Loss of GSTO2 contributes to cell growth and mitochondria function via the p38 signaling in lung squamous cell carcinoma.

Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity, but it exhibits thioltransferase activity. The significance of GSTO2 in lung function has been reported; however, the precise expression and molecular function of GSTO2 in the lungs remain unclear. In the present study, we found that GSTO2 is expressed in airway basal cells, non-ciliated, columnar Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. Contrastingly, no GSTO2 expression was observed in 94 lung squamous cell carcinoma (LSCC) samples. When human LSCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant GSTO2 hypermethylation in LSCC is the cause of its downregulation. Forced GSTO2 expression in LSCC cell lines inhibited cell growth and colony formation in vitro. In a subcutaneous xenograft model, GSTO2-transfected cells formed smaller tumors in nude mice than mock-transfected cells. Upon intravenous injection into nude mice, the incidence of liver metastasis was lower in mice injected with GSTO2-transfected cells than in those injected with mock-transfected cells. In addition, GSTO2 induction suppressed the expression of ß-catenin and the oxygen consumption rate, but it did not affect the extracellular acidification rate. Furthermore, GSTO2-transfected cells displayed lower mitochondrial membrane potential than mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, ß-catenin expression and mitochondrial membrane potential were recovered. Our study indicated that the loss of GSTO2 via DNA hypermethylation contributes to the growth and progression of LSCC, probably by modulating cancer metabolism via the p38/ß-catenin signaling pathway.

Patchwork metasurface quantum well photodetectors with broadened photoresponse.

Complex lightwave manipulation such as broadband absorption has been realized with metasurfaces based on laterally arranged metal-dielectric-metal cavities with different geometries. However, application of these metasurfaces for optoelectronic devices by incorporating functional dielectrics remains challenging. Here, we integrate a quantum well infrared photodetector (QWIP) with a metasurface made of a patchwork of square cavities with different dimensions arranged in a subwavelength unit cell. Our detector realizes wideband photoresponse approaching the entire responsivity spectrum of the QWIP-single-sized square cavities can utilize only 60% of the possible bandwidth-and external quantum efficiencies of up to 78% at 6.8 µm. Our highly flexible design scheme enables integration of photodetectors and metasurfaces with arbitrary arrangements of cavities selectively responding to incidence with a specific wavefront.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRß) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRß, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRß. The presence of a subclonal population of tumor cells characterized by PDGFRß expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRß axis.

Selective Plasmonic Enhancement of Electric- and Magnetic-Dipole Radiations of Er Ions.

Lanthanoid series are unique in atomic elements. One reason is because they have 4f electronic states forbidding electric-dipole (ED) transitions in vacuum and another reason is because they are very useful in current-day optical technologies such as lasers and fiber-based telecommunications. Trivalent Er ions are well-known as a key atomic element supporting 1.5 µm band optical technologies and also as complex photoluminescence (PL) band deeply mixing ED and magnetic-dipole (MD) transitions. Here we show large and selective enhancement of ED and MD radiations up to 83- and 26-fold for a reference bulk state, respectively, in experiments employing plasmonic nanocavity arrays. We achieved the marked PL enhancement by use of an optimal design for electromagnetic (EM) local density of states (LDOS) and by Er-ion doping in deep subwavelength precision. We moreover clarify the quantitative contribution of ED and MD radiations to the PL band, and the magnetic Purcell effect in the PL-decay temporal measurement. This study experimentally demonstrates a new scheme of EM-LDOS engineering in plasmon-enhanced photonics, which will be a key technique to develop loss-compensated and active plasmonic devices.

Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads.

Trastuzumab conjugates consisting of exatecan derivatives were prepared and their biological activities and physicochemical properties were evaluated. The ADCs showed strong efficacy and a low aggregation rate. The exatecan derivatives were covalently connected via a peptidyl spacer (Gly-Gly-Phe-Gly), which is assumed to be stable in circulation, and were cleaved by lysosomal enzymes following ADC internalization into tumor tissue. These anti-HER2 ADCs exhibited a high potency, specifically against HER2-positive cancer cell lines in vitro. The ADCs, bearing exatecan derivatives which have more than two methylene chains, exhibited superior cytotoxicity. It was speculated that steric hindrance of the cleavable amide moiety could be involved in the drug release. The adequate alkyl lengths of exatecan derivatives (13, 14, 15) were from two to four in terms of aggregation rate. The ADC having a hydrophilic moiety showed good efficacy in a HER2-positive and Trastuzumab-resistant breast carcinoma cell model in mice.

