Srcasm Regulates Tyrosine Kinases in Skin Cancer: Implications for Precision Medicine.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in humans, with an incidence of approximately 700,000 cases per year in the United States (Rogers et al., 2010). It is known that cSCC is strongly associated with sun exposure, specifically UVB and UVA, as well as other risk factors, such as human papillomavirus infection, immunodeficiency, and specific medications (Ratushny et al., 2012). However, the precise sequence of biological events leading to tumor development remains unknown. With projected higher incidence of patients with cSCCs in the future, there is a strong need to elucidate the molecular pathways that regulate formation of cSCCs.

[A Case of Remnant Gastric Cancer That Completely Responded to Neoadjuvant S-1 and Cisplatin Therapy].

A 69-year-old man, who had undergone distal gastrectomy for duodenal ulcer, was diagnosed with remnant gastric cancer and jejunal mesenteric lymph node metastasis. To improve curability, we planned 2 courses of S-1 and cisplatin therapy. After chemotherapy, primary lesion and lymph node metastases reduced in size drastically. Completion gastrectomy and lymph node dissection were performed with curative intent. The tumor was found to have a pathological complete response(pCR) to chemotherapy on histological examination.

Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium.

Autophagy is an evolutionarily conserved catabolic mechanism that relieves cellular stress by removing/recycling damaged organelles and debris through the action of lysosomes. Compromised autophagy has been implicated in many neurodegenerative diseases, including retinal degeneration. Here we examined retinal phenotypes resulting from RPE-specific deletion of the autophagy regulatory gene Atg7 by generating Atg7(flox/flox);VMD2-rtTA-cre+ mice to determine whether autophagy is essential for RPE functions including retinoid recycling. Atg7-deficient RPE displayed abnormal morphology with increased RPE thickness, cellular debris and vacuole formation indicating that autophagy is important in maintaining RPE homeostasis. In contrast, 11-cis-retinal content, ERGs and retinal histology were normal in mice with Atg7-deficient RPE in both fasted and fed states. Because A2E accumulation in the RPE is associated with pathogenesis of both Stargardt disease and age-related macular degeneration (AMD) in humans, deletion of Abca4 was introduced into Atg7(flox/flox);VMD2-rtTA-cre+ mice to investigate the role of autophagy during A2E accumulation. Comparable A2E concentrations were detected in the eyes of 6-month-old mice with and without Atg7 from both Abca4(-/-) and Abca4(+/+) backgrounds. To identify other autophagy-related molecules involved in A2E accumulation, we performed gene expression array analysis on A2E-treated human RPE cells and found up-regulation of four autophagy related genes; DRAM1, NPC1, CASP3, and EIF2AK3/PERK. These observations indicate that Atg7-mediated autophagy is dispensable for retinoid recycling and A2E deposition; however, autophagy plays a role in coping with stress caused by A2E accumulation.

[A Case of Locally Far-Advanced Colon Cancer Resected by Laparoscopic Surgery after Colonic Stent Insertion and Neoadjuvant Chemotherapy].

We report a case of locally far-advanced colon cancer resected by laparoscopic surgery after colonic stent insertion and neoadjuvant chemotherapy. A 71-year-old man with obstructive symptoms was admitted to our hospital in July 2015. CT revealed a sigmoid colon tumor infiltrating the retroperitoneum and small intestine. Lower gastrointestinal endoscopy showed a sigmoid colon cancer. Self-expandable metallic stent insertion for obstructive colon cancer alleviated the patient's symptoms quickly. Four courses of neoadjuvant chemotherapy(XELOX)reduced the primary tumor in size, allowing for laparoscopic surgical resection. Combination therapy with colonic stenting and neoadjuvant chemotherapy can be an effective treatment for obstructive colon cancer. However, further studies and additional cases are needed to assess the safety and efficacy of this combination therapy.

[New FP Therapy Was Effective for a Case of Massive Hepatocellular Carcinoma].

A 62 year-old woman was hospitalized with the diagnosis of pneumonia, and a huge mass was recognized in the right lobe of the liver during a CT scan. AFP and PIVKA-Ⅱ were elevated to 101.05 ng/mL and 2,177 mAU/mL. The liver function test indicated Child-Pugh classification A, liver damage degree B, and ICG R15 34%. We judged a radical cure resection impossible. We treated the patient with arterial injections of modified new FP therapy. No side effect occurred during the first course. Liver dysfunction with fever and hematuria occurred during the second course, leading to discontinuation of therapy. Because a prominent reduction in the size of the tumor was achieved, liver resection is scheduled. New FP therapy can be expected to attain a favorable result that may allow for curative resection of the tumor.

[A Case of Locally Advanced Gastric Cancer after Neoadjuvant Chemotherapy].

