Myostatin: A Skeletal Muscle Chalone.

Myostatin (GDF-8) was discovered 25 years ago as a new transforming growth factor-ß family member that acts as a master regulator of skeletal muscle mass. Myostatin is made by skeletal myofibers, circulates in the blood, and acts back on myofibers to limit growth. Myostatin appears to have all of the salient properties of a chalone, which is a term proposed over a half century ago to describe hypothetical circulating, tissue-specific growth inhibitors that control tissue size. The elucidation of the molecular, cellular, and physiological mechanisms underlying myostatin activity suggests that myostatin functions as a negative feedback regulator of muscle mass and raises the question as to whether this type of chalone mechanism is unique to skeletal muscle or whether it also operates in other tissues.

Gonadotropin elevation is ootoxic to ovulatory oocytes and inhibits oocyte maturation, and activin decoy receptor ActRIIB:Fc therapeutically restores maturation.

BACKGROUND: Elevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates. METHODS: The senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation. RESULTS: The high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG. CONCLUSIONS: FSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis ("FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients. Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies.

Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-ß signaling pathway.

Skeletal muscle and bone homeostasis are regulated by members of the myostatin/GDF-11/activin branch of the transforming growth factor-ß superfamily, which share many regulatory components, including inhibitory extracellular binding proteins and receptors that mediate signaling. Here, we present the results of genetic studies demonstrating a critical role for the binding protein follistatin (FST) in regulating both skeletal muscle and bone. Using an allelic series corresponding to varying expression levels of endogenous Fst, we show that FST acts in an exquisitely dose-dependent manner to regulate both muscle mass and bone density. Moreover, by employing a genetic strategy to target Fst expression only in the posterior (caudal) region of the animal, we show that the effects of Fst loss are mostly restricted to the posterior region, implying that locally produced FST plays a much more important role than circulating FST with respect to regulation of muscle and bone. Finally, we show that targeting receptors for these ligands specifically in osteoblasts leads to dramatic increases in bone mass, with trabecular bone volume fraction being increased by 12- to 13-fold and bone mineral density being increased by 8- to 9-fold in humeri, femurs, and lumbar vertebrae. These findings demonstrate that bone, like muscle, has an enormous inherent capacity for growth that is normally kept in check by this signaling system and suggest that the extent to which this regulatory mechanism may be used throughout the body to regulate tissue mass may be more significant than previously appreciated.

The effects of Pycnogenol, a pine bark extract on pulmonary inflammation by Asian sand dust in mice.

Asian sand dust (ASD), also called China dust or yellow dust, mainly occurs in East Asia during spring and autumn. Because ASD enters the body mainly through the respiratory system, it can cause respiratory disorders or worsen underlying diseases. Because of this, it has become an important health concern that threatens the well-being of humans and animals. In this study, we investigated the effects of 15 and 30 mg/kg of Pycnogenol (PYC15 and 30 groups), a pine bark extract, on ASD-induced pulmonary inflammation in mice. We evaluated the inflammatory cell counts, inflammatory cytokines, and matrix-metalloproteinase (MMP)-9 expression in animal models. PYC administration significantly decreased inflammatory cell infiltration into lung tissue; this was accompanied by a reduction in the levels of proinflammatory mediators including interleukin (IL)-1ß (P < 0.01), IL-6 (P < 0.01) and tumour necrosis factor-α (P < 0.01) in bronchoalveolar lavage fluids of ASD-exposed mice (ASD group). Histological analysis revealed that PYC suppressed ASD-induced pulmonary inflammation. Moreover, PYC suppressed the levels of matrix-metalloproteinase (MMP)-9 in the lung tissue of ASD-exposed mice, indicating that PYC reduced ASD-induced pulmonary inflammation by suppressing MMP-9. Together, these results indicate that PYC as the potential to treat ASD-driven pulmonary inflammation.

