Enhanced Efficiencies of Perovskite Solar Cells by Incorporating Silver Nanowires into the Hole Transport Layer.

In this study, we incorporated silver nanowires (AgNWs) into poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) as a hole transport layer (HTL) for inverted perovskite solar cells (PVSCs). The effect of AgNW incorporation on the perovskite crystallization, charge transfer, and power conversion efficiency (PCE) of PVSCs were analyzed and discussed. Compared with neat PEDOT:PSS HTL, incorporation of few AgNWs into PEDOT:PSS can significantly enhance the PCE by 25%. However, the AgNW incorporation may result in performance overestimation due to the lateral charge transfer. The corrosion of AgNWs with a perovskite layer was discussed. Too much AgNW incorporation may lead to defects on the interface between the HTL and the perovskite layer. An extra PEDOT:PSS layer over the pristine PEDOT:PSS-AgNW layer can prevent AgNWs from corrosion by iodide ions.

Primary peritoneal carcinosarcoma: A report of two cases.

OBJECTIVE: Carcinosarcomas also known as malignant mixed mullerian tumors (MMMTs) contain both carcinomatous and sarcomatous elements. Most MMMTs are arising from female genital tract, including ovaries, uterus and fallopian tubes. Extragenital carcinosarcomas are extremely rare, with an estimation less than 40 cases so far. CASE REPORT: We report two cases of primary peritoneal carcinosarcomas. An 81-year-old woman with pelvic peritoneal carcinosarcoma, heterologous type, was treated with incomplete surgery without further chemotherapy, and died of disease soon. The other one was a 76 year-old woman with abdominal peritoneal carcinosarcoma, homologous type. After optimal debulking surgery and subsequent 6 cycles of combination of paclitaxel and carboplatin chemotherapy, the patient is free of tumor half of year. CONCLUSION: Active therapy, including complete cytoreduction surgery and carboplatin-paclitaxel chemotherapy might offer a chance of disease control for these unusual primary peritoneal carcinosarcomas.

Organelle-Derived Acetyl-CoA Promotes Prostate Cancer Cell Survival, Migration, and Metastasis via Activation of Calmodulin Kinase II.

Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer, its role in prostate cancer tumorigenesis is largely unknown. Here, we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes prostate cancer tumorigenesis. In human prostate cancer specimens, metastatic prostate cancer expressed higher levels of active CaMKII compared with localized prostate cancer. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of prostate cancer metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the ß-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, whereas overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle ß-oxidation and acetyl-CoA transport with cell survival, migration, and prostate cancer metastasis.Significance: This study identifies a cell metabolic pathway that promotes prostate cancer metastasis and suggests prostate cancer may be susceptible to ß-oxidation inhibitors. Cancer Res; 78(10); 2490-502. ©2018 AACR.

Mass-like Dieulafoy's lesion associated with advanced gastric cancer at the antrum of stomach: a case report and literature review.

BACKGROUND: Dieulafoy's lesion, also known as a caliber-persistent artery, is a shallow, small, and rare lesion that occurs along the lesser curvature of proximal stomach. It is rare for a Dieulafoy's lesion to present as a mass-like lesion that coexists with gastric cancer. To our best knowledge, we report the first case and histopathological pictures of a mass-like Dieulafoy's lesion coexisting with advanced gastric cancer in the antrum of the stomach. CASE PRESENTATION: A 57-year-old female presented with a 6-month history of intermittent epigastric dull pain and dyspepsia. Subsequent upper gastrointestinal endoscopy revealed a friable mass that was located between the distal antrum and the pyloric ring. Biopsy revealed it to be an intestinal type adenocarcinoma. Subtotal gastrectomy was performed after neoadjuvant chemotherapy. Grossly, a large irregular plaque-like tumor lesion was noted at the anterior wall of the distal antrum and pylorus ring near the lesser curvature, measuring 5.6 × 4.8 × 1.0 cm. Histopathological examination of the resected stomach revealed that the plaque-like lesion largely consisted of numerous abnormally large-caliber and tortuous arteries in the submucosa. The increased fibrosis of the submucosa resulted in the formation of elevated plaque. The intestinal type adenocarcinoma was noted to be largely confined to the mucosa layer, with focal submucosal and muscular propria involvement. The patient was discharged one week after the subtotal gastrectomy, and she was alive and well 17 months after discharge, with no major complications. CONCLUSION: This is the first case of a mass-like Dieulafoy's lesion coexisting with advanced gastric cancer at the distal antrum area. This case highlights the possibility of life-threatening gastric bleeding after mucosal resection or biopsy that could be encountered by endoscopists.

Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer.

Prostate cancer (PCa) bone metastasis is frequently associated with bone-forming lesions, but the source of the osteoblastic lesions remains unclear. We show that the tumor-induced bone derives partly from tumor-associated endothelial cells that have undergone endothelial-to-osteoblast (EC-to-OSB) conversion. The tumor-associated osteoblasts in PCa bone metastasis specimens and patient-derived xenografts (PDXs) were found to co-express endothelial marker Tie-2. BMP4, identified in PDX-conditioned medium, promoted EC-to-OSB conversion of 2H11 endothelial cells. BMP4 overexpression in non-osteogenic C4-2b PCa cells led to ectopic bone formation under subcutaneous implantation. Tumor-induced bone was reduced in trigenic mice (Tie2cre/Osxf/f/SCID) with endothelial-specific deletion of osteoblast cell-fate determinant OSX compared with bigenic mice (Osxf/f/SCID). Thus, tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa.

Extrarenal rhabdoid tumor presented with an immobile arm in a one-year-old boy.

Infants with an immobile arm may be easily overlooked in primary care settings. Differential diagnoses include injuries, infections, neuropathies, ischemia and rarely, neoplasms. We report the case of a one-year-old boy with weakness in his left arm after minor trauma with a diagnosis of brachial plexus palsy initially. After rehabilitation for 2months, his weakness progressed to unsteady gait and quadriparesis. MRI revealed a huge solid tumor in the left supraclavicular fossa, which also involved the left brachial plexus, upper thoracic cavity, and left paravertebral space with invasion into the spinal canal. Microscopically, the medium-large polygonal tumor cells had an eccentric eosinophilic cytoplasm and immunostaining showed a loss of nuclear INI1 expression. Array comparative genomic hybridization of the tumor tissue confirmed a segmental deletion at chromosome region 22q11.23 involving the SMARCB1 gene. The final diagnosis was cervical paravertebral malignant rhabdoid tumor with intraspinal epidural and intradural invasion, a rare case of extrarenal extracranial rhabdoid tumor (ERRT). The intraspinal part of the tumor was resected followed by interval-compressed chemotherapy with vincristine-doxorubicin-cyclophosphamide alternating with ifosfamide-etoposide (VDC/IE). The tumor showed very good partial response to four cycles of chemotherapy with gradual recovery of neurological symptoms. ERRT is a very rare and aggressive tumor that mainly occurs in infants and children and may manifest with vague neurological symptoms when it involves the spinal cord and/or peripheral nerves. A neoplasm such as ERRT originating from or involving the brachial plexus should be considered in the differential diagnosis of an immobile arm in infancy.

Angiomotin regulates prostate cancer cell proliferation by signaling through the Hippo-YAP pathway.

Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3, DU145, and BPH1 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80, but not AMOT p130, functioned as a tumor promoter by enhancing PCa cell proliferation. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.

Identification of Bone-Derived Factors Conferring De Novo Therapeutic Resistance in Metastatic Prostate Cancer.

Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a "resistance niche" adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed "osteocrines") found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer.

Local injection of mesenchymal stem cells protects testicular torsion-induced germ cell injury.

INTRODUCTION: Testicular torsion is a urological emergency and infertility is a common complication due to ischemic injury. Surgical reduction and orchiopexy is indicated, but to date there is no effective method for restoration of spermatogenesis. The effects of mesenchymal stem cells (MSCs) on acute tissue injury have been demonstrated, and the abilities of paracrine support, differentiation and immune-modulation may benefit to testicular torsion-induced infertility. We investigate the therapeutic efficacy and the mechanisms of MSCs in testicular torsion-induced germ cell injury when injected locally. METHODS: Six to eight-week-old Sprague-Dawley rats received surgical 720 degree torsion for 3 hours, followed by detorsion on the left testis. 20 µl of phosphate-buffered saline (PBS) without or with 3 x 10(4) MSCs from human orbital fat tissues (OFSCs) were given for 10 rats, respectively, via local injection into the left testis 30 minutes before detorsion. 20 µl of PBS injection for 6 rats with surgical exposure without torsion served as sham control. Histopathology with Johnsen's score analysis, Western blot analysis for superoxide dismutase 2, Bax, Caspase-3, human insulin growth factor-1 and human stem cell factor, malondialdehyde (MDA) assay in testis and plasma, hormones level including testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by ELISA Kits, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and fluorescence staining for P450, Sox-9 and VASA were performed. RESULTS: Animals were sacrificed and bilateral orchiectomy was performed 7 days after torsion-detorsion. Local injections of OFSCs prevented torsion-induced infertility judging from Johnsen's score. TUNEL assay and Western blot analysis on caspase 3 and Bax demonstrated that OFSCs prevented ischemic/reperfusion induced intrinsic apoptosis. MDA assay revealed that OFSCs significantly reduced the oxidative stress in the damaged testicular tissues. After the OFSC injection, serum testosterone secretion was increased, while the elevation of FSH triggered by testicular injury was balanced. OFSCs also produced stem cell factor in the damaged testis. Immunofluorescence staining revealed that most transplanted cells surrounded the Leydig cells. Some of transplanted cells differentiated into p450 expressing cells within 7 days. CONCLUSIONS: Local injection of allogenic MSCs before surgical detorsion is a simple, clinical friendly procedure to rescue torsion-induced infertility.

Yes-mediated phosphorylation of focal adhesion kinase at tyrosine 861 increases metastatic potential of prostate cancer cells.

To study the role of FAK signaling complexes in promoting metastatic properties of prostate cancer (PCa) cells, we selected stable, highly migratory variants, termed PC3 Mig-3 and DU145 Mig-3, from two well-characterized PCa cell lines, PC3 and DU145. These variants were not only increased migration and invasion in vitro, but were also more metastatic to lymph nodes following intraprostatic injection into nude mice. Both PC3 Mig-3 and DU145 Mig-3 were specifically increased in phosphorylation of FAK Y861. We therefore examined potential alterations in Src family kinases responsible for FAK phosphorylation and determined only Yes expression was increased. Overexpression of Yes in PC3 parental cells and src-/-fyn-/-yes-/- fibroblasts selectively increased FAK Y861 phosphorylation, and increased migration. Knockdown of Yes in PC3 Mig-3 cells decreased migration and decreased lymph node metastasis following orthotopic implantation of into nude mice. In human specimens, Yes expression was increased in lymph node metastases relative to paired primary tumors from the same patient, and increased pFAK Y861 expression in lymph node metastases correlated with poor prognosis. These results demonstrate a unique role for Yes in phosphorylation of FAK and in promoting PCa metastasis. Therefore, phosphorylated FAK Y861 and increased Yes expression may be predictive markers for PCa metastasis.

RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival.