A 60s male was admitted to our hospital because of appetite loss and nausea. After examination, he was diagnosed with type 3 advanced gastric cancer in the antrum. Abdominal computed tomography showed gastric cancer invasion to the left liver lobe. We initiated neoadjuvant chemotherapy using S-1 plus CDDP after laparoscopic gastrojejunostomy. S-1 was orally administered for 3 weeks followed by a 2-week drug-free period. CDDP was administered intravenously on day 8 of each course. After 5 courses of chemotherapy, the gastric cancer was reduced in size. We therefore performed total gastrectomy with D2-affiliated left liver resection. S-1 plus CDDP is expected to improve outcomes in unresectable or locally advanced gastric cancer.

[A case of juvenile colon cancer with peritoneal dissemination treated effectively by use of resection and chemotherapy].

A 37 -year-old man experienced abdominal pain and vomiting. Computed tomography showed massive ascites and obstruction of the colon by a tumor at the left colic flexure. The tumor was classified as advanced Borrmann type 3 on the basis of a colonoscopy. Palliative resection of the colon and colostomy on the oral side were performed. Operative findings showed massive peritoneal dissemination of the tumor. We administered palliative chemotherapy consisting of capecitabine/oxaliplatin (XELOX) and bevacizumab. After 4 courses of chemotherapy, the primary and disseminated tumors and ascites had disappeared, and tumor marker expression levels were within normal range. Palliative resection and subsequent chemotherapy was effective for this young patient with very advanced colon cancer that had disseminated and caused obstruction.

[Large bowel malignant obstruction treated with SEMS placement as a bridge to surgery procedure].

We treated 5 cases of preoperative decompression using the self-expandable metallic stent (SEMS) against obstructive left side colon cancer since October 2013. The obstruction site was the descending colon in one patient, sigmoid colon in 2, rectal-sigmoid colon in 1, and rectum in 1. Colonic stent placements were successful in all cases. Oral intake started an average of 3.7 days after SEMS placement. All patients underwent radical surgery an average of 17.2 days after SEMS placement. Two patients waited for surgery while out of the hospital. All patients underwent colonoscopy. One patient had advanced colon cancer. Our findings show that SEMS placement can treat obstructive left-sided colon cancer.

[A case of advanced gastric cancer with esophageal severe dysplasia resected after neoadjuvant S-1+cisplatin therapy].

A 72-year-old man was admitted to our hospital complaining of upper abdominal pain and back pain. Advanced gastric cancer was found at the fundus of the stomach, and severe dysplasia was found at the lower esophagus. We proceeded with neoadjuvant chemotherapy (S-1+CDDP) because the lymph nodes in the lesser curvature of the stomach were metastasized and invasion of the pancreas and some vessels was suspected by computed tomography. The tumor size was reduced remarkably, the esophageal dysplasia disappeared after preoperative chemotherapy, and we were able to perform total gastrectomy.

In Situ Observation of Liquid Solder Alloys and Solid Substrate Reactions Using High-Voltage Transmission Electron Microscopy.

The complex reaction between liquid solder alloys and solid substrates has been studied ex-situ in a few studies, utilizing creative setups to "freeze" the reactions at different stages during the reflow soldering process. However, full understanding of the dynamics of the process is difficult due to the lack of direct observation at micro- and nano-meter resolutions. In this study, high voltage transmission electron microscopy (HV-TEM) is employed to observe the morphological changes that occur in Cu6Sn5 between a Sn-3.0 wt%Ag-0.5 wt%Cu (SAC305) solder alloy and a Cu substrate in situ at temperatures above the solidus of the alloy. This enables the continuous surveillance of rapid grain boundary movements of Cu6Sn5 during soldering and increases the fundamental understanding of reaction mechanisms in solder solid/liquid interfaces.

Distinct transcriptomes define rostral and caudal serotonin neurons.

The molecular architecture of developing serotonin (5HT) neurons is poorly understood, yet its determination is likely to be essential for elucidating functional heterogeneity of these cells and the contribution of serotonergic dysfunction to disease pathogenesis. Here, we describe the purification of postmitotic embryonic 5HT neurons by flow cytometry for whole-genome microarray expression profiling of this unitary monoaminergic neuron type. Our studies identified significantly enriched expression of hundreds of unique genes in 5HT neurons, thus providing an abundance of new serotonergic markers. Furthermore, we identified several hundred transcripts encoding homeodomain, axon guidance, cell adhesion, intracellular signaling, ion transport, and imprinted genes associated with various neurodevelopmental disorders that were differentially enriched in developing rostral and caudal 5HT neurons. These findings suggested a homeodomain code that distinguishes rostral and caudal 5HT neurons. Indeed, verification studies demonstrated that Hmx homeodomain and Hox gene expression defined an Hmx(+) rostral subtype and Hox(+) caudal subtype. Expression of engrailed genes in a subset of 5HT neurons in the rostral domain further distinguished two subtypes defined as Hmx(+)En(+) and Hmx(+)En(-). The differential enrichment of gene sets for different canonical pathways and gene ontology categories provided additional evidence for heterogeneity between rostral and caudal 5HT neurons. These findings demonstrate a deep transcriptome and biological pathway duality for neurons that give rise to the ascending and descending serotonergic subsystems. Our databases provide a rich, clinically relevant resource for definition of 5HT neuron subtypes and elucidation of the genetic networks required for serotonergic function.