BMP10 functions independently from BMP9 for the development of a proper arteriovenous network.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-ß (TGF-ß) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

Risk Stratification for Sarcopenic Obesity in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The impact of the severity of sarcopenic obesity (SO) in nonalcoholic fatty liver disease (NAFLD) on the risk of significant liver fibrosis or cardiovascular disease (CVD) remains unclear. We aimed to identify high-risk subjects with SO for significant liver fibrosis or CVD among subjects with SO and NAFLD. METHODS: This multicenter, retrospective study involved 23,889 subjects with NAFLD who underwent a health screening program (2014-2020). Sarcopenia was defined based on gender-specific sarcopenia index cutoff using multi-frequency bioelectric impedance analysis. High-risk subjects with SO were defined as those with significant liver fibrosis by fibrosis-4 index >2.67 or atherosclerotic CVD risk score >20%. Multivariable logistic regression analysis for identifying high-risk subjects with SO was performed in a cross-sectional cohort with SO, and further validation was performed in a longitudinal cohort. RESULTS: SO prevalence was 5.4% (n = 1297 of 23,889). Older age (unstandardized beta [ß] = 3.23; P < .001), male (ß = 1.66; P = .027), sarcopenia index (ß = -6.25; P = .019), and metabolic syndrome (ß = 1.75; P < .001) were significant risk factors for high-risk SO. Based on a high-risk SO screening model, high-risk subjects with SO had significantly higher odds of significant liver fibrosis (training: adjusted odds ratio [aOR], 3.72; validation: aOR, 2.38) or CVD (training: aOR, 5.20; validation: aOR, 3.71) than subjects without SO (all P < .001). In subgroup analyses, the cumulative incidence of significant liver fibrosis or CVD development was significantly higher in high-risk subjects with SO than in low-risk subjects with SO in a longitudinal cohort considering all-cause mortality and liver transplantation as competing risks (sub-distribution hazard ratio, 5.37; P < .001). CONCLUSION: The high-risk screening model may enable the identification of high-risk subjects with SO with NAFLD.

Real-world treatment patterns and outcomes for patients with advanced melanoma treated with immunotherapy or targeted therapy.

OBJECTIVE: To identify real-world patterns of first line treatment, treatment sequence and outcomes for older adults diagnosed with advanced melanoma who received immunotherapy or targeted therapy. METHODS: The study population included older adults (ages 65+) diagnosed with unresectable or metastatic melanoma between 2012 and 2017 and who received first line immunotherapy or targeted therapy. Using the linked surveillance, epidemiology, and end results-medicare data, we described patterns of first line treatment and treatment sequence through 2018. We used descriptive statistics to report patient and provider characteristics by first line treatment receipt and changes in first line therapy use over calendar time. We also described overall survival (OS) and time to treatment failure (TTF) by first line treatment using the Kaplan-Meier method. For patterns of treatment sequence, we reported commonly observed treatment switch patterns by treatment sub-category and calendar year. RESULTS: The analyses included 584 patients (mean age = 76.3 years). A majority (n = 502) received first line immunotherapy. There was a sustained increase in immunotherapy uptake, most notably from 2015 to 2016. The estimated median OS and TTF were longer with first line immunotherapy than with targeted therapy. Individuals treated with CTLA-4 + PD-1 inhibitors had the longest median OS (28.4 months). The most common treatment switch pattern was from a first line CTLA-4 inhibitor to a second line PD-1 inhibitor. CONCLUSIONS: Our findings inform understanding of treatment patterns of currently used immunotherapies and targeted therapies in older adults with advanced melanoma. Immunotherapy use has increased steadily with PD-1 inhibitors becoming a dominant treatment option since 2015.

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A.

Myostatin (MSTN) is a transforming growth factor-ß (TGF-ß) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-ß family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone.

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor ß (TGF-ß) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality of Gdf11 null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show that Gdf11 null mice, despite significantly down-regulating Mstn expression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed in Mstn null mice that display enhanced bone mass. Mechanistically, Mstn deletion up-regulates Gdf11 expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlike Mstn null mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight.

Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights of Mstn-/- mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions.

Cold-induced adaptive thermogenesis is impaired by exposure of Asian sand dust in mice.

