Seungjoo Lee

Amelioration of sepsis by TIE2 activation–induced vascular protection

Vascular protection through TIE2 activation is a potential treatment strategy to ameliorate sepsis. Antibody TIEs sepsis up in knots Sepsis, or severe systemic inflammation caused by infection, has a high mortality despite the availability of antibiotic treatment, and more specific therapies are urgently needed. One of the difficult-to-treat and potentially life-threatening components of sepsis is vascular disintegration and leakage. Han et al. have discovered an antibody, called ABTAA, which binds to a ligand called angiopoietin 2 (ANG2) in the vasculature, but then activates it instead of blocking its activity like standard antibodies. When ABTAA binds to ANG2, it causes clustering of ANG2 and subsequently its receptor TIE2 at the site, and the resulting signaling cascade protects the vascular walls and blunts the damaging effects of sepsis, greatly increasing survival in mouse models of the disease. Protection of endothelial integrity has been recognized as a frontline approach to alleviating sepsis progression, yet no effective agent for preserving endothelial integrity is available. Using an unusual anti–angiopoietin 2 (ANG2) antibody, ABTAA (ANG2-binding and TIE2-activating antibody), we show that activation of the endothelial receptor TIE2 protects the vasculature from septic damage and provides survival benefit in three sepsis mouse models. Upon binding to ANG2, ABTAA triggers clustering of ANG2, assembling an ABTAA/ANG2 complex that can subsequently bind and activate TIE2. Compared with a conventional ANG2-blocking antibody, ABTAA was highly effective in augmenting survival from sepsis by strengthening the endothelial glycocalyx, reducing cytokine storms, vascular leakage, and rarefaction, and mitigating organ damage. Together, our data advance the role of TIE2 activation in ameliorating sepsis progression and open a potential therapeutic avenue for sepsis to address the lack of sepsis-specific treatment.

Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment

A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.

Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice

Little is known about the transcriptional regulation of tumor angiogenesis, and tumor ECs (tECs) remain poorly characterized. Here, we studied the expression pattern of the transcription factor Sox17 in the vasculature of murine and human tumors and investigated the function of Sox17 during tumor angiogenesis using Sox17 genetic mouse models. Sox17 was specifically expressed in tECs in a heterogeneous pattern; in particular, strong Sox17 expression distinguished tECs with high VEGFR2 expression. Whereas overexpression of Sox17 in tECs promoted tumor angiogenesis and vascular abnormalities, Sox17 deletion in tECs reduced tumor angiogenesis and normalized tumor vessels, inhibiting tumor growth. Tumor vessel normalization by Sox17 deletion was long lasting, improved anticancer drug delivery into tumors, and inhibited tumor metastasis. Sox17 promoted endothelial sprouting behavior and upregulated VEGFR2 expression in a cell-intrinsic manner. Moreover, Sox17 increased the percentage of tumor-associated CD11b+Gr-1+ myeloid cells within tumors. The vascular effects of Sox17 persisted throughout tumor growth. Interestingly, Sox17 expression specific to tECs was also observed in highly vascularized human glioblastoma samples. Our findings establish Sox17 as a key regulator of tumor angiogenesis and tumor progression.

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

Background— Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. Methods and Results— The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. Conclusions— Our findings demonstrate that Sox17 deficiency in mouse can induce IA under hypertensive conditions, suggesting Sox17 deficiency as a potential genetic factor for IA formation. The Sox17-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.

Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas

OBJECT Although stereotactic radiosurgery were established as an effective treatment modality for intracranial meningiomas, there have been no comprehensive studies focused on long-term outcomes and histologic results for purely small-sized meningiomas after radiosurgery. Therefore, we investigated long-term outcomes and histology of small-sized meningiomas after radiosurgery. METHODS The authors reviewed the data retrospectively of a total of 920 patients treated with single-session Gamma Knife radiosurgery with intracranial meningioma (Radiosurgery center, Asan Medical Center). After stratifying meningiomas by size, it was defined as small-sized meningiomas less than 1000 mm(3) in tumor volume. The patients with newly diagnosed small-sized meningiomas were enrolled in this study (113 patients). All patients had a minimum follow up of 12 months (12-120 months), clinical symptoms and brain MRI were checked by neurosurgeons. When the tumors grew readily with newly developed neurologic symptoms, microsurgical resection was performed. Histologic analysis was done with resected tumors by neuropathologists. RESULTS Among 113 patients, 9 patients (7.9%) showed the increased tumors with clinical symptoms after radiosurgery, followed by microsurgical resection in 4 patients (3.5%). The other 5 (4.4%) patients showed that the size of tumor slightly increased after GKRS that is transient. Interestingly, the histologic results of resected meningiomas due to increased volume after radiosurgery were all revealed as WHO grade II meningiomas (1 clear cell type and 3 atypical meningiomas). Although the histologic confirmation was performed only in 4 patients underwent surgery, it is interesting that all tumors readily grew after radiosurgery were high grade meningiomas. CONCLUSION In this study, we revealed the long-term outcomes of small meningiomas following stereotactic radiosurgery in the aspect of tumor control. The tumor control rate of radiosurgery in small meningiomas reached to 92.1% and there were perilesional edema in 6.1%. The 7.9% of tumors grew readily and 3.5% were finally underwent microsurgical resection. The histologic results were all WHO grade II meningiomas (1 clear cell and 3 atypical meningiomas).

