Urban dust particles disrupt mitotic progression by dysregulating Aurora kinase B-related functions.

Particulate matter (PM), a major component of outdoor air pollution, damages DNA and increases the risk of cancer. Although the harmful effects of PM at the genomic level are known, the detailed mechanism by which PM affects chromosomal stability remains unclear. In this study, we investigated the novel effects of PM on mitotic progression and identified the underlying mechanisms. Gene set enrichment analysis of lung cancer patients residing in countries with high PM concentrations revealed the downregulation of genes associated with mitosis and mitotic structures. We also showed that exposure of lung cancer cells in vitro to urban dust particles (UDPs) inhibits cell proliferation through a prolonged M phase. The mitotic spindles in UDP-treated cells were hyperstabilized, and the number of centrioles increased. The rate of ingression of the cleavage furrow and actin clearance from the polar cortex was reduced significantly. The defects in mitotic progression were attributed to inactivation of Aurora B at kinetochore during early mitosis, and spindle midzone and midbody during late mitosis. While previous studies demonstrated possible links between PM and mitosis, they did not specifically identify the dysregulation of spatiotemporal dynamics of mitotic proteins and structures (e.g., microtubules, centrosomes, cleavage furrow, and equatorial and polar cortex), which results in the accumulation of chromosomal instability, ultimately contributing to carcinogenicity. The data highlight the novel scientific problem of PM-induced mitotic disruption. Additionally, we introduce a practical visual method for assessing the genotoxic outcomes of airborne pollutants, which has implications for future environmental and public health research.

Histopathology and surgical outcome of symptomatic treatment-related changes after gamma knife radiosurgery in patients with brain metastases.

A late-onset treatment-related changes (TRCs), which represent radiographic radiation necrosis (RN), frequently occur after stereotactic radiosurgery (SRS) for brain metastases and often need surgical treatment. This study aimed to validate the true pathology and investigate clinical implication of surgically resected TRCs on advanced magnetic resonance imaging (MRI). Retrospective analyses of 86 patients who underwent surgical resection after radiosurgery of brain metastases were performed. Fifty-four patients displayed TRCs on preoperative MRI, comprising pure RN in 19 patients (TRC-RN group) and mixed viable tumor cells in 35 patients (TRC-PD group). Thirty-two patients revealed the consistent diagnosis of progressive disease in both MRI and histopathology (PD-PD group). The TRC-PD group showed larger prescription isodose volume (9.4 cm3) than the TRC-RN (4.06 cm3, p = 0.014) group and a shorter time interval from SRS to preoperative MRI diagnosis (median 4.07 months) than the PD-PD group (median 8.77 months, p = 0.004). Progression-free survival was significantly different among the three groups (p < 0.001), but not between TRC-RN and TRC-PD (post hoc test, p = 1.00), while no difference was observed in overall survival (p = 0.067). Brain metastases featured as TRCs after SRS frequently contained viable tumor cells. However, this histologic heterogeneity had a minor impact on benign local prognosis of TRCs after surgical resection.

Expandability of Cephalic Veins after Brachial Plexus Block in Arteriovenous Fistula Formation for Hemodialysis.

BACKGROUND: Arteriovenous fistula (AVF) for hemodialysis is essential for patients with end-stage renal disease. However, it is difficult to maintain AVF reliably. It is vitally important to select proper blood vessels for AVF formation. In a previous study, a minimum diameter of 3 mm for the autologous vein was proposed. However, patients who did not meet the minimum vascular diameter before anesthesia, but fulfilled other criteria, showed satisfactory venous dilatation after brachial plexus block (BPB). This study investigated the extent of vein expansion by BPB and the surgical outcomes of dilated veins after BPB. METHODS: Sixty-one patients who underwent AVF formation using an autologous vein between August 2018 and December 2019 were included in the study. The clinical characteristics of the patient groups, hemodynamic parameters including the diameter of blood vessels before and after BPB, and complications were investigated. Based on the venous diameter measured by sonography before anesthesia, patients were divided into group A (26 patients) and group B (35 patients), with venous diameters <3 mm and ≥3 mm, respectively. RESULTS: The venous diameter expanded after anesthesia by 41% overall, by 62% in group A, and by 25% in group B. This difference between groups A and B was statistically significant (p=0.001). No other variables showed statistically significant differences. CONCLUSION: Sufficient venous dilatation was observed after BPB. Therefore, if the vein is sufficiently dilated after BPB, even in patients with a pre-anesthesia venous diameter <3 mm, surgery may still be performed with an expected desirable outcome.