Desertification and desert sandstorms caused by the worsening global warming pose increasing risks to human health. In particular, Asian sand dust (ASD) exposure has been related to an increase in mortality and hospital admissions for respiratory diseases. In this study, we investigated the effects of ASD on metabolic tissues in comparison to diesel particulate matter (DPM) that is known to cause adverse health effects. We found that larger lipid droplets were accumulated in the brown adipose tissues (BAT) of ASD-administered but not DPM-administered mice. Thermogenic gene expression was decreased in these mice as well. When ASD-administered mice were exposed to the cold, they failed to maintain their body temperature, suggesting that the ASD administration had led to impairments in cold-induced adaptive thermogenesis. However, impaired thermogenesis was not observed in DPM-administered mice. Furthermore, mice fed a high-fat diet that were chronically administered ASD demonstrated unexplained weight loss, indicating that chronic administration of ASD could be lethal in obese mice. We further identified that ASD-induced lung inflammation was not exacerbated in uncoupling protein 1 knockout mice, whose thermogenic capacity is impaired. Collectively, ASD exposure can impair cold-induced adaptive thermogenic responses in mice and increase the risk of mortality in obese mice.

"If I wasn't in a rural area, I would definitely have more support": social needs identified by rural cancer caregivers and hospital staff.

BACKGROUND: The social needs of rural families facing cancer warrant investigation to inform psychosocial care planning and policy development. METHODS: Using purposive sampling, we interviewed 24 rural caregivers and 17 hospital staff from an academic cancer center in the U.S. South. Social needs were defined as the support needed to effectively provide informal caregiving across economic, physical, interpersonal, and service domains. We used the framework method to code and synthesize findings. FINDINGS: Caregiver economic and physical needs were interconnected and most pressing, including common examples of distance to care and transportation barriers. Caregivers desired additional support from the health system, insurance providers, and community resources. Staff identified similar need patterns and gaps in health system capacity. CONCLUSIONS: Rural cancer caregivers experience multiple unmet social needs. Supportive interventions for this population will benefit from flexible implementation and multilevel, multisector approaches. In particular, interventions that address financial hardship and limited internet access are needed.

Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques.

Amyloid-ß (Aß) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-Aß drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood-brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-Aß peptidomimetics that exploit the self-assembling nature of Aß and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of Aß, DAB, found to cross the BBB and solubilize Aß oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-Aß interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.

Trends in clinical outcomes and long-term survival after robotic gastrectomy for gastric cancer: a single high-volume center experience of consecutive 2000 patients.

BACKGROUND: Minimally invasive surgery is now a standard treatment for gastric cancer. Many retrospective studies have reported that robotic gastrectomy is safe and feasible, with similar short- and long-term outcomes as laparoscopic gastrectomy. However, no studies have reported the details of surgical and survival outcomes for robotic gastrectomy. This study aimed to evaluate the surgical trends and techniques of robotic gastrectomy and analyze the surgical outcomes of 2000 consecutive patients with gastric cancer who underwent robotic gastrectomy over 14 years. METHODS: Between July 2005 and January 2019, 2000 consecutive robotic gastrectomies were performed. We evaluated short- and long-term outcomes as well as surgical trends after robotic gastrectomy. RESULTS: There were 1,560 subtotal gastrectomies (78%), 324 total gastrectomies (16.2%), 83 proximal gastrectomies (4.2%), and 33 completion total gastrectomies (1.7%). The rates of major complications and mortality were 3.1% and 0.3%, respectively. In a subgroup analysis, there were no significant differences in the rate of complications over time (P = 0.696). Five-year overall survival rates were 97.6% for stage I, 91.9% for stage II, and 69.2% for stage III, with a total recurrence rate of 5.3%. Since its adoption in 2005, the proportion of robotic gastrectomies, as well as technically demanding procedures have increased over time. CONCLUSIONS: Our 14 years' experience of 2000 robotic gastrectomies has shown the proportion, as well as the number of robotic gastrectomies, have tended to increase and trends toward to technically demanding procedures. Outcomes of robotic gastrectomy appear safe and feasible with acceptable short- and long-term outcomes.

Fluorescent lymphography during minimally invasive total gastrectomy for gastric cancer: an effective technique for splenic hilar lymph node dissection.

