Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity.

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes, and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A. Adenosine 5'-triphosphate-citrate lyase-mediated accumulation of acetyl-coenzyme A and histone acetyltransferases further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases completely inhibited high-glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

In vivo imaging of renal microvasculature in a murine ischemia-reperfusion injury model using optical coherence tomography angiography.

Optical coherence tomography angiography (OCTA) provides three-dimensional structural and semiquantitative imaging of microvasculature in vivo. We developed an OCTA imaging protocol for a murine kidney ischemia-reperfusion injury (IRI) model to investigate the correlation between renal microvascular changes and ischemic damage. Mice were divided into mild and moderate IRI groups according to the duration of ischemia (10 and 35 mins, respectively). Each animal was imaged at baseline; during ischemia; and at 1, 15, 30, 45, and 60 mins after ischemia. Amplitude decorrelation OCTA images were constructed with 1.5-, 3.0-, and 5.8-ms interscan times, to calculate the semiquantitative flow index in the superficial (50-70 µm) and the deep (220-340 µm) capillaries of the renal cortex. The mild IRI group showed no significant flow index change in both the superfial and the deep layers. The moderate IRI group showed a significantly decreased flow index from 15 and 45 mins in the superficial and deep layers, respectively. Seven weeks after IRI induction, the moderate IRI group showed lower kidney function and higher collagen deposition than the mild IRI group. OCTA imaging of the murine IRI model revealed changes in superficial blood flow after ischemic injury. A more pronounced decrease in superficial blood flow than in deep blood flow was associated with sustained dysfunction after IRI. Further investigation on post-IRI renal microvascular response using OCTA may improve our understanding of the relationship between the degree of ischemic insult and kidney function.

Clinical Characteristics of TZAP (ZBTB48) in Hepatocellular Carcinomas from Tissue, Cell Line, and TCGA.

Background and Objectives: ZBTB48 is a telomere-related protein that has been renamed telomeric zinc finger-associated protein (TZAP). It favorably binds to elongated telomeres to regulate their appropriate length. However, TZAP expression has not been investigated in hepatocellular carcinomas (HCC). Materials and Methods: The clinical significance of TZAP expression in 72 HCC was investigated. Additionally, its findings were supported by open big data and cancer cell lines. Results: TZAP expression level was not associated with the clinical parameters of HCC. TZAP expression induced a poorer survival result (overall survival, p = 0.020; disease-free survival, p = 0.012). TCGA data showed TZAP expression was more frequently found in HCCs with hepatitis C infection (p = 0.023). However, TCGA data revealed that TZAP expression did not predict HCC prognosis. In a cell line study, TZAP inhibition via siRNA suppressed PLC/PRF/5 cell growth; however, cell viability was increased in HepG2 cells. Conclusions: We presented the clinical and prognostic values of TZAP expression in HCC tissues and cancer cell lines. Additionally, the TCGA results also revealed a significant role for TZAP expression. TZAP expression may involve HCC progression and its prognosis.

Clinical Value of EZH2 in Hepatocellular Carcinoma and Its Potential for Target Therapy.

Background and objectives: EZH2 is overexpressed in hepatocellular carcinoma (HCC) and is correlated with poor prognosis. However, its clinical significance and molecular mechanism have not been studied in HCC. In this study, clinical and prognostic values of EZH2 was studied using Total Cancer Genome Atlas (TCGA) data and then, these data were confirmed in Huh1 and HepG2 cell lines. Materials and Methods: We used the TCGA database from cBioPortal. In addition, we analyzed EZH2 mRNA levels in HCC cell lines and its correlation with STAT3 and EZH2. Results: According to TCGA, EZH2 had a prognostic value in various cancers, especially in HCC. Furthermore, EZH2 in HCC was correlated with N stage (p = 0.045) and alpha-fetoprotein (AFP) > 20 ng/mL (p < 0.01). However, a negative association between EZH2 and age (p = 0.027) was found. The overall survival result of HCC was significantly poorer in patients with high EZH2 expression. In addition, the recurrence rate was also significantly higher in patients with high expression of EZH2 than those with low expression (χ2 = 16.10, p < 0.001). EZH2 expression was negatively correlated with STAT3 expression among EZH2-associated genes (R = -0.163, p = 0.002). EZH2 expression level was down-regulated to 50% or less compared to the control group treated negative siRNA. MTT assays showed that EZH2-siRNA affected on the viability of HCC cell line significantly. Conclusions: In conclusion, the overexpression of EZH2 was an independent biomarker for poor outcomes of HCC. However, more in vivo studies are required to identify the downstream target genes in HCC to improve our understanding of the biological role of EZH2 in HCC.