Localized Pretibial Varicose Vein Caused by an Intraosseous Venous Anomaly.

A 36-year-old man presented to the hospital with protruding blood vessels in his left lower leg accompanied by cramping. An ultrasonographic examination of the leg revealed focal reflux without truncal vein reflux. During phlebectomy, the varix was found to be connected to the intraosseous vein through a tibial opening. Postoperative computed tomography and magnetic resonance imaging showed an osteolytic lesion in the tibial shaft and an intraosseous vascular anomaly. The patient was discharged without complications and scheduled for periodic follow-ups. This young man's varicose vein seemed to be from a tibial intraosseous vascular anomaly, which is extremely rare.

Resuscitative endovascular balloon occlusion of the aorta for retroperitoneal hemorrhage and shock after ipsilateral antegrade angioplasty with vascular closure device.

Percutaneous intervention is widely used to treat peripheral vascular disease. Ipsilateral antegrade femoral arterial access for femoropopliteal disease provides a mechanical advantage with regard to wire and stent control; however, it is associated with vascular complications and significant morbidity and mortality secondary to retroperitoneal hemorrhage from a high puncture site or vascular closure device (VCD) failure. Currently, resuscitative endovascular balloon occlusion of the aorta (REBOA) is performed as damage control surgery in patients with non-compressible torso hemorrhage. We describe a patient with hemorrhagic shock secondary to VCD failure, who was successfully treated by REBOA as damage control surgery. To our knowledge, this is the first reported case in the English literature of successful REBOA in a patient with hemorrhagic shock secondary to VCD failure.

Clinical Outcomes of Arteriovenous Graft in End-Stage Renal Disease Patients with an Unsuitable Cephalic Vein for Hemodialysis Access.

BACKGROUND: As the population of patients with end-stage renal disease has grown older, the proportion of patients with poorly preserved vasculature has concomitantly increased. Thus, arteriovenous grafts (AVG) have been used more frequently to access blood vessels for hemodialysis. Despite this increasing demand, studies of AVG are limited. In this study, we examined the surgical outcomes of upper-limb AVG creation. METHODS: Among the arteriovenous fistula formation procedures performed between January 2014 and March 2019 at Dankook University Hospital, 42 cases involved AVG creation. We compared patients in whom the axillary vein was used (group A; brachioaxillary AVG [B-Ax AVG]; n=20) with those in whom upper limb veins were used (group B; brachiobasilic AVG or brachioantecubital AVG; n=22). RESULTS: The 1-year primary patency rate was higher in group A than in group B (57.9% vs. 41.7%; p=0.262). The incidence of postoperative complications was not significantly different between groups. CONCLUSION: AVG using the axillary vein showed no major differences in safety or functionality compared to AVG using other veins. Therefore, accounting for age, underlying disease, and expected patient lifespan, B-Ax AVG can be considered an acceptable surgical method.

SIRT2 Affects Primary Cilia Formation by Regulating mTOR Signaling in Retinal Pigmented Epithelial Cells.

SIRT2, a member of the Class III HDAC family, participates in diverse cellular processes and regulates several pathological conditions. Although a few reports show that SIRT2 regulates the cell cycle, the causes and outcomes of SIRT2-dependent cell proliferation remain unclear. Here, we examined the effects of SIRT2 suppression in human RPE1 cells using siRNA targeting SIRT2, and AK-1, a SIRT2-specific inhibitor. The number of primary cilia in SIRT2-suppressed cells increased under serum-present conditions. Suppressing SIRT2 induced cell cycle arrest at G0/G1 phase by inactivating mammalian target of rapamycin (mTOR) signaling, possibly through mTORC1. Treatment with torin 1, an inhibitor of mTORC1/mTORC2, yielded results similar to those observed after SIRT2 suppression. However, SIRT2 suppression did not affect primary cilia formation or mTOR signaling following serum starvation. This suggests that SIRT2 acts as a critical sensor that links growth factor-dependent signal transduction and primary cilia formation by regulating the cell cycle.

Tat-Dependent Heterologous Secretion of Recombinant Tyrosinase by Pseudomonas fluorescens Is Aided by a Translationally Fused Caddie Protein.

Tyrosinase is a monooxygenase that catalyzes both the hydroxylation of p-hydroxyphenyl moieties to o-catechols and the oxidation of o-catechols to o-quinones. Apart from its critical functionality in melanogenesis and the synthesis of various neurotransmitters, this enzyme is also used in a variety of biotechnological applications, most notably mediating covalent cross-linking between polymers containing p-hydroxyphenyl groups, forming a hydrogel. Tyrosinases from the genus Streptomyces are usually secreted as a complex with their caddie protein. In this study, we report an increased secretion efficiency observed when the Streptomyces antibioticus tyrosinase gene melC2 was introduced into Pseudomonas fluorescens along with its caddie protein gene melC1, which has the DNA sequence for the Tat (twin-arginine translocation) signal.IMPORTANCE We observed that the S. antibioticus extracellular tyrosinase secretion level was even higher in its nonnatural translationally conjugated fusion protein form than in the natural complex of two separated polypeptides. The results of this study demonstrate that tyrosinase-expressing P. fluorescens can be a stable source of bacterial tyrosinase through exploiting the secretory machinery of P. fluorescens.

CCAR2/DBC1 and Hsp60 Positively Regulate Expression of Survivin in Neuroblastoma Cells.

CCAR2 (cell cycle and apoptosis regulator 2) controls a variety of cellular functions; however, its main function is to regulate cell survival and cell death in response to genotoxic and metabolic stresses. Recently, we reported that CCAR2 protects cells from apoptosis following mitochondrial stress, possibly by co-operating with Hsp60. However, it is not clear how CCAR2 and Hsp60 control cell survival and death. Here, we found that depleting CCAR2 and Hsp60 downregulated expression of survivin, a member of the inhibitor of apoptosis (IAP) family. Survivin expression in neuroblastoma tissues and human cancer cell lines correlated positively with expression of CCAR2 and Hsp60. Furthermore, high expression of CCAR2, Hsp60, and survivin was associated with poor survival of neuroblastoma patients. In summary, both CCAR2 and Hsp60 are required for expression of survivin, and both promote cancer cell survival, at least in part, by maintaining survivin expression. Therefore, CCAR2, Hsp60, and survivin are candidate tumor biomarkers and prognostic markers in neuroblastomas.

Zingerone Suppresses Tumor Development through Decreasing Cyclin D1 Expression and Inducing Mitotic Arrest.

Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, is a nontoxic and inexpensive compound with varied pharmacological activities. In this study, the therapeutic effect of zingerone as an anti-mitotic agent in human neuroblastoma cells was investigated. Following treatment of BE(2)-M17 cells with zingerone, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and colony-formation assay to evaluate cellular proliferation, in addition to immunofluorescence cytochemistry and flow cytometry to examine the mitotic cells. The association of gene expression with tumor stage and survival was analyzed. Furthermore, to examine the anti-cancer effect of zingerone, we applied a BALB/c mouse-tumor model using a BALB/c-derived adenocarcinoma cell line. In human neuroblastoma cells, zingerone inhibited cellular viability and survival. Moreover, the number of mitotic cells, particularly those in prometaphase, increased in zingerone-treated neuroblastoma cells. Regarding specific molecular mechanisms, zingerone decreased cyclin D1 expression and induced the cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The decrease in cyclin D1 and increase in histone H3 phosphorylated (p)-Ser10 were confirmed by immunohistochemistry in tumor tissues administered with zingerone. These results suggest that zingerone induces mitotic arrest followed by inhibition of growth of neuroblastoma cells. Collectively, zingerone may be a potential therapeutic drug for human cancers, including neuroblastoma.

An Aurora kinase inhibitor, AMG900, inhibits glioblastoma cell proliferation by disrupting mitotic progression.

The Aurora kinase family of serine/threonine protein kinases comprises Aurora A, B, and C and plays an important role in mitotic progression. Several inhibitors of Aurora kinase have been developed as anti-cancer therapeutics. Here, we examined the effects of a pan-Aurora kinase inhibitor, AMG900, against glioblastoma cells. AMG900 inhibited proliferation of A172, U-87MG, and U-118MG glioblastoma cells by upregulating p53 and p21 and subsequently inducing cell cycle arrest and senescence. Abnormal cell cycle progression was triggered by dysregulated mitosis. Mitosis was prolonged due to a defect in mitotic spindle assembly. Despite the presence of an unattached kinetochore, BubR1, a component of the spindle assembly checkpoint, was not recruited. In addition, Aurora B was not recruited to central spindle at anaphase. Abnormal mitotic progression resulted in accumulation of multinuclei and micronuclei, a type of chromosome missegregation, and ultimately inhibited cell survival. Therefore, the data suggest that AMG900-mediated inhibition of Aurora kinase is a potential anti-cancer therapy for glioblastoma.

The Protein Phosphatase PPM1G Destabilizes HIF-1α Expression.

Hypoxia-inducible factors (HIFs) are key regulators of hypoxic responses, and their stability and transcriptional activity are controlled by several kinases. However, the regulation of HIF by protein phosphatases has not been thoroughly investigated. Here, we found that overexpression of Mg2+/Mn2+-dependent protein phosphatase 1 gamma (PPM1G), one of Ser/Thr protein phosphatases, downregulated protein expression of ectopic HIF-1α under normoxic or acute hypoxic conditions. In addition, the deficiency of PPM1G upregulated protein expression of endogenous HIF-1α under normoxic or acute oxidative stress conditions. PPM1G decreased expression of HIF-1α via the proteasomal pathway. PPM1G-mediated HIF-1α degradation was dependent on prolyl hydroxylase (PHD), but independent of von Hippel-Lindau (VHL). These data suggest that PPM1G is critical for the control of HIF-1α-dependent responses.

Delayed massive hemothorax requiring surgery after blunt thoracic trauma over a 5-year period: complicating rib fracture with sharp edge associated with diaphragm injury.

Delayed massive hemothorax requiring surgery is relatively uncommon and can potentially be life-threatening. Here, we aimed to describe the nature and cause of delayed massive hemothorax requiring immediate surgery. Over 5 years, 1,278 consecutive patients were admitted after blunt trauma. Delayed hemothorax is defined as presenting with a follow-up chest radiograph and computed tomography showing blunting or effusion. A massive hemothorax is defined as blood drainage >1,500 mL after closed thoracostomy and continuous bleeding at 200 mL/hr for at least four hours. Five patients were identified all requiring emergency surgery. Delayed massive hemothorax presented 63.6±21.3 hours after blunt chest trauma. All patients had superficial diaphragmatic lacerations caused by the sharp edge of a broken rib. The mean preoperative chest tube drainage was 3,126±463 mL. We emphasize the high-risk of massive hemothorax in patients who have a broken rib with sharp edges.

Surgical Outcomes of Forearm Loop Arteriovenous Fistula Formation Using Tapered versus Non-Tapered Polytetrafluoroethylene Grafts.

BACKGROUND: Tapered grafts, which have a smaller diameter on the arterial side, have been increasingly used for arteriovenous fistula (AVF) formation. We compared the outcomes of 4-6-mm tapered and 6-mm straight forearm loop arteriovenous grafts. METHODS: A total of 103 patients receiving forearm loop arteriovenous grafts between March 2005 and March 2015 were retrospectively analyzed and separated into 2 groups (group A, 4- to 6-mm tapered grafts, n=78; group B, 6-mm straight grafts, n=25). In each group, complications and patency rates after surgery were assessed. RESULTS: Clinical characteristics and laboratory results, except for cerebrovascular disease history (group A, 7.7%; group B, 28.0%; p=0.014), were similar between the groups. No significant differences were found for individual complications. Kaplan-Meier survival analysis revealed no significant differences in 1-year, 3-year, and 5-year patency rates between groups (61.8%, 44.9%, and 38.5% vs. 62.7%, 41.1%, and 35.3%, respectively). CONCLUSION: We found no significant differences in complication and patency rates between the tapered and straight graft groups. If there are no differences in complication and patency between the two graft types, tapered grafts may be a valuable option for AVF formation in light of their other advantages.

A Case of Recurrent Aortic Rupture Associated with Klebsiella pneumoniae Pericarditis Treated by Two Separate Aortic Operations.

A 49-year-old female presented with severe dyspnea. She was diagnosed with cardiac tamponade combined with ascending aortic pseudoaneurysm and rupture, which was caused by Klebsiella pneumoniae infection. This extremely rare condition was managed by an emergency pericardiostomy and two separate aortic operations. Antibiotics active for the K. pneumoniae isolate were used throughout. The patient was well for nine months after discharge and continues to be followed up for signs of possible reinfection.

Intranodal lymphangiography as a possible therapeutic option for patients with isolated thoracic duct injury from penetrating chest trauma.

A 49-year-old female presented to the emergency department after multiple stab injuries. Bilateral thoracostomy was performed due to a right hemopneumothorax and a left pneumothorax without tracheoesophageal and vascular injury. On admission day 4, a significant amount of milky fluid was collected in the drain after initiation of regular diet. Under suspicion of chylothorax, conservative management was initiated, but failed. Surgery was considered, but ruled out due to the patient's refusal. As an alternative, lymphangiography was performed, which resulted in decreased thoracic drainage and eventual removal of the chest tube. This is an unusual case of an isolated thoracic duct injury that was successful treated by closure of the duct after intranodal lymphangiography.

A case of advanced malignant pleural mesothelioma treatment with chemotherapy and photodynamic therapy.

Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant, and generally fatal disease. A 68-year-old male who was diagnosed with MPM at another hospital came to our hospital with dyspnea. We advised him to take combination chemotherapy but he refused to take the treatment. That was because he had already received chemotherapy with supportive care at another hospital but his condition worsened. Thus, we recommended photodynamic therapy (PDT) to deal with the dyspnea and MPM. After PDT, the dyspnea improved and the patient then decided to take the combination chemotherapy. Our patient received chemotherapy using pemetrexed/cisplatin. Afterwards, he received a single PDT treatment and then later took chemotherapy using gemcitabine/cisplatin. The patient showed a survival time of 27 months, which is longer than median survival time in advanced MPM patients. Further research and clinical trials are needed to demonstrate any synergistic effect between the combination chemotherapy and PDT.

Complete Vascular Ring Caused by Kommerell's Diverticulum and Right Aortic Arch with Mirror Image Branching.

Vascular ring, caused by Kommerell's diverticulum and ligamentum arteriosum, in a patient with right aortic arch and mirror image branching is extremely rare. A 10-month-old boy with coughing and stridor was diagnosed as having tracheo-esophageal stenosis, which is caused by a vascular ring with Kommerell's diverticulum, ligamentum arteriosum, right aortic arch, and mirror image branching. Kommerell's diverticulum was successfully resected via a left thoracotomy. The patient has been free from tracheo-esophageal stenosis for a year after the surgery.

Surgical treatment of native valve Aspergillus endocarditis and fungemic vascular complications.

Systemic infection with Aspergillus is an opportunistic disease that affects mainly immunocompromised hosts, and is associated with a high mortality rate. It typically occurs in patients with several predisposing factors, but Aspergillus endocarditis of native valves is rare and experience in diagnosis and treatment is limited. We report a case of native valve endocarditis caused by Aspergillus. A 35-yr-old male patient who underwent pericardiocentesis four months previously for pericardial effusion of unknown etiology presented with right leg pain and absence of the right femoral artery pulse. Cardiac echocardiography revealed severe mitral insufficiency with large mobile vegetations, and computed tomographic angiography showed embolic occlusion of both common iliac arteries. We performed mitral valve replacement and thromboembolectomy, and Aspergillus was identified as the vegetation. We started intravenous amphotericin B and oral itraconazole, but systemic complications developed including superior mesenteric artery aneurysm and gastrointestinal bleeding. After aggressive management, the patient was discharged 78 days post surgery on oral itraconazole. He was well at 12 months post discharge but died in a traffic accident 13 months after discharge.

Complete atelectasis of the lung in patients with primary spontaneous pneumothorax.

BACKGROUND: Complete atelectasis of primary spontaneous pneumothorax (PSP) requires immediate air reduction. Surgical intervention has been considered proper treatment for persistent air leakage or recurrence. We examined whether this is the proper treatment by evaluating the natural course and treatment outcomes of complete lung atelectasis. METHODS: We retrospectively analyzed the records of 286 patients with a first episode of PSP. We classified patients as partial atelectasis (n = 201, 71%) and complete atelectasis (n = 85, 29%) by initial radiography. Surgical intervention was done for persistent air leakage or recurrence, and all surgery was performed by video-assisted thoracoscopic surgery. We compared both groups for demographic and operative variables. RESULTS: In all, 29.4% of the complete atelectasis group and 10% of the partial atelectasis group showed persistent air leakage. The ipsilateral recurrence rate was 70% for the complete atelectasis group and 39.2% for the partial atelectasis group. Video-assisted thoracoscopic surgery was performed in 78.8% and 45.3% of the complete atelectasis and partial atelectasis groups, respectively. The postoperative course and recurrence rate were not different between the two groups during 40.2 months of follow-up. CONCLUSIONS: The PSP patients with complete atelectasis showed a higher incidence of persistent air leakage and ipsilateral recurrence than did PSP patients with partial atelectasis. Operative outcomes were good. Complete atelectasis of the lung in PSP patients is an indication for surgical intervention at their first PSP episode.