BACKGROUND: Fluorescent lymphography is an excellent technique for complete lymph node dissection during minimally invasive surgery for gastric cancer. This study aimed to evaluate the role of fluorescent lymphography in splenic hilar lymph node dissection during minimally invasive total gastrectomy. METHODS: We retrospectively analyzed 168 gastric cancer patients who underwent minimally invasive total gastrectomy with D2 + No. 10 lymph node dissection from 2013 to 2018. Fluorescent lymphography was used whenever it is possible. However, when near-infrared imaging system and endoscopic indocyanine green injection were not available, we performed surgery without fluorescent lymphography. A total of 74 patients underwent surgery with fluorescent lymphography (FL group) and 94 underwent surgery without it (non-FL group). Perioperative and long-term outcomes including the number of retrieved lymph nodes at each nodal station were compared between groups. RESULTS: The median number of retrieved lymph nodes at the splenic hilum was larger in the FL group {2.5 [Interquartile range (IQR), 1-5]} than in the non-FL group [1 (IQR, 1-3); P = 0.012]. The negative predictive value of fluorescent lymphography for lymph node metastasis at the splenic hilum was 97.1%, although the sensitivity was 66.7%. The overall survival (FL: 96.9% vs. non-FL: 88.9%; P = 0.334) and relapse-free survival (FL: 90.5% vs. non-FL: 65.5%; P = 0.054) were higher in the FL group, although there were no statistical differences. However, among the patients without lymph node metastasis, the relapse-free survival was significantly higher in the FL group (100%) than in the non-FL group (67.1%; P = 0.017). CONCLUSIONS: Fluorescent lymphography is an effective tool for complete lymph node dissection at the splenic hilum. Moreover, it may help select patients who do not need splenic hilar lymph node dissection during a total gastrectomy.

Applicability of endoscopic submucosal dissection for patients with early gastric cancer beyond the expanded indication for endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) application for patients with tumors beyond the expanded indication for ESD is inconclusive. This study aimed to identify the preoperative clinical features that can be curatively treated with ESD in patients with early gastric cancer (EGC) beyond the indication of ESD. METHODS: From 2006 to 2016, 673 patients who underwent gastrectomy for EGC beyond the expanded indication for ESD based on preoperative assessments were retrospectively reviewed. We identified tumors curatively resected by ESD based on the postoperative pathologic findings. We also analyzed the clinical and pre-treatment features to determine the risk factors associated with curative resection of ESD. RESULTS: 39% of the patients (263/673) who had undergone gastrectomy had tumors of endoscopic curability A or B (eCuraA/B) that could be treated by ESD alone. In multivariate analysis, tumor size ≤ 10 mm (OR 0.240; 95% CI = 0.12-0.46), no ulceration (OR 0.500; 95% CI = 0.29-0.87), differentiated histology (OR 0.599; 95% CI = 0.43-0.84), and location in the distal two-thirds of the stomach (OR 0.499; 95% CI = 0.28-0.88) in pre-treatment assessment were identified as independent predictors of eCuraA/B. Considering the risk factors, 63.6% (7/11)/61.3% (19/31) of patients with a differentiated/undifferentiated tumor size ≤ 10 mm located in distal two-third of the stomach without ulceration were deemed as eCuraA/B. CONCLUSIONS: This study suggests that patients with EGC indicated for surgery can be treated by ESD by adding tumor locations in the indication for ESD. Thus, ESD can be applied for patients with a tumor size ≤ 10 mm located in the lower/middle stomach without ulceration.

Intraoperative microembolic signals during carotid endarterectomy.

OBJECTIVES: Transcranial Doppler ultrasonography (TCD) can detect microembolic signals (MESs) that are one of the pathogenic indications of ischemic stroke. However, MESs are not uncommon findings during carotid endarterectomy (CEA). The aim of this study was to evaluate the association between MESs and postoperative neurologic events (transient ischemic attack [TIA] or stroke) or new brain lesions (NBLs) on magnetic resonance imaging (MRI). METHODS: Of the 205 patients who underwent CEA, 160 who were monitored intraoperatively for MES using TCD were enrolled and reviewed retrospectively. MESs were counted until carotid cross-clamping. Postoperative neurologic examination and MRI was performed between postoperative day 1 and 7 in 131 patients. The binary logistic regression model was used to identify independent predictors of postoperative neurologic events or NBLs. RESULTS: MESs during dissection or carotid clamping was observed in 50 patients (31%) and 20 patients (13%) showed MESs > 10. The postoperative ischemic stroke rate was 3% (4/160), and MRI revealed NBLs in 19% (25/131). On univariate analysis, the presence of MESs or MESs > 10 was not related to postoperative neurologic events or NBLs. On binary logistic regression analysis, MESs > 10 was not an independent predictor of NBLs (P = 0.873, OR: 1.129, CI: 0.256 - 4.972). CONCLUSIONS: MESs were frequently found during CEA. However, they were not associated with NBLs.