In-Situ Observation of the Continuous Phase Transition in Determining the High Thermoelectric Performance of Polycrystalline Sn0.98Se.

We report a comprehensive in-situ phase-change study on polycrystalline Sn0.98Se via high-temperature X-ray diffraction and in-situ high-voltage transmission electron microscopy from room temperature to 843 K. The results clearly demonstrate a continuous phase transition from Pnma to Cmcm starting from 573 to 843 K, rather than a sudden transition at 800 K. We also find that the thermal-conductivity rise at high temperature after the phase transition, as commonly seen in pristine SnSe, does not occur in Sn0.98Se, leading to a high thermoelectric figure of merit. Density functional theory calculations reveal the origin to be the suppression of bipolar thermal conduction in the Cmcm phase of Sn0.98Se due to the enlarged bandgap. This work fills the gap of in-situ characterization on polycrystalline Sn0.98Se and provides new insights into the outstanding thermoelectric performance of polycrystalline Sn0.98Se.

Synthesis of zero-valent iron nanoparticles via laser ablation in a formate ionic liquid under atmospheric conditions.

Transition metal nanoparticles (NPs) are promising materials for use as catalysts in many processes, although they are easily oxidized under ambient conditions. In this communication, a novel synthetic method is proposed for producing zero-valent iron (Fe) NPs by laser ablation under atmospheric conditions using the reducing properties of a formate-based ionic liquid solvent. The valence state of Fe was confirmed using X-ray absorption near edge structure (XANES) spectroscopy. The Fe NPs adopt a face centered cubic structure after synthesis, which gradually transforms to a body centered cubic structure after one month. The method can be extended to the synthesis of other transition metal NPs that are easily oxidized.

Imaging the Polymorphic Transformation in a Single Cu6Sn5 Grain in a Solder Joint.

In-situ observations of the polymorphic transformation in a single targeted Cu6Sn5 grain constrained between Sn-0.7 wt % Cu solder and Cu-Cu3Sn phases and the associated structural evolution during a solid-state thermal cycle were achieved via a high-voltage transmission electron microscope (HV-TEM) technique. Here, we show that the monoclinic η'-Cu6Sn5 superlattice reflections appear in the hexagonal η-Cu6Sn5 diffraction pattern upon cooling to isothermal 140 °C from 210 °C. The in-situ real space imaging shows that the η'-Cu6Sn5 contrast pattern is initiated at the grain boundary. This method demonstrates a new approach for further understanding the polymorphic transformation behavior on a real solder joint.

Enriched environments influence depression-related behavior in adult mice and the survival of newborn cells in their hippocampi.

Major depression is a highly prevalent mental disorder and environmental factors have been strongly implicated in its pathophysiology. Clinical studies have demonstrated that stress or depression can lead to atrophy and cell loss in the hippocampus. Studies of animal models of depression have suggested that reduced neurogenesis in the adult hippocampus might contribute to such structural changes and to the behavior of these animals. On the other hand, increased hippocampal neurogenesis can be induced by the administration of antidepressants or electroconvulsive seizure, suggesting that increased neurogenesis might be related to the treatment of depression. Thus, an enriched environment (EE), which also enhances neurogenesis, is expected to have therapeutic effects on depression-related behaviors. To investigate the effects of an EE during adulthood on these behaviors, we subjected adult mice housed in an EE for five weeks to behavioral tests. In an open field test, EE mice exhibited a decrease in the distance traveled and an increase in the amount of time spent in the center. The startle response was smaller in EE mice than in control mice. EE mice also showed reduced immobility time in a forced swim test. The immobility time in EE mice was approximately half that observed in mice treated with a tricyclic antidepressant, imipramine. In our experimental condition, increased survival of newborn cells was observed in EE mice by 5-bromo-2'-deoxyuridine (BrdU)-labeled immunohistochemistry. Double-staining of BrdU and a mature neuron marker, NeuN, revealed that the majority of surviving cells were neurons. Our results suggest that EE, which enhanced the survival of newborn neurons, shows beneficial effects on behavioral despair and habituation to a novel environment.

Our experiences in surgical treatment for hilar cholangiocarcinoma.