UNLABELLED: Prostate cancer has a proclivity to metastasize to bone. The mechanism by which prostate cancer cells are able to survive and progress in the bone microenvironment is not clear. Identification of molecules that play critical roles in the progression of prostate cancer in bone will provide essential targets for therapy. Ribosomal S6 protein kinases (RSK) have been shown to mediate many cellular functions critical for cancer progression. Whether RSK plays a role in the progression of prostate cancer in bone is unknown. IHC analysis of human prostate cancer specimens showed increased phosphorylation of RSK in the nucleus of prostate cancer cells in a significant fraction of human prostate cancer bone metastasis specimens, compared with the primary site or lymph node metastasis. Expression of constitutively active myristylated RSK in C4-2B4 cells (C4-2B4/RSK) increased their survival and anchorage-independent growth compared with C4-2B4/vector cells. Using an orthotopic bone injection model, it was determined that injecting C4-2B4/RSK cells into mouse femurs enhanced their progression in bone compared with control cells. In PC3-mm2 cells, knockdown of RSK1 (RPS6KA1), the predominant RSK isoform, but not RSK2 (RPS6KA2) alone, decreased anchorage-independent growth in vitro and reduced tumor progression in bone and tumor-induced bone remodeling in vivo. Mechanistic studies showed that RSK regulates anchorage-independent growth through transcriptional regulation of factors that modulate cell survival, including ING3, CKAP2, and PTK6. Together, these data provide strong evidence that RSK is an important driver in prostate cancer progression in bone. IMPLICATIONS: RSK, an important driver in prostate cancer progression in bone, has promising potential as a therapeutic target for prostate cancer bone metastasis.

Cadherin-11 in renal cell carcinoma bone metastasis.

Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.

Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition.

Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-associated multi-domain SCUBE protein family. We previously demonstrated that SCUBE2 is a novel breast-tumor suppressor and could be a useful prognostic marker. However, the role of SCUBE2 in breast-cancer cell migration and invasion and how it is regulated during the epithelial-mesenchymal transition (EMT) remain undefined. In this study, we showed that ectopic SCUBE2 overexpression could enhance the formation of E-cadherin-containing adherens junctions by ß-catenin-SOX-mediated induction of forkhead box A1 (a positive regulator of E-cadherin) and upregulation of E-cadherin, which in turn led to epithelial transition and inhibited migration and invasion of aggressive MDA-MB-231 breast-carcinoma cells. SCUBE2 expression was repressed together with that of E-cadherin in TGF-ß-induced EMT; direct expression of SCUBE2 alone was sufficient to inhibit the TGF-ß-induced EMT. Furthermore, quantitative DNA methylation, methylation-specific PCR, and chromatin immunoprecipitation analyses revealed that SCUBE2 expression was inactivated by DNA hypermethylation at the CpG islands by recruiting and binding DNA methyltransferase 1 during TGF-ß-induced EMT. Together, our results suggest that SCUBE2 plays a key role in suppressing breast-carcinoma-cell mobility and invasiveness by increasing the formation of the epithelial E-cadherin-containing adherens junctions to promote epithelial differentiation and drive the reversal of EMT.

Transformation of a post-cesarean section placental site nodule into a coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor: a case report.

Placental site nodules (PSNs) and epithelioid trophoblastic tumors (ETTs) respectively represent non-neoplastic and neoplastic lesions of chorionic-type intermediate trophoblasts (ITs). Many patients with a PSN have a history of a cesarean section (CS) or therapeutic abortion. Recent evidence shows that a PSN may progress to an ETT. Herein, we describe a coexisting ETT and placental site trophoblastic tumor (PSTT) intimately associated with PSNs in the post-cesarean lower uterine segment of a 41-year-old woman. The patient presented with abnormal vaginal bleeding 1 year after a cesarean delivery for her most recent pregnancy. We speculated that the neoplasms had transformed from PSNs, the formation of which was related to faulty expulsion of the placental tissue or abnormal colonization of chorionic-type ITs during the CS. Neoplastic trophoblastic cells derived from PSNs displayed differentiation plasticity toward chorionic-type ITs and implantation site ITs that were respectively constituted of an ETT and PSTT. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1597949195882123.