Variation of serratus anterior muscle originated from the clavipectoral fascia: a case report / Variación del músculo serrato anterior originado en la fascia clavipectoral: reporte de un caso

SUMMARY: The variations in the serratus anterior (SA) muscle are common. Here, we report a rare variation of the muscle origin with a potentially great clinical implication. We found an aberrant SA variation in an 81-year-old Korean male cadaver during a routine dissection for medical students. Additional slip (AS) of the SA originated from the clavipectoral fascia and the pectoralis minor. It traveled inferiorly and merged to the typical SA part. Precise knowledge about SA variations is clinically valuable; therefore, clinicians should be aware of the possible variation.

RESUMEN: Las variaciones en el músculo serrato anterior (MSA) son comunes. En este trabajo informamos una variación rara del origen muscular con una implicación clínica potencialmente importante. Encontramos una variación aberrante del MSA en un cadáver masculino, coreano de 81 años, durante una disección de rutina para estudiantes de medicina, con un fascículo adicional del MSA originado en la fascia clavipectoral y el músculo pectoral menor. Este fascículo se dirigió inferiormente y se fu- sionó con la parte común de MSA. El conocimiento preciso sobre las variaciones de MSA es útil clínicamente; por lo tanto, los médicos deben ser conscientes de esta posible variación.

Silencing CDCA8 Suppresses Hepatocellular Carcinoma Growth and Stemness via Restoration of ATF3 Tumor Suppressor and Inactivation of AKT/ß-Catenin Signaling.

Big data analysis has revealed the upregulation of cell division cycle associated 8 (CDCA8) in human hepatocellular carcinoma (HCC) and its poorer survival outcome. However, the functions of CDCA8 during HCC development remain unknown. Here, we demonstrate in vitro that CDCA8 silencing inhibits HCC cell growth and long-term colony formation and migration through the accumulation of the G2/M phase cell population. Conversely, CDCA8 overexpression increases the ability to undergo long-term colony formation and migration. RNA sequencing and bioinformatic analysis revealed that CDCA8 knockdown led to the same directional regulation in 50 genes (25 down- and 25 upregulated). It was affirmed based on protein levels that CDCA8 silencing downregulates the levels of cyclin B1 and p-cdc2 and explains how it could induce G2/M arrest. The same condition increased the protein levels of tumor-suppressive ATF3 and GADD34 and inactivated AKT/ß-catenin signaling, which plays an important role in cell growth and stemness, reflecting a reduction in sphere-forming capacity. Importantly, it was demonstrated that the extent of CDCA8 expression is much greater in CD133+ cancer stem cells than in CD133- cancer cells, and that CDCA8 knockdown decreases levels of CD133, p-Akt and ß-catenin and increases levels of ATF3 and GADD34 in the CD133+ cancer stem cell (CSC) population. These molecular changes led to the inhibition of cell growth and sphere formation in the CD133+ cell population. Targeting CDCA8 also effectively suppressed tumor growth in a murine xenograft model, showing consistent molecular alterations in tumors injected with CDCA8siRNA. Taken together, these findings indicate that silencing CDCA8 suppresses HCC growth and stemness via restoring the ATF3 tumor suppressor and inactivating oncogenic AKT/ß-catenin signaling, and that targeting CDCA8 may be the next molecular strategy for both primary HCC treatment and the prevention of metastasis or recurrence.

Clinicopathological Characteristics of TZAP Expression in Colorectal Cancers.