Ultraviolet-nanoimprinted packaged metasurface thermal emitters for infrared CO2 sensing.

Packaged dual-band metasurface thermal emitters integrated with a resistive membrane heater were manufactured by ultraviolet (UV) nanoimprint lithography followed by monolayer lift-off based on a soluble UV resist, which is mass-producible and cost-effective. The emitters were applied to infrared CO2 sensing. In this planar Au/Al2O3/Au metasurface emitter, orthogonal rectangular Au patches are arrayed alternately and exhibit nearly perfect blackbody emission at 4.26 and 3.95 µm necessary for CO2 monitoring at the electric power reduced by 31%. The results demonstrate that metasurface infrared thermal emitters are almost ready for commercialization.

Expression of platelet-derived growth factor receptor ß is maintained by Prox1 in lymphatic endothelial cells and is required for tumor lymphangiogenesis.

The lymphatic system plays important roles not only in the physiological processes, such as maintenance of tissue fluid homeostasis, but also in pathological processes including the lymph node metastasis of tumor cells. Therefore, understanding of the molecular mechanisms underlying lymphatic vessel formation is crucial. Previous studies have shown that proliferation and migration of lymphatic endothelial cells (LECs) are activated by multiple types of signals mediated by tyrosine kinase receptors such as vascular endothelial growth factor receptor (VEGFR) 3. Although signals mediated by platelet-derived growth factor receptor ß (PDGFRß) have been implicated in lymphangiogenesis, the mechanisms explaining how PDGFRß expression is maintained in LECs remain to be fully elucidated. In the present study, we show that PDGFRß expression in LECs is maintained by Prox1 transcription factor. Knockdown of Prox1 expression in human dermal LECs decreased the expression of PDGFRß, leading to the lowered migration of human dermal LECs towards PDGF-BB. Furthermore, we found that PDGF signals play important roles in inflammatory lymphangiogenesis in a chronic aseptic peritonitis model. Intraperitoneal administration of imatinib, a potent inhibitor of PDGFRß, and transduction of PDGFRß/Fc chimeric protein by an adenoviral system both reduced inflammatory lymphangiogenesis induced by thioglycollate in mice. We also found that the expression of PDGFRß/Fc reduced tumor lymphangiogenesis in a BxPC3 human pancreatic cancer xenograft model. These findings suggest that PDGFRß is one of the key mediators of lymphatic vessel formation acting downstream of Prox1.

The COUP-TFII variant lacking a DNA-binding domain inhibits the activation of the Cyp7a1 promoter through physical interaction with COUP-TFII.

The COUP-TFII (chicken ovalbumin upstream promoter-transcription factor II) nuclear receptor, which is composed of a DNA-binding domain and a ligand-binding domain, exerts pleiotropic effects on development and cell differentiation by regulating the transcription of its target genes, including Cyp7a1 (cytochrome P450, family 7, subfamily a, polypeptide 1), which plays important roles in catabolism of cholesterol in the liver. Although multiple variants of COUP-TFII exist, their roles in the regulation of Cyp7a1 expression have not been elucidated. In the present study, we investigated the roles of COUP-TFII-V2 (variant 2), which lacks a DNA-binding domain, in the regulation of the transcriptional control of the Cyp7a1 gene by COUP-TFII in hepatocellular carcinoma cells. We found that COUP-TFII-V2 was significantly expressed in Huh7 cells, in which Cyp7a1 was not expressed. Furthermore, knockdown of COUP-TFII-V2 enhanced endogenous Cyp7a1 expression in Huh7 cells. Although COUP-TFII activates the Cyp7a1 promoter through direct binding to DNA, this activation was affected by COUP-TFII-V2, which physically interacted with COUP-TFII and inhibited its DNA-binding ability. Chromatin immunoprecipitation assays showed that COUP-TFII-V2 inhibited the binding of endogenous COUP-TFII to the intact Cyp7a1 promoter. The results of the present study suggest that COUP-TFII-V2 negatively regulates the function of COUP-TFII by inhibiting its binding to DNA to decrease Cyp7a1 expression.

