Esophageal leiomyosarcoma is a rare tumor that accounts for less than 1% of all malignant esophageal tumors. Esophageal leiomyosarcoma combined with squamous cell carcinoma is even rarer than solitary leiomyosarcoma. We experienced a case of leiomyosarcoma combined with squamous cell carcinoma that progressed very rapidly.
Leiomyosarcoma; Carcinoma; Squamous cell; Esophagus; Sarcoma
The role of microRNAs (miRNAs) as a post-transcriptional gene regulator has been elucidated in a broad range of organisms including domestic animals. Characterization of miRNAs in normal tissues is an important step to investigate the functions of miRNAs in various physiological and pathological conditions. Using Illumina Next Generation Sequencing (NGS) technology, we identified a total of 292 known and 329 novel miRNAs in normal horse tissues including skeletal muscle, colon and liver. Distinct sets of miRNAs were differentially expressed in a tissue-specific manner. The miRNA genes were distributed across all the chromosomes except chromosomes 29 and 31 in the horse reference genome. In some chromosomes, multiple miRNAs were clustered and considered to be polycistronic transcript. A base composition analysis showed that equine miRNAs had a higher frequency of A+U than G+C. Furthermore, U tended to be more frequent at the 5′ end of miRNA sequences. This is the first experimental study that identifies and characterizes the global miRNA expression profile in normal horse tissues. The present study enriches the horse miRNA database and provides useful information for further research dissecting biological functions of miRNAs in horse.
Identification of novel biomarkers for tumor-initiating cells (TICs) is of critical importance for developing diagnostic and therapeutic strategies against cancers. Here we identified the role of KIAA1114, a full-length translational product of the trophinin gene, as a distinctive marker for TICs in human liver cancer by developing a DNA vaccine-induced monoclonal antibody targeting the putative extracellular domain of KIAA1114. Compared with other established markers of liver TICs, KIAA1114 was unique in that its expression was detected in both alpha fetoprotein (AFP)-positive and AFP-negative hepatocellular carcinoma (HCC) cell lines with the expression levels of KIAA1114 being positively correlated to their tumorigenic potentials. Notably, KIAA1114 expression was strongly detected in primary hepatic tumor, but neither in the adjacent non-tumorous tissue from the same patient nor normal liver tissue. KIAA1114high cells isolated from HCC cell lines displayed TIC-like features with superior functional and phenotypic traits compared to their KIAA1114low counterparts, including tumorigenic abilities in xenotransplantation model, in vitro colony- and spheroid-forming capabilities, expression of stemness-associated genes, and migratory capacity. Our findings not only address the value of a novel antigen, KIAA1114, as a potential diagnostic factor of human liver cancer, but also as an independent biomarker for identifying TIC populations that could be broadly applied to the heterogeneous HCC subtypes.
Tumor-initiating cells; hepatocellular carcinoma; KIAA1114; cell surface marker; monoclonal antibody
A 38-year-old female with a history of alcoholic liver cirrhosis visited our hospital with a massive hematochezia. An esophagogastroduodenoscopy did not demonstrate any bleeding source, and a colonoscopy showed a massive hemorrhage in the ascending colon but without an obvious focus. The source of the bleeding could not be found with a mesenteric artery angiography. We performed an enhanced abdominal computed tomography, which revealed a distal ascending colonic varix, and assumed that the varix was the source of the bleeding. We performed a venous coil embolization and histoacryl injection to obliterate the colon varix. The intervention appeared to be successful because the vital signs and hemoglobin laboratory data remained stable and because the hematochezia was no longer observed. We report here on a rare case of colonic variceal bleeding that was treated with venous coil embolization.
Colon ascending; Varicose veins; Liver cirrhosis; Therapeutic embolization
Myostracum, which is connected from the umbo to the edge of a scar, is not a single layer composed of prismatic layers, but a hierarchically complex multilayered shape composed of minerals and an organic matrix. Through the analysis of the secondary structure, the results revealed that a β-antiparallel structure was predominant in the mineral phase interface between the myostracum (aragonite) and bottom folia (calcite). After the complete decalcification and deproteinization, the membrane obtained from the interface between the myostracum buried in upper folia, and the bottom folia was identified as chitin. The transitional zone in the interface between the adductor muscle scar and folia are verified. The myostracum disappeared at the edge of the scar of the posterior side. From this study, the entire structure of the myostracum from the adult oyster shell of Crassostrea gigas could be proposed.
Angiosarcoma is a rare tumor that account for less than 1% of all sarcomas. Although hepatic angiosarcoma usually presents with unspecific symptoms, it rapidly progresses and has a high mortality. We report a rare case of primary hepatic angiosarcoma manifested as recurrent hemoperitoneum.