PURPOSE: The zinc finger protein, ZBTB48, is a telomere-associated protein. It was renamed as telomeric zinc finger-associated protein (TZAP) binding to elongated telomeres. However, its expression level was not measured in cancers. PATIENTS AND METHODS: We analyzed TZAP mRNA levels in 60 colorectal cancers (CRC) and its correlation with telomere length and TERT was studied. RESULTS: TZAP mRNA in CRC was higher statistically than that in paired non-cancerous tissues (p = 0.033). Higher TZAP was found in carcinoembryonic antigen (CEA)-positive CRCs (>5 ng/mL) (p = 0.012). Shorter telomere was found in CRCs with high TZAP expression than that with low TZAP expression (p = 0.010). According to quantitative correlation analysis, TZAP has a correlation with age (r = -0.349, p = 0.007), TERT (r = 0.279, p = 0.041) and telomere length (r = -0.305, p = 0.021). TZAP expression did not harbor prognostic value in CRC. Inhibition of TZAP expression by siRNA suppresses cell growth in HT29 cells; however, it resulted in increased cell viability in HCT116 cells. TZAP inhibition induces a decrease in mRNA levels of TERT in both HT29 and HCT116 cells. TCGA data analysis showed higher expression of TZAP showed poorer overall survival in colon cancer (p = 0.001); however, it did not have a significance in rectal cancer (p = 0.951). CONCLUSION: We suggested that TZAP may be a possible biomarker for CRC.

The Prognostic Significance of TERT Locus Polymorphism (rs36115365) in Surgically Resected Non-Small Cell Lung Cancer.

OBJECTIVE: Telomere length is an important factor for the development of non-small cell lung cancer (NSCLC), and current articles focused on telomere associated genes. We studied the clinicopathological and prognostic implications of rs36115365 polymorphism of the TERT-CLPTM1L locus in NSCLC. The association between rs36115365 and telomere length was investigated in 176 NSCLCs. METHODS: DNA was extracted from NSCLC tissues and polymorphism and telomere length were analyzed. RESULTS: The rs36115365 polymorphism showed the following frequencies according to the genotype: G/G in 81.8% of the patients, G/C in 14.2%, and C/C in 4.0%. Average telomere length in the tumor tissues were 3.06-fold longer than telomeres in paired non-tumor tissues (SD=1.87), and telomere length was not significantly different according to rs36115365 (p=0.134). The rs36115365 polymorphism did not have any relationships with clinicopathological characteristics. A poor overall survival result was found in NSCLC with C allele carriers than that with G/G allele (p=0.034). However, disease free survival rate was not different statistically (p=0.938). CONCLUSIONS: These findings suggest that rs36115365 may contribute to the progression of NSCLC.

Different TERT Expression between Colorectal Adenoma and Serrated Polyp.

Background and Objectives: Telomere regulation have an association with colorectal cancer. Previous studies demonstrated its implication in colorectal carcinogenesis. This study aimed to identify the role of telomerase reverse transcriptase (TERT) in colorectal carcinogenesis and determine TERT expression and their associated genes in precancerous lesions. Materials and Methods: TERT expression in 93 colorectal precursor lesions was analyzed. This included 61 tubular adenomas (TAs) and 32 serrated polyps (SPs). Furthermore, KRAS and BRAF gene mutations and microsatellite instability were analyzed. Statistical tests were performed to analyze the relationship between variables. Results: TERT expression in TAs, when compared with those observed in paired adjacent nontumor tissues, was 0.92 ± 0.78. TERT expression levels were significantly lower in SPs (0.38 ± 0.14, p < 0.001). KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001). TERT expression tended to be associated with KRAS mutations (46.7% vs. 22.0%, p = 0.098) and low-grade tumors (35.0% vs. 16.0%, p = 0.096), but this difference was insignificant. Conclusions: TERT expression has a pivotal role in progression to TAs in colorectal tissue. Considering the association between TERT expression and KRAS mutation, therapeutic drugs targeting this pathway can be developed for cancer prevention.

Clinicopathological Characteristics of PIK3CA Mutation and Amplification in Korean Patients with Breast Cancers.

The frequency of PIK3CA mutation and amplification was various and their clinical significances have not been clarified in Korean patients with invasive breast carcinoma (IBC). The study aimed to investigate the clinical and prognostic significances of PIK3CA mutation and amplification in IBC patients. DNA was isolated from paired normal and tumoral tissues in 128 IBC patients and the mutation and expression of PIK3CA gene were analyzed. PIK3CA mutation and expression was detected in 14.3% and 21.9% of IBC patients, respectively. And the level of PIK3CA expression was not different according to the presence of PIK3CA mutation (p = 0.775). PIK3CA mutation and expression were significantly associated with Luminal A type (p = 0.017 and p = 0.011, respectively). However, they did not have any clinical and prognostic values for IBC patients. This result suggested that alterations of PIK3CA pathway contribute to the pathogenesis of specific type of IBC.

Loss of the Association between Telomere Length and Mitochondrial DNA Copy Number Contribute to Colorectal Carcinogenesis.

Positive association between telomere length and mitochondrial DNA (mtDNA) copy number were introduced in healthy and patients with psychiatric disorder. Based on frequent genetic changes of telomere and mitochondria in colorectal carcinomas (CRC), we studied their clinical characteristics and their association in colorectal carcinogenesis. DNA was extracted from 109 CRCs, 64 colorectal tubular adenomas (TAs), and 28 serrated polyps (SPs), and then, telomere length and mtDNA copy number were analyzed in these legions by using a real-time PCR assay. Telomere length and mtDNA copy number (mean ± S.D) in CRCs was 1.87 ± 1.52 and 1.61 ± 1.37, respectively. In TAs and SPs, relative mtDNA copy number was 0.92 ± 0.71 and 1.84 ± 1.06, respectively, shoing statistical difference (p = 0.017). However, telomere length was similar in these precancerous legions. Telomere length and mtDNA copy number did not show clinical and prognostic values in CRCs, however, positive correlation between telomere length and mitochondrial DNA copy number were found in CRC (r = 0.408, p < 0.001). However, this association was not shown in precancerous lesions (r = -0.031, p = 0.765). This result suggests that loss of co-regulation between telomeres and mitochondrial function may induce the initiation or play a role as trigger factor of colorectal carcinogenesis.

Telomere shortening in non-tumorous and tumor mucosa is independently related to colorectal carcinogenesis in precancerous lesions.

Telomere shortening is associated with colorectal carcinogenesis and recent studies have focused on its characteristics in both normal mucosa and tumor tissues. To clarify the role of telomeres in colorectal carcinogenesis, we analyzed telomere shortening in normal and tumor regions of 93 colorectal precursor lesions. Telomere length was examined in 61 tubular adenomas (TAs) and 32 serrated polyps (SPs), and PIK3CA expression, KRAS mutation, BRAF mutation, and MSI were also analyzed. Telomere length was similar in normal and tumor tissues of TAs and SPs. In normal tissues of TAs, telomere shortening was associated with PIK3CA amplification (81.3% vs. 18.8%, p < 0.001), whereas it was associated with BRAF mutation in normal tissues of SPs (66.7% vs. 23.1%, p = 0.060). According to the analysis on tumor tissues, KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001), and telomere shortening was associated with mitochondrial microsatellite instability (63.6% vs. 36.4%, p = 0.030). These data suggested a pivotal role of telomere shortening in normal colorectal tissue for proceeding to TAs or SPs along with PIK3CA amplification and BRAF mutation, respectively. Moreover, telomeres in TAs may collaborate with mitochondrial instability for disease progression.

Topography of the middle genicular artery is associated with the superior and inferior genicular arteries / La topografía de la arteria genicular media está asociada con las arterias geniculares superiores e inferiores

Total knee arthroplasty has increased substantially, however anatomical studies of the genicular arteries (GAs) in this region are rare. The aim of this study was to identify the pattern and branching points of GAs and their relationship. In 42 lower limbs, the pattern and branching points of GAs were confirmed. The horizontal line which extends between the most prominent point of the lateral and medial margins of patella was defined as a reference line. The distance of branching point of the GAs from the reference line was measured, and the correlations between these points were analyzed. The superior lateral and medial genicular arteries (SLGA and SMGA) were located at + 38.17 ± 3.10 mm and + 32.68 ± 3.83 mm from the reference line, respectively. The middle genicular artery (MGA) was originated from + 7.57 ± 3.98 mm. The inferior lateral and medial genicular arteries (ILGA and IMGA) were located at - 18.46 ± 2.63 mm and - 24.09 ± 3.52 mm, respectively. The branching points of the SLGA changed significantly according to the arterial branching pattern with the MGA. In addition, the branching point of the MGA had positive relationships with that of the IMGA (r = 0.385, p <0.05) and that of the ILGA (r = 0.348, p <0.05), respectively. In this study, topography of the GAs and its anatomical association were demonstrated for the first time in Korean cadavers. Knowledge of the topography about frequent variation would be useful for safe surgery and clinical procedures.

La artroplastía total de rodilla ha aumentado sustancialmente, sin embargo los estudios anatómicos de las arterias geniculares (AGs) en esta región son escasos. El objetivo de este estudio fue identificar los patrones y puntos de ramificación de las AGs y sus relaciones. En 42 miembros inferiores, se identificaron el patrón y los puntos de ramificación de las AGs. La línea horizontal que se extiende entre el punto más prominente de los márgenes lateral y medial de la patela se definió como una línea de referencia. Se midió la distancia entre el punto de ramificación de las AGs y la línea de referencia, y se analizaron las correlaciones entre estos puntos. Las arterias geniculares superiores lateral y medial (AGSL y AGSM, respectivamente) se situaron a + 38,17 ± 3,10 mm y + 32,68 ± 3,83 mm de la línea de referencia, respectivamente, y la arteria genicular media (AGM) se originó a partir de + 7,57 ± 3,98 mm. Las arterias geniculares inferiores lateral y medial (AGIL e AGIM, respectivamente) se localizaron a - 18,46 ± 2,63 mm y - 24,09 ± 3,52 mm, respectivamente. Los puntos de ramificación de la AGSL cambiaron significativamente de acuerdo con el patrón de ramificación arterial con respecto a la AGSM. Además, el punto de ramificación de la AGSM tuvo relaciones positivas con el de la AGIM (r = 0.385, p <0.05) y el de la AGIL (r = 0.348, p <0.05). En este estudio, la topografía de las AGs y su asociación anatómica se demostraron por primera vez en cadáveres coreanos. El conocimiento de la topografía sobre la variación frecuente sería útil para su aplicación en el desarrollo de cirugías y procedimientos clínicos seguros.

Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer.

Mutations in the promoter region of telomerase reverse transcriptase (TERT) and alterations in telomere length (TL) have been the focus of research in various types of cancer. In the present study, the frequency and clinical characteristics of TERT promoter mutations and TL were studied in non-small cell lung cancers (NSCLC). TERT promoter mutations and TL were analyzed in 188 patients using DNA sequencing and the reverse transcription-quantitative polymerase chain reaction, respectively. The TERT promoter mutation rate was observed to be 2.2% (4/188 NSCLC cases), and it was significantly associated with regional lymph node invasion (P<0.001). No significant difference in TL was observed between the patients with and without TERT promoter mutations. TL was decreased in males (P=0.058 vs. females) and smokers (P=0.008 vs. non-smokers). Survival analyses demonstrated poor prognoses for patients with NSCLC with TERT promoter mutations (P<0.001). Multivariate survival analyses demonstrated that TERT promoter mutations were an independent prognostic marker for poor overall survival (P=0.045). The results of the present study demonstrated that TERT promoter mutation was not frequent in NSCLC; however, it may have value as a prognostic marker in NSCLC.

Telomere length is correlated with mitochondrial DNA copy number in intestinal, but not diffuse, gastric cancer.

A positive correlation between telomere length and mitochondrial DNA (mtDNA) copy number has previously been observed in healthy individuals, and in patients with psychiatric disorders. In the present study, telomere length and mtDNA copy number were evaluated in gastric cancer (GC) tissue samples. DNA was extracted from 109 GC samples (including 82 intestinal, and 27 diffuse cases), and the telomere length and mtDNA copy number were analyzed using a quantitative-polymerase chain reaction assay. The relative telomere length and mtDNA copy number in tumor tissue, as compared with in normal tissue, (mean ± standard deviation) in all GC samples were 11.48±1.14 and 14.86±1.35, respectively. Telomere length and mtDNA copy number were not identified as exhibiting clinical or prognostic value for GC. However, positive correlations between telomere length and mitochondrial DNA copy number were identified in GC (r=0.408, P<0.001) and in the adjacent normal mucosa (r=0.363; P<0.001). When stratified by Lauren classification, the correlation was identified in intestinal type GC samples (r=0.461; P<0.001), but not in diffuse type GC samples (r=0.225; P=0.260). This result indicated that loss of the correlation of telomeres and mitochondrial function may induce the initiation or progression of GC pathogenesis.

Topographical relations between the Gantzer's muscle and neurovascular structures.

PURPOSE: Gantzer's muscle (GM) is an additional muscle in the forearm, which develops as an accessory head of the flexor pollicis longus or the flexor digitorum profundus. The study aimed to determine the topography of the GM and to define the topographical relationship between the GM and the neurovascular structures surrounding it. METHODS: After confirming the presence of GM, its topography and the neurovascular structures were analyzed to determine the correlation between them in 73 upper limbs. RESULTS: The incidence of GM was 47.95% (35/73) and the average insertion point of GM was identified at 49.33 ± 7.47‰ (119.82 ± 20.80 mm) on the reference line between the medial epicondyle and the pisiform bone. And the branching points of the median nerve and the ulnar artery were located 19.91 ± 11.23‰ (52.21 ± 24.67 mm), 17.45 ± 8.39‰ (42.53 ± 20.54 mm) on the reference line, respectively. The presence of GM had no significant correlation with the position of the nerve branches. On the other hand, the branching point of the ulnar artery was distally located in the cases with the presence of the GM (17.35 ± 8.65 vs 19.42 ± 10.87, p = 0.031). There was a significant positive correlation between the point of arterial bifurcation and the length of the GM (r = 0.407, p = 0.015). CONCLUSIONS: This study suggested that the GM has a topographical relation with the arterial structures, perhaps for embryological reasons.

Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma.

Promoter mutations in telomerase reverse transcriptase (TERT) and telomere length have been studied in various tumors. In the present study, the frequency and clinical characteristics of TERT promoter mutation and telomere length were studied in hepatocellular carcinoma (HCC). TERT promoter mutation and telomere length were analyzed in 162 tumor samples of the patients with HCC by sequencing and real-time PCR, respectively. The TERT promoter mutation rate was 28.8% (46/160) in HCC and was associated with males (P = 0.027). The telomere length was not significantly different in the presence of a TERT promoter mutation but was shorter in high-grade tumor stages (P = 0.048). Survival analyses showed that poor overall survival was associated with longer telomere length (P = 0.013). However, the TERT promoter mutation did not have a prognostic value for HCC. Multivariate survival analyses demonstrated that the telomere length was an independent prognostic marker for poor overall survival (hazard ratio = 1.75, 95% confidence interval: 1.046-2.913, P = 0.033). These data demonstrated that TERT promoter mutation is a frequent event in HCC; however, telomere length, but not the presence of a TERT promoter mutation, might have potential value as a prognostic indicator of HCC.

Muscular axillary arch accompanying variation of the musculocutaneous nerve: axillary arch.

Continuous attention has been developed on the anatomical variations of the axilla in anatomist and surgeon due to their clinical importance. The axillary region is an anatomical space between the lateral part of the chest wall and the medial aspect of the upper limb. During the routine dissection of embalmed cadavers, we found variant muscular slip originating from the lateral border of tendinous part of the latissimus dorsi and continuing 9 cm more crossing the axilla. And then, it inserted into the superior margin of the insertion of the pectoralis major. We considered this muscular variation as axillary arch muscle. Correct identification of the relevant anatomy and subsequent simple surgical division is curative, paying special attention to anatomical variations in this region and its clinical importance due to its close relationship to the neurovascular elements of the axilla.

Antitumor effect and safety profile of systemically delivered oncolytic adenovirus complexed with EGFR-targeted PAMAM-based dendrimer in orthotopic lung tumor model.

Adenovirus (Ad)-mediated cancer gene therapy has been proposed as a promising alternative to conventional therapy for cancer. However, success of systemically administered naked Ad has been limited due to the immunogenicity of Ad and the induction of hepatotoxicity caused by Ad's native tropism. In this study, we synthesized an epidermal growth factor receptor (EGFR)-specific therapeutic antibody (ErbB)-conjugated and PEGylated poly(amidoamine) (PAMAM) dendrimer (PPE) for complexation with Ad. Transduction of Ad was inhibited by complexation with PEGylated PAMAM (PP) dendrimer due to steric hindrance. However, PPE-complexed Ad selectively internalized into EGFR-positive cells with greater efficacy than either naked Ad or Ad complexed with PP. Systemically administered PPE-complexed oncolytic Ad elicited significantly reduced immunogenicity, nonspecific liver sequestration, and hepatotoxicity than naked Ad. Furthermore, PPE-complexed oncolytic Ad demonstrated prolonged blood retention time, enhanced intratumoral accumulation of Ad, and potent therapeutic efficacy in EGFR-positive orthotopic lung tumors in comparison with naked Ad. We conclude that ErbB-conjugated and PEGylated PAMAM dendrimer can efficiently mask Ad's capsid and retarget oncolytic Ad to be efficiently internalized into EGFR-positive tumor while attenuating toxicity induced by systemic administration of naked oncolytic Ad.