Clinical Interrogation for Unveiling an Isolated Hypophysitis Mimicking Pituitary Adenoma

BACKGROUND Hypophysitis is a rare disease entity mimicking a pituitary adenoma. Despite crucial disease involving a pituitary gland which is a main component of the hormonal axis, there have been minimal researches regarding the hypophysitis. In this study, we described the constellation of the preoperative findings including clinical, radiologic, and endocrinologic features, as well as postoperative outcomes of the hypophysitis. METHODS The authors reviewed the data retrospectively of a total of 2814 patients who underwent microsurgery at our institution to treat a pituitary mass lesion. Among them, the patients proven as hypophysitis in histologic examination were enrolled, followed by stratification into tumor-associated hypophysitis and isolated hypophysitis depending on the existence of associated tumor lesion. As a result, a total 21 cases were enrolled consisting of the 13 cases of tumor-associated and the 8 cases of isolated hypophysitis. In this study, the isolated hypophysitis was focused on the analysis. All patients with isolated hypophysitis were evaluated the clinical, radiologic, and endocrinologic tests preoperatively. After microsurgery, all patients had a minimum follow up of 6 months (6∼72 months). The clinical symptoms, endocrinologic tests, and brain MRI were checked at every 6 months during first 2 year, since then, at every 12 months. RESULTS Among 2814 cases of pituitary mass lesion underwent microsurgery, the hypophysitis were found 21 cases (0.74 %). The 13 cases were the tumor-associated hypophysitis, consisting of rathkes cleft cyst (7 cases), craniopharyngioma (3 cases), pituitary adenoma (2 cases), and germinoma (1 case). The 8 cases were the isolated hypophysitis including lymphocytic (4 cases), granulomatous (3 cases), and IgG4-related (1 case) hypophysitis. The patients presented a wide range of clinical symptoms from general weakness to panhypopituitarism. In addition, the most remarkable radiologic features of the isolated hypophysitis were infundibular thickening and the low signal intensity in T1WI and T2WI. All 8 patients with isolated hypophysitis presented endocrinologic deficiency with various extent in a preoperative biochemistry. After surgery, the hormonal status were not changed in 4 patients (50%), however, aggravated in 4 patients (50%). The 3 patients (37.5%) complained visual field defects in preoperative ophthalmologic test, but improved all after surgery. CONCLUSION In this study, the preoperative clinical manifestations, radiologic and endocrinologic features of hypophysitis were described comprehensively. In addition, we also revealed the long-term outcomes of hypophysitis in the aspect of visual function and endocrinologic outcomes. Preexisting visual field defects were improved in all patients (3 cases). However, all patients presented endocrinologic deficiency in preoperative biochemistry, among them, the 4 patients (50 %) were unchanged and the 4 patients (50 %) were exacerbated after surgery. In conclusion, the visual outcomes were satisfactory, however, the endocrinologic outcomes were vice versa, because the preoperative endocrinologic deterioration was unchanged or even aggravated after surgery in some cases.

Erratum: Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment (Cancer Cell (2016) 30(6) (953–967) (S1535610816305050) (10.1016/j.ccell.2016.10.018))

(Cancer Cell 30, 953–967; December 12, 2016) In the original Figure 4J and Figure 7H, amagnified image of ABTAA groupwas inadvertently used in duplicate. Also in the Fc group of Figure 4J, the square box indicating a metastatic nodule was misplaced, resulting in a mismatch between the magnified image and the indicated area in whole lung image. This was a mistake made by the authors during the assembly of the figures. These errors do not affect or alter any of the findings reported in the paper. These errors have now been corrected here and in the original article online. The authors apologize for any confusion or inconvenience that these errors may have caused.

Paroxysmal sympathetic hyperactivity in brainstem-compressing huge benign tumors: clinical experiences and literature review

Severe paroxysmal sympathetic overactivity occurs in a subgroup of patients with acquired brain injuries including traumatic brain injury, hypoxia, infection and tumor-related complications. This condition is characterized by sudden increase of heart rate, respiratory rate, blood pressure, body temperature and excessive diaphoresis. The episodes may be induced by external stimulation or may occur spontaneously. Frequent occurrence of this condition could result in secondary morbidities, therefore, should be diagnosed and managed insightfully. These symptoms could be confused with seizures or other medical conditions, leading to unnecessary treatment. Despite clinical significance of paroxysmal sympathetic hyperactivity (PSH), brain tumor-induced PSH has not been studied nearly. In this report, two cases of the PSH in patients with brainstem-compressing benign tumors were introduced. The most useful pharmacologic agents were opioid (e.g., fentanyl patch) in preventing PSH attack, and nonselective β-blocker (e.g., propranolol) in relieving the symptoms. Clinical experiences of the rare cases of benign tumor-induced PSH can be helpful as an essential basis for further research.

Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality

High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. Sox7 deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, Sox17 deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing Sox17-deficient abnormal vessels with high Sox7 levels but promoted it by regressing Sox7-deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG.

Study on Demand Elderly Foods and Food Preferences among Elderly People at Senior Welfare Centers in Seoul

【The purpose of this study was to investigate the need to develop foods for the elderly based on their food preferences. A one-to-one survey method was used for data collection, and the survey was conducted on 165 elderly people (male: 47, female: 118) attending senior welfare centers in Seoul. The results of this study show that the preferred cooking method was steaming rather than stir-frying. Vegetables (4.24), fruits (4.22), Kimchi (3.87), fish (3.83), tofu (3.81), rice-cakes (3.65), dairy products/eggs (3.47), meat (3.45), noodles (3.44), seafood (3.44), poultry (3.23), bread/cookies (3.10) showed high preferences in order (p】