Evaluation of 28-day repeated oral dose toxicity of aluminum chloride in rats.

The present study investigated the potential adverse effects of aluminum chloride (AlCl3) following a 4-week repeated oral administration in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 100, 300, and 900 mg/kg/day for 4 weeks. After administration of AlCl3 at 900 mg/kg/day, treatment-related systemic toxicity manifested as significant increases in salivation incidence, neutrophil percentage, reticulocytes, serum triglyceride, adrenal gland and liver weights, and single-hepatocyte necrosis, as well as significant decreases in body weight gain, food intake, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration (MCHC), lymphocyte percentage, serum total protein and albumin, and thymus weight in male rats; and significant increases in salivation incidence, serum triglyceride, and liver weight, as well as a significant decrease in lymphocyte percentage in female rats. At 300 mg/kg/day, a significant decrease in MCHC was found in male rats, but not in female rats. However, this finding was not toxicologically significant because the reduction was minimal and was not accompanied by changes in any other parameters. No treatment-related effects were observed in the 100 mg/kg/day group of both genders. Under the experimental conditions of this study, the target organs of AlCl3 were determined to be the blood, liver, and thymus in rats. The no-observed-adverse-effect level was found to be 300 mg/kg/day in rats of both genders.

Calibration of BRDF Based on the Field Goniometer System Using a UAV Multispectral Camera.

The bidirectional reflectance distribution function (BRDF) is important for estimating the physical properties of a surface in remote sensing. In the laboratory, the BRDF can be estimated quickly and accurately using a goniometer, but it is very difficult to operate in the field. The purpose of this study was to evaluate whether estimating the BRDF with reasonable accuracy using an unmanned aerial vehicle (UAV) with a multispectral camera is possible in the field. Hemispherical reflectance was created from images taken using an UAV multispectral camera. The ground targets were four calibrated reference tarps (CRTs) of different reflectance, and the UAV was operated five times. Down-welling irradiance for reflectance calculation was measured in two ways: a sunlight sensor was mounted on a UAV, and a spectroradiometer with a remote cosine receptor (RCR) was installed on the ground. The BRDF was assessed through the anisotropy factor (ANIF) of the CRT reflectance derived from the collected data. As a result, the irradiance data for the reflectance calculation were more effective from the spectroradiometer with RCR on the ground than from the sunlight sensor mounted on an UAV. Furthermore, the high reflectance CRTs, ANIF, and BRDF had similar results. Therefore, when analyzing the BRDF, the effectiveness can be guaranteed when the reflectance of the target is over 21~46%, because a low reflectance tendency differs due to the adjacency effect. In addition, weather affects irradiance, so it is more effective to conduct fieldwork in clear weather.

Lymphovascular Invasion: Traditional but Vital and Sensible Prognostic Factor in Early Gastric Cancer.

BACKGROUND: Although patients with early gastric cancer have good prognosis, recurrence after treatment may occur. Lymphovascular invasion (LVI) in gastric cancer has long been suggested as a poor prognostic indicator. This study sought to evaluate the prognostic effect of LVI in patients with early gastric cancer. METHODS: From 2005 to 2016, 6516 patients with early gastric cancer who underwent radical gastrectomy were analyzed. The patients were categorized according to LVI and lymph node (LN) status. RESULTS: LVI was present in 853 patients (13.1%). Patients with LVI or LN metastasis had more aggressive tumor characteristics than patients without both LVI and LN metastasis. The overall and relapse-free survival in patients with LVI were significantly worse than in patients without LVI. When we compared the survival rate of patients stratified by LVI and LN status, there was a significant overall and relapse-free survival difference between patients without both LVI and LN metastasis compared with those with LVI but without LN metastasis (p < 0.001). The overall and relapse-free survival of patients with LVI but without LN metastasis were similar to those without LVI but with LN metastasis (p = 0.818). Patients with LVI or LN metastasis showed a high frequency of recurrence (p < 0.001). Multivariate analysis showed that LVI and LN status were independent risk factors for relapse-free survival of early gastric cancer patients. CONCLUSIONS: Early gastric cancer with LVI is associated with poor prognosis and frequent recurrence. When predicting the prognosis of patients with early gastric cancer, LVI should be considered.