Angiosarcoma; Hemoperitoneum; Primary hepatic tumor
AIM: To evaluate the efficacy of short-term overlap lamivudine therapy with adefovir in patients with lamivudine-resistant and naïve chronic hepatitis B, we compared patients receiving overlap therapy with those receiving adefovir alone.
METHODS: Eighty patients who had received lamivudine treatment for various periods and had a lamivudine-resistant liver function abnormality were enrolled. Forty of these patients received adefovir treatment combined with lamivudine treatment for ≥ 2 mo, while the other 40 received adefovir alone. We assessed the levels of hepatitis B virus (HBV) DNA at 0, 12 and 48 wk and serum alanine aminotransferase (ALT) levels after 0, 12, 24 and 48 wk of adefovir treatment in each group.
RESULTS: We found serum ALT became normalized in 72 (87.5%) of the 80 patients, and HBV DNA decreased by ≥ 2 log10 copies/mL in 60 (75%) of the 80 patients at the end of a 48-wk treatment. HBV DNA levels were not significantly different between the groups. The improvements in serum ALT were also not significantly different between the two groups.
CONCLUSION: These findings suggest short-term overlap lamivudine treatment results in no better virological and biological outcomes than non-overlap adefovir monotherapy.
Adefovir dipivoxil; Chronic hepatitis B; Hepatitis B virus DNA; Overlap
T follicular helper (Tfh) cells are specialized providers of cognate B cell help, which is important in promoting the induction of high-affinity antibody production in germinal centers (GCs). Interleukin-6 (IL-6) and IL-21 have been known to play important roles in Tfh cell differentiation. Here, we demonstrate that IL-7 plays a pivotal role in Tfh generation and GC formation in vivo, as treatment with anti-IL-7 neutralizing antibody markedly impaired the development of Tfh cells and IgG responses. Moreover, codelivery of mouse Fc-fused IL-7 (IL-7-mFc) with a vaccine enhanced the generation of GC B cells as well as Tfh cells but not other lineages of T helper cells, including Th1, Th2, and Th17 cells. Interestingly, a 6-fold-lower dose of an influenza virus vaccine codelivered with Fc-fused IL-7 induced higher antigen-specific and cross-reactive IgG titers than the vaccine alone in both mice and monkeys and led to markedly enhanced protection against heterologous influenza virus challenge in mice. Enhanced generation of Tfh cells by IL-7-mFc treatment was not significantly affected by the neutralization of IL-6 and IL-21, indicating an independent role of IL-7 on Tfh differentiation. Thus, IL-7 holds promise as a critical cytokine for selectively inducing Tfh cell generation and enhancing protective IgG responses.
IMPORTANCE Here, we demonstrate for the first time that codelivery of Fc-fused IL-7 significantly increased influenza virus vaccine-induced antibody responses, accompanied by robust expansion of Tfh cells and GC B cells as well as enhanced GC formation. Furthermore, IL-7-mFc induced earlier and cross-reactive IgG responses, leading to striking protection against heterologous influenza virus challenge. These results suggest that Fc-fused IL-7 could be used for inducing strong and cross-protective humoral immunity against highly mutable viruses, such as HIV and hepatitis C virus, as well as influenza viruses.
Agonistic anti–4-1BB suppresses autoimmune and allergic inflammation via binding to Galectin-9, which facilitates 4-1BB aggregation, signaling, and functional activity.
Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fcγ receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agonist anti–4-1BB in suppressing autoimmune and allergic inflammation was completely dependent on Galectin-9 (Gal-9). Gal-9 directly bound to 4-1BB, in a site distinct from the binding site of antibodies and the natural ligand of 4-1BB, and Gal-9 facilitated 4-1BB aggregation, signaling, and functional activity in T cells, dendritic cells, and natural killer cells. Conservation of the Gal-9 interaction in humans has important implications for effective clinical targeting of 4-1BB and possibly other TNFR superfamily molecules.
The ChlR1 DNA helicase is mutated in Warsaw breakage syndrome characterized by developmental anomalies, chromosomal breakage, and sister chromatid cohesion defects. However, the mechanism by which ChlR1 preserves genomic integrity is largely unknown. Here, we describe the roles of ChlR1 in DNA replication recovery. We show that ChlR1 depletion renders human cells highly sensitive to cisplatin; an interstrand-crosslinking agent that causes stalled replication forks. ChlR1 depletion also causes accumulation of DNA damage in response to cisplatin, leading to a significant delay in resolution of DNA damage. We also report that ChlR1-depleted cells display defects in the repair of double-strand breaks induced by the I-PpoI endonuclease and bleomycin. Furthermore, we demonstrate that ChlR1-depeleted cells show significant delays in replication recovery after cisplatin treatment. Taken together, our results indicate that ChlR1 plays an important role in efficient DNA repair during DNA replication, which may facilitate efficient establishment of sister chromatid cohesion.