BACKGROUND/AIMS: Although resection for hilar cholangiocarcinoma usually requires difficult surgical manipulations, it is only one therapeutic modality for a permanent cure or a desirable prognosis. We verified our own experiences after surgical treatment for hilar cholangiocarcinoma. METHODOLOGY: This study included 24 patients with hilar cholangiocarcinoma from 1981 to 2002. The current study mainly evaluated postoperative complications and overall prognosis after resection. RESULTS: Twenty-one patients received tumor resection. Hepatic resection including extended hepatectomy was required in 19 patients (90.5%). Postoperative morbidity was observed in 16 (71.2%), and motality in 2 (9.5%). The overall 5-year survival rate was 33.7%, and median survival was 35.7 months. Tumor extent in the TNM stage (p = 0.011) and the existence of lymph node metastases (p = 0.038) were identified as significant prognostic factors in overall survival after operation by univariate analysis. Postoperative adjuvant radio-chemotherapy after resection improved their prognosis (p = 0.010). CONCLUSIONS: Our results suggest that aggressive resection and appropriate adjuvant therapies for hilar cholangiocarcinoma might make a better prognosis possible, especially in patients without lymph node metastases excluding advanced tumor.

Differential roles of glial and neuronal glutamate transporters in Purkinje cell synapses.

Glutamate transporters are essential for terminating excitatory neurotransmission. Two distinct glutamate transporters, glutamate-aspartate transporter (GLAST) and excitatory amino acid transporter 4 (EAAT4), are expressed most abundantly in the molecular layer of the cerebellar cortex. GLAST is expressed in Bergmann glial processes surrounding excitatory synapses on Purkinje cell dendritic spines, whereas EAAT4 is concentrated on the extrasynaptic regions of Purkinje cell spine membranes. To clarify the functional significance of the coexistence of these transporters, we analyzed the kinetics of EPSCs in Purkinje cells of mice lacking either GLAST or EAAT4. There was no difference in the amplitude or the kinetics of the rising and initial decay phase of EPSCs evoked by stimulations of climbing fibers and parallel fibers between wild-type and EAAT4-deficient mice. However, long-lasting tail currents of the EPSCs appeared age dependently in most of Purkinje cells in EAAT4-deficient mice. These tail currents were never seen in mice lacking GLAST. In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice. The results indicate that these transporters play differential roles in the removal of synaptically released glutamate. GLAST contributes mainly to uptake of glutamate that floods out of the synaptic cleft at early times after transmitter release. In contrast, the main role of EAAT4 is to remove low concentrations of glutamate that escape from the uptake by glial transporters at late times and thus prevents the transmitter from spilling over to neighboring synapses.

Self-Assembly of a Multifunctional Lipid With Core-Shell Dendrimer DNA Nanoparticles Enhanced Efficient Gene Delivery at Low Charge Ratios into RPE Cells.

Development of safe and effective gene delivery systems is essential in treating ocular genetic disorders. A hybrid nonviral system composed of a multifunctional lipid ECO and a G4 nanoglobule was designed for efficient gene delivery into RPE cells at low charge ratios. This system formed stable DNA nanoparticles at low N/P ratios, exhibited low cytotoxicity, and induced higher GFP expression in ARPE-19 cells at N/P = 6. The hybrid nanoparticles mediated significant reporter gene GFP expression ex-vivo in the retina from wild type C57 mice and in vivo in BALB/c mice. These hybrid nanoparticles are promising for in vitro and in vivo gene delivery at low charge ratios.

Comparison of mice deficient in the high- or low-affinity neurotensin receptors, Ntsr1 or Ntsr2, reveals a novel function for Ntsr2 in thermal nociception.

Neurotensin (NT) is a neuropeptide that induces a wide range of biological activities including hypothermia and analgesia. Such effects are mediated by the NT receptors Ntsr1, Ntsr2 and Ntsr3, although the involvement of each receptor in specific NT functions remains unknown. To address nociceptive function in vivo, we generated both Ntsr1-deficient and Ntsr2-deficient mice. In addition, histochemical analyses of both Ntsr1 and Ntsr2 mRNAs were performed in the mouse brain regions involved in NT-related nociception. The expression of Ntsr2 mRNA was greater than that of Ntsr1 in the periaqueductal gray (PAG) and the rostral ventral medulla (RVM). The mutant and control mice were subjected to the examination of thermal nociception, and in the hot plate test, a significant alteration in jump latency was observed in Ntsr2-deficient mice compared to Ntsr1-deficient or wild-type control mice. Latencies of tail flick and hind paw licking of the mutant mice were not affected compared to control mice. These results suggest that Ntsr2 has an important role in thermal nociception compared to Ntsr1, and that these mutant mice may represent a useful tool for the development of analgesic drugs.