Anomalous enhancement of thermoelectric power factor in multiple two-dimensional electron gas system.

Toward drastic enhancement of thermoelectric power factor, quantum confinement effect proposed by Hicks and Dresselhaus has intrigued a lot of researchers. There has been much effort to increase power factor using step-like density-of-states in two-dimensional electron gas (2DEG) system. Here, we pay attention to another effect caused by confining electrons spatially along one-dimensional direction: multiplied 2DEG effect, where multiple discrete subbands contribute to electrical conduction, resulting in high Seebeck coefficient. The power factor of multiple 2DEG in GaAs reaches the ultrahigh value of ~100 µWcm-1 K-2 at 300 K. We evaluate the enhancement rate defined as power factor of 2DEG divided by that of three-dimensional bulk. The experimental enhancement rate relative to the theoretical one of conventional 2DEG reaches anomalously high (~4) in multiple 2DEG compared with those in various conventional 2DEG systems (~1). This proposed methodology for power factor enhancement opens the next era of thermoelectric research.

A case of pseudomyxoma peritonei arising from a perforated intraductal papillary mucinous neoplasm that underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Pseudomyxoma peritonei (PMP) of pancreatic origin arising from an intraductal papillary mucinous neoplasm (IPMN) is rare. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been established as the optimal treatment for PMP. However, the benefits and safety of CRS with HIPEC for treating PMP of pancreatic origin remain unclear. Herein, we describe a case of PMP of pancreatic origin that was treated with CRS and HIPEC without postoperative complications. A 75-year-old woman was referred to our department. Computed tomography (CT) revealed a multilocular cystic tumor in the pancreatic tail, notable mucinous ascites in the abdominal cavity, and scalloping of the liver and spleen. CT did not reveal the appendix, and the ovaries were normal in size. The patient was diagnosed with PMP of pancreatic origin, and CRS and HIPEC were performed. Intraoperatively, the pancreatic tumor was perforated, and there was a large amount of mucinous ascites. We performed distal pancreatectomy in addition to CRS and HIPEC, with no intraoperative complications. The postoperative course was uneventful, and the patient survived after 6 months without recurrence. CRS with HIPEC may be a feasible treatment option for PMP of pancreatic origin.

A case of gastric adenocarcinoma with pyloric gland-type infiltrating submucosa.

BACKGROUND: The development of immunohistochemical staining has revealed that gastric adenocarcinoma with the gastric phenotype can be divided into the foveolar, fundic gland, and pyloric gland phenotypes. Gastric adenocarcinoma of the pyloric gland type is difficult to diagnose using biopsy because of its low atypia and rarity. Herein, we describe a case of gastric adenocarcinoma of the pyloric gland type that was diagnosed immunohistochemically after endoscopic resection. CASE PRESENTATION: A 67-year-old man was referred to our hospital for the diagnosis and treatment of a 30-mm elevated lesion on the lesser curvature side of the middle of the gastric body. Although four biopsies were performed, it was difficult to determine whether the lesion was benign or malignant. Therefore, endoscopic submucosal dissection was performed, and the presence of tumor cells infiltrating the submucosa with venous invasions was identified. Immunohistochemical staining revealed that the tumor cells were positive for MUC5AC and MUC6 and negative for Pepsinogen I and H + /K + -ATPase. From the above findings, he was diagnosed as having gastric adenocarcinoma with pyloric gland type. The patient underwent a laparoscopic distal gastrectomy and was discharged without any adverse events. CONCLUSIONS: Gastric adenocarcinoma of the pyloric gland type is a rare disease, and endoscopic resection can serve as a viable diagnostic option for this condition when it is difficult to diagnose using biopsy. Immunohistochemical pathology images can aid in the diagnosis of gastric adenocarcinoma of the pyloric gland type.

Diffraction-unlimited optical imaging of unstained living cells in liquid by electron beam scanning of luminescent environmental cells.

An environmental cell with a 50-nm-thick cathodoluminescent window was attached to a scanning electron microscope, and diffraction-unlimited near-field optical imaging of unstained living human lung epithelial cells in liquid was demonstrated. Electrons with energies as low as 0.8 - 1.2 kV are sufficiently blocked by the window without damaging the specimens, and form a sub-wavelength-sized illumination light source. A super-resolved optical image of the specimen adhered to the opposite window surface was acquired by a photomultiplier tube placed below. The cells after the observation were proved to stay alive. The image was formed by enhanced dipole radiation or energy transfer, and features as small as 62 nm were resolved.

Wavefront control by stacked metal-dielectric hole array with variable hole shapes.

A stacked metal-dielectric hole array (SHA) containing rectangular holes whose shape gradually varies in-plane is proposed as a means of achieving wavefront control. The dependence of the transmitted phase on the frequency can be tuned by the hole shape, in particular the length of the sides that are normal to the incident polarization. The combination of periodic holes along the polarization direction and the gradual change in hole shape normal to the polarization direction produce an inclined wavefront for 1-dimensional beam steering. An in-plane phase difference of 0.6π using an SHA with a thickness of one-sixth of the wavelength has been experimentally demonstrated.

Multilocular thymic cyst detected during COVID­19 treatment in an HIV­positive adult man: A case report and literature review.

A multilocular thymic cyst (MTC) is a rare mediastinal tumor with multiloculated cyst-like structures in the anterior mediastinum. This tumfor is associated with inflammatory diseases, including human immunodeficiency virus (HIV) infection. The present study reports a case of MTC detected during coronavirus disease 2019 (COVID-19) treatment in an adult who was tested HIV positive. An anterior mediastinal tumor was incidentally detected on computed tomography in a 52-year-old man with a 20-year history of HIV infection on the 9th day of COVID-19. The patient was asymptomatic with no notable physical findings. Magnetic resonance imaging revealed a 28-mm bilocular cyst. Robot-assisted thoracoscopic tumor resection was performed. Pathological examination showed that the cyst was lined with squamous or cuboidal epithelium, and the cystic lesion wall was mainly composed of thymic tissue with follicular hyperplasia. Based on these findings, the patient was diagnosed with MTC. To date, only 15 MTC cases have been reported in patients with HIV, and the majority of cases showed HIV infection-related symptoms such as lymphoid interstitial pneumonia and parotid gland enlargement. The present case was atypical for an HIV-related MTC because it did not involve HIV infection-related symptoms, suggesting the possibility for an alternative etiology such as COVID-19. Further reports on MTC development in patients with COVID-19 are required to elucidate the relationship between MTC and COVID-19.

Low Dark Current Operation in InAs/GaAs(111)A Infrared Photodetectors: Role of Misfit Dislocations at the Interface.

We demonstrate an extended short-wave infrared (e-SWIR) photodetector composed of an InAs/GaAs(111)A heterostructure with interface misfit dislocations. The layer structure of the photodetector consists simply of an n-InAs optical absorption layer directly grown with a thin undoped-GaAs spacer layer on n-GaAs by molecular beam epitaxy. The lattice mismatch was abruptly relaxed by forming a misfit dislocation network at the initial stage of the InAs growth. We found high-density threading dislocations (1.5 × 109 cm-2) in the InAs layer. The current-voltage characteristics of the photodetector at 77 K had a very low dark current density (<1 × 10-9 A cm-2) at a positive applied voltage (electrons flow from n-GaAs to n-InAs) of up to ∼+1 V. Simulation of the band structure revealed that the direct connection of GaAs and InAs and the formation of interfacial states by the misfit dislocations play significant positive roles in suppressing dark current. Under illumination with e-SWIR light at 77 K, a clear photocurrent signal was observed with a 2.6 µm cutoff wavelength, which is consistent with the bandgap of InAs. We also demonstrated e-SWIR detection at room temperature with a 3.2 µm cutoff wavelength. The maximum detectivity at 294 K exceeds 2 × 108 cm Hz0.5 W-1 for the detection of e-SWIR light at 2 µm.

Kallikrein-related peptidase 13 expression and clinicopathological features in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LSCC) is associated with poor prognosis. Molecular targeting drugs have been demonstrated to be effective for lung adenocarcinoma; however, they are often not effective for LSCC. Kallikrein-related peptidase 13 (KLK13) expression enhances the malignancy of lung adenocarcinoma; however, its expression and crucial role in LSCC remain largely unknown. The present study examined the relationship between the KLK13 expression and clinicopathological features of LSCC. A total of 94 patients diagnosed with LSCC who underwent lobectomy, segmentectomy or wedge resection were selected. KLK13 expression was evaluated through immunostaining of formalin-fixed paraffin-embedded sections of surgical specimens. Of the 94 LSCC samples, 70 exhibited no KLK13 expression, while the remaining 24 exhibited ectopic expression. KLK13 expression in tumors was focal and restricted to the cytoplasm of keratinized cells. LSCC cases were classified into KLK13-negative and KLK13-positive groups, and KLK13 expression was positively associated with E-cadherin expression (P=0.0143). Associations between KLK13 expression and keratinization (P=0.0052) or absence of lymphatic vessel invasion (P=0.0603) were observed; however, these trends did not reach statistical significance. The present findings indicated that KLK13 expression in keratinized LSCC may have a protective role in lymphatic vessel invasion of LSCC, which suggests its significance for therapeutic applications against LSCC.

Relationship between surgical field contamination by patient's exhaled air and the state of the drapes during eye surgery.

The coronavirus disease (COVID-19) pandemic has led to a dramatic increase in facemask use. Consequently, it has been reported that exhaled airflow toward the eyes can cause the dispersal of bacteria into the eyes, potentially increasing the incidence of postoperative endophthalmitis. In addition to wearing a facemask, gaps between the surgical drape and skin can also direct exhaled airflow toward the eyes. Here, we aimed to examine how the risk of contamination varies depending on the state of the drapes. We used a carbon dioxide imaging camera to visualize changes in exhaled airflow under different drape conditions and a particle counter to evaluate changes in the number of particles around the eye. The results revealed airflow present around the eye and a significant increase in the number of particles when the nasal side of the drape was detached from the skin. However, when a metal rod called "rihika" was used to create space above the body, the airflow and number of particles were significantly reduced. Thus, if drape coverage becomes incomplete during surgery, exhaled airflow toward the eye may contaminate the surgical field. On hanging up the drape, airflow can escape in the direction of the body, potentially preventing contamination.

Transmission phase control by stacked metal-dielectric hole array with two-dimensional geometric design.

Transmission phase control is experimentally demonstrated using stacked metal-dielectric hole arrays with a two-dimensional geometric design. The transmission phase varies drastically with small frequency shifts due to structural resonances. Laterally propagating surface plasmon polaritons excited by the periodic hole array roughly determine the resonance frequency, whereas localized resonances in each hole determine the dispersion. The transmission phase at various frequencies is directly evaluated using interferometric microscopy, and the formation of an inclined wavefront is demonstrated using a beam steering element in which the hole shapes gradually change in-plane from square to circular.

Pulmonary leiomyoma with iceberg tumor growth pattern: A case report.

Pulmonary leiomyoma is a rare disease, accounting for ~2% of cases of benign lung tumors. Pulmonary leiomyomas can be classified as tracheobronchial or pulmonary parenchymal, or as having an iceberg growth pattern, wherein the tumor extends into both the bronchial and pulmonary cavities. In the present report, a 41-year-old man complaining of sputum and discomfort during swallowing was referred to the National Center for Global Health and Medicine, because of an abnormal shadow on chest radiography and computed tomography (CT). Since the follow-up CT showed that the tumor in the third right lung segment had increased and progressed along the intra-bronchus over time, thoracoscopic right upper lobectomy was performed and leiomyoma was pathologically diagnosed. After resection, the symptoms of airway irritation improved. Since respiratory symptoms and radiographical findings are nonspecific with tracheobronchial and pulmonary parenchymal types of pulmonary leiomyoma, the identification of symptoms and determination of the extent of the lesion are necessary for treatment. In cases of iceberg growth pattern, in which the tumor extends into both the bronchial and pulmonary cavities, surgical resection should be considered.