Direct observation of split-mode exciton-polaritons in a single MoS2 nanotube.

A single nanotube synthesized from a transition metal dichalcogenide (TMDC) exhibits strong exciton resonances and, in addition, can support optical whispering gallery modes. This combination is promising for observing exciton-polaritons without an external cavity. However, traditional energy-momentum-resolved detection methods are unsuitable for this tiny object. Instead, we propose to use split optical modes in a twisted nanotube with the flattened cross-section, where a gradually decreasing gap between the opposite walls leads to a change in mode energy, similar to the effect of the barrier width on the eigenenergies in the double-well potential. Using micro-reflectance spectroscopy, we investigated the rich pattern of polariton branches in single MoS2 tubes with both variable and constant gaps. Observed Rabi splitting in the 40-60 meV range is comparable to that for a MoS2 monolayer in a microcavity. Our results, based on the polariton dispersion measurements and polariton dynamics analysis, present a single TMDC nanotube as a perfect polaritonic structure for nanophotonics.

III-nitride tunable cup-cavities supporting quasi whispering gallery modes from ultraviolet to infrared.

Rapidly developing nanophotonics needs microresonators for different spectral ranges, formed by chip-compatible technologies. In addition, the tunable ones are much in demand. Here, we present site-controlled III-nitride monocrystal cup-cavities grown by molecular beam epitaxy. The cup-cavities can operate from ultraviolet to near-infrared, supporting quasi whispering gallery modes up to room temperature. Besides, their energies are identical in large 'ripened' crystals. In these cavities, the refractive index variation near an absorption edge causes the remarkable effect of mode switching, which is accompanied by the spatial redistribution of electric field intensity with concentration of light into a subwavelength volume. Our results shed light on the mode behavