature teratoma in the pre-operative findings, the adhesion to the surrounding structure should be considered.

Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism.

EphA2, a member of the Eph receptor family, is frequently overexpressed in a variety of human cancers, including breast cancers, and promotes cancer cell motility and invasion independently of its ligand ephrin stimulation. In this study, we identify Ephexin4 as a guanine nucleotide exchange factor (GEF) for RhoG that interacts with EphA2 in breast cancer cells, and knockdown and rescue experiments show that Ephexin4 acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. The activation of RhoG recruits its effector ELMO2 and a Rac GEF Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. In addition, the Dock4-mediated Rac activation is required for breast cancer cell migration. Our findings reveal a novel link between EphA2 and Rac activation that contributes to the cell motility and invasiveness of breast cancer cells.

Locally infiltrative glomus tumor of the bronchus: a case report.

We report a glomus tumor of the bronchus that showed invasion of the neural area and extrabronchial extension without significant histological malignancy. The patient was a male in his late 30s with the chief complaint being hemosputum. CT revealed a nodal shadow 15 mm in diameter in the right bronchus intermedius. An irregularly protruding lesion on the tumor surface was observed by bronchoscopy immediately under the second carina in the right truncus intermedius, but could not be diagnosed because of bleeding. Sleeve lobectomy of the right upper lobe was performed, since carcinoid tumor was suspected in open chest biopsy and intraoperative frozen section diagnosis. A solid growth of spherical and cubic uniform cells with a clear eosinophilic cytoplasm and spherical nuclei was observed. Immunohistochemistry was positive for α-smooth muscle actin and type IV collagen, weakly positive for synaptophysin, and negative for keratin, neural cell adhesion molecule, chromogranin A, desmin, CD34, and S100, leading to a diagnosis of glomus tumor. Neuroinvasion and extrabronchial tumor extension were observed, but an atypical cytology, bleeding, or necrosis was found histologically. This is the first description of infiltrative glomus tumor of the bronchus.

Schwarzschild radius from Monte Carlo calculation of the Wilson loop in supersymmetric matrix quantum mechanics.

In the string-gauge duality it is important to understand how the space-time geometry is encoded in gauge theory observables. We address this issue in the case of the D0-brane system at finite temperature T. Based on the duality, the temporal Wilson loop W in gauge theory is expected to contain the information of the Schwarzschild radius RSch of the dual black hole geometry as log(W)=RSch/(2pialpha'T). This translates to the power-law behavior log(W)=1.89(T/lambda 1/3)-3/5, where lambda is the 't Hooft coupling constant. We calculate the Wilson loop on the gauge theory side in the strongly coupled regime by performing Monte Carlo simulations of supersymmetric matrix quantum mechanics with 16 supercharges. The results reproduce the expected power-law behavior up to a constant shift, which is explainable as alpha' corrections on the gravity side. Our conclusion also demonstrates manifestly the fuzzball picture of black holes.

Higher derivative corrections to black hole thermodynamics from supersymmetric matrix quantum mechanics.

We perform a direct test of the gauge-gravity duality associated with the system of N D0-branes in type IIA superstring theory at finite temperature. Based on the fact that higher derivative corrections to the type IIA supergravity action start at the order of alpha;{'3}, we derive the internal energy in expansion around infinite 't Hooft coupling up to the subleading term with one unknown coefficient. The power of the subleading term is shown to be nicely reproduced by the Monte Carlo data obtained nonperturbatively on the gauge theory side at finite but large effective (dimensionless) 't Hooft coupling constant. This suggests, in particular, that the open strings attached to the D0-branes provide the microscopic origin of the black hole thermodynamics of the dual geometry including alpha;{'} corrections. The coefficient of the subleading term extracted from the fit to the Monte Carlo data provides a prediction for the gravity side.