ChlR1 DNA helicase; DNA replication; DNA damage; replication recovery; sister chromatid cohesion; Warsaw breakage syndrome
The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment epithelial cell fate. In contrast, absence of ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating ephrin and Wnt/β-catenin signaling may, thus, represents a viable approach to activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.
Adult stem cells; cell signaling; neural differentiation; retina; stem cell plasticity
Hemolytic uremic syndrome (HUS) is a rare thrombotic complication characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS may be caused by several different conditions, including infection, malignancy, and chemotherapeutic agents, such as mitomycin, cisplatin, and most recently, gemcitabine. The outcome of gemcitabine-induced HUS is poor, and the disease has a high mortality rate. This study reports a case of gemcitabine-induced HUS in a patient with pancreatic cancer in Korea.
Hemolytic-uremic syndrome; Gemcitabine; Pancreatic neoplasms
We evaluated the safety and accuracy of ultrasonography-guided percutaneous core biopsy collection in patients with renal masses.
Materials and Methods
From June 2008 to August 2012, 30 percutaneous core biopsies of renal masses were performed. The biopsies obtained were small tumors (<4 cm) with ambiguous radiologic findings or that met classic renal biopsy indications. The biopsy results were compared with the final pathological results after definitive surgical treatment. Ultrasonography was performed on the day after biopsy collection to rule out any complications.
The mean age of the patients was 57.7 years, and the mean tumor size was 3.39 cm. Twelve of the lesions were in the left kidney, and 18 were in the right kidney. All but one core biopsy contained sufficient material for histopathological analysis. The biopsy results showed 17 renal cell carcinomas (56.7%), 3 angiomyolipomas (10.0%), 2 oncocytomas (6.7%), 1 adenocarcinoma (3.3%), and 7 benign lesions (23.3%). A total of 18 cases underwent surgery, and the pathological results confirmed the initial biopsy diagnosis for 17 of 18 cases (94.4%). The one (5.9%) inaccurate biopsy result was found to be a urothelial carcinoma of the kidney. No needle tract seeding was found in the pathological specimens or on follow-up imaging. A small perinephric hematoma (1-2 cm) was seen in 5 cases (16.7%), but all patients remained hemodynamically stable.
Ultrasonography-guided renal biopsy is a safe, effective, and accurate method for evaluating small renal masses. This procedure may help in selecting treatment modalities for small renal masses.
Fine-needle biopsy; Kidney
Dendritic cells (DC) in the gut promote immune tolerance by expressing retinal dehydrogenase (RALDH), an enzyme that promotes retinoic acid (RA), which aids differentiation of inducible Foxp3+ Treg (iTreg) in the intestinal mucosa. How RALDH expression is regulated is unclear. We found that 4-1BB (CD137), a member of the TNFR family, together with CD103, marked mesenteric lymph node DC with the highest level of RALDH activity, and ligation of 4-1BB maintained RALDH expression in these gut DC. Moreover, 4-1BB signals synergized with those through TLR2 or GM-CSFR to promote RALDH activity in undifferentiated DC. Correspondingly, 4-1BB-deficient mice were impaired in their ability to generate iTreg in the GALT when exposed to oral antigen, and 4-1BB-deficient mesenteric lymph node DC displayed weak RALDH activity and were poor at promoting iTreg development. Thus, our data demonstrate a novel activity of 4-1BB in controlling RALDH expression and the regulatory activity of DC.
A variety of telomere protection programs are utilized to preserve telomere structure. However, the complex nature of telomere maintenance remains elusive. The Timeless protein associates with the replication fork and is thought to support efficient progression of the replication fork through natural impediments, including replication fork block sites. However, the mechanism by which Timeless regulates such genomic regions is not understood. Here, we report the role of Timeless in telomere length maintenance. We demonstrate that Timeless depletion leads to telomere shortening in human cells. This length maintenance is independent of telomerase, and Timeless depletion causes increased levels of DNA damage, leading to telomere aberrations. We also show that Timeless is associated with Shelterin components TRF1 and TRF2. Timeless depletion slows telomere replication in vitro, and Timeless-depleted cells fail to maintain TRF1-mediated accumulation of replisome components at telomeric regions. Furthermore, telomere replication undergoes a dramatic delay in Timeless-depleted cells. These results suggest that Timeless functions together with TRF1 to prevent fork collapse at telomere repeat DNA and ensure stable maintenance of telomere length and integrity.
TRF1; replication efficiency; telomere; telomere aberration; the fork protection complex; timeless
To report the three-year outcomes of macular laser photocoagulation following intravitreal injection of triamcinolone acetonide (IVTA) for diffuse diabetic macular edema (DME).
A prospective, randomized controlled study was completed. Eighty-six eyes of 74 patients with diffuse DME were randomized into two groups. Eyes assigned to the combination group (n = 48) were subjected to macular laser photocoagulation three weeks after IVTA. Eyes in the IVTA group (n = 38) underwent IVTA alone. Central macular thickness was measured by optical coherence tomography, and the number of additional treatments and mean time to recurrence were assessed.
Thirty-seven eyes in the combination group and 26 eyes in the IVTA group completed the three-year follow-up. Recurrence of DME after initial treatment was not observed for nine of the 37 (24.3%) eyes in the combination group or for one of the 26 (3.9$) eyes in the IVTA group (p = 0.028). DME was absent for 19.9 months after treatment in the combination group compared to 10.3 months in the IVTA group (p = 0.027). The mean number of additional treatments was 0.92 in the combination group and 1.88 in the IVTA group (p = 0.001).
Results in the subset of subjects who completed the three-year follow-up demonstrated that laser photocoagulation following IVTA is more effective than IVTA monotherapy for diffuse DME. Combination therapy required fewer additional treatments and resulted in a lower recurrence rate than IVTA monotherapy.
Diabetic retinopathy; Intravitreal injections; Laser therapy; Macular edema; Triamcinolone
A laparoscopic transperitoneal approach allowed for resection of a pulmonary sequestration avoiding an open thoracoabdominal incision.
Pulmonary sequestration is a rare cystic malformation composed of bronchopulmonary tissue that is discontinuous from the tracheobronchial tree and has an anomalous systemic blood supply. We present a case of a 40-y-old male who presented with an extralobar pulmonary sequestration and underwent a laparoscopic retroperitoneal mass excision. Preoperative imaging revealed a large 11.3-cm retroperitoneal tumor consisting of a multiloculated cystic lesion. The patient was discharged home, and at 3-mo follow-up no complaints were reported.
Laparoscopy; Bronchopulmonary sequestration
The Bosniak renal cyst classification has been accepted by urologists and radiologists as a way of diagnosing cystic renal masses and determining the management approach. We report two cases of a renal cystic mass that showed a category change from category II on the basis of enhanced computed tomography to category IV after further gadolinium-enhanced magnetic resonance imaging. In both cases, the cysts were later confirmed as kidney cancer by pathology.
Cysts; Kidney; Magnetic resonance imaging
TGF-β can induce Foxp3+ inducible regulatory T cells (Treg) and also synergize with IL-6 and IL-4 to induce Th17 and Th9 cells. We now report that NO modulates TGF-β activity away from Treg but toward the Th1 lineage. NO potentiated Th1 differentiation in the presence of TGF-β in both IL-12–independent and –dependent fashions by augmenting IFN-γ–activated STAT-1 and T-bet. Differentiation into Treg, Th1, and Th17 lineages could be modulated by NO competing with other cofactors, such as IL-6 and retinoic acid. NO antagonized IL-6 to block TGF-β–directed Th17 differentiation, and together with IL-6, NO suppressed Treg development induced by TGF-β and retinoic acid. Furthermore, we show that physiologically produced NO from TNF and inducible NO synthase-producing dendritic cells can contribute to Th1 development predominating over Treg development through a synergistic activity induced when these cells cocluster with conventional dendritic cells presenting Ag to naive Th cells. This illustrates that NO is another cofactor allowing TGF-β to participate in development of multiple Th lineages and suggests a new mechanism by which NO, which is associated with protection against intracellular pathogens, might maintain effective Th1 immunity.
Here we report a case of central retinal artery occlusion after chiropractic manipulation on the neck. A 49-year old man presented at the hospital because of sudden visual loss in his right eye after chiropractic neck manipulation. He had received chiropractic manipulation of the neck by a chiropractor eight days prior. When he first visited us, his best corrected visual acuity in his right eye was hand motion. A full ophthalmic examination was performed. There was cherry-red spot in the macula in his right eye. We performed a fluorescein angiogram and cervical color Doppler. The arterio-venous transit time in the fluorescein angiogram was delayed, and we detected stenosis of the right internal carotid artery with diffuse atherosclerotic plaques in the right common carotid artery. We prescribed ginko biloba extract (Tanamin). Three years after his first visit, the best corrected visual acuity of his right eye was 20 / 200.
Chiropractic manipulation; Retinal artery occlusion
Signal transducers and activators of transcription (STATs) are a family of transcription factors that are activated in response to cytokines and growth factors. STAT3 activation has been implicated in modulating the activity of downstream mediators, such as Bcl-xL and matrix metalloproteinase-2 (MMP-2). The aim of this study was to investigate the immunohistochemical expression of STAT3, B-cell lymphoma-extra large (Bcl-xL), and MMP-2 proteins according to histopathological parameters in colon adenocarcinomas, including lymph node metastasis, tumor differentiation, the TNM stage and the tumor size.
Immunohistochemical staining with monoclonal STAT3, Bcl-xL, and MMP-2 antibodies was performed on paraffin-embedded specimens from 20 colon adenomas and 39 adenocarcinomas.
The expression of STAT3, Bcl-xL, and MMP-2 was increased in the adenocarcinomas as compared with the adenomas (p<0.001). STAT3 expression was stronger in tumors with a distant metastasis than in tumors without a distant metastasis (p=0.012). A larger tumor size was related to an increase in STAT3 expression (p=0.035).
STAT3, Bcl-xL, and MMP-2 may play important roles in the tumorigenesis of colorectal carcinoma. STAT3 may be indicative of a poor prognosis due to its correlation with distant metastases and a larger tumor size.
Colon; Signal transducers and activators of transcription 3; B-cell lymphoma-extra large; Matrix metalloproteinase-2
Two-component triblock magnetic nanorods with gold end blocks and nickel interior blocks have been synthesized and used as affinity templates for the simultaneous and efficient separation of a three component protein mixture. The gold blocks were selectively functionalized with 11-amino-1-undecanethiol, and then glutaraldehyde was used to covalently attach nitrostreptavidin to them. His-tagged proteins bind to the nickel block and biotin-tagged proteins bind to the functionalized gold ends, allowing one to separate a mixture of three proteins with a single material. Each surface bound protein can be released selectively using imidazole for the His-tagged protein and biotin for the biotinylated protein.
Biotin tagged protein; Histidine tagged protein; Magnetic nanorod; Protein separation
The initial requirement for the emergence of CMV-specific CD8+ T cells is poorly understood. Mice deficient in the cosignaling TNF superfamily member, 4-1BB, surprisingly developed exaggerated early CD8+ T-cell responses to mouse CMV (MCMV). CD8+ T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations. Paradoxically, 4-1BB-deficient mice displayed reduced accumulation of memory CD8+ T cells that expand during chronic/latent infection. Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8+ T cells, whereas suppression of acute CD8+ T cells was independent of 4-1BBL. These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.
4-1BB; CD8+ T cells; CMV; Memory
To describe the clinical characteristics of idiopathic juxtafoveal telangiectasis (IJT) in Koreans.
Medical records of 16 patients with IJT were analyzed during the period from 1997 to 2009. Diagnosis was based on biomicrosopic and fluorescein angiographic findings and the group was determined according to the Gass and Blodi classification.
We analyzed eight patients in group 1A (50%), two in group 1B (12.5%), and six in group 2A (37.5%). Diverse treatment modalities, such as macular laser photocoagulation, photodynamic therapy, intravitreal antiangiogenic agent, and steroid injection, were applied for macular edema in nine eyes; however, only two eyes showed visual improvement.
In this case series, group 1A was the most common. For macular edema related to IJT, current treatment strategies had no consistent effect.
Idiopathic Juxtafoveal Retinal Telangiectasia; Intravitreal Injection; Macular edema; Photochemotherapy
A respiratory monitoring system based on a quartz crystal microbalance (QCM) sensor with a functional film was designed and investigated. Porphyrins 5,10,15,20-tetrakis-(4-sulfophenyl)-21H,23H-porphine (TSPP) and 5,10,15,20-tetrakis-(4-sulfophenyl)-21H, 23H-porphine manganese (III) chloride (MnTSPP) used as sensitive elements were assembled with a poly(diallyldimethyl ammonium chloride) (PDDA). Films were deposited on the QCM resonators using layer-by-layer method in order to develop the sensor. The developed system, in which the sensor response reflects lung movements, was able to track human respiration providing respiratory rate (RR) and respiratory pattern (RP). The sensor system was tested on healthy volunteers to compare RPs and calculate RRs. The operation principle of the proposed system is based on the fast adsorption/desorption behavior of water originated from human breath into the sensor films deposited on the QCM electrode.
respiratory monitoring; quartz crystal microbalance; porphyrin based thin films; layer-by layer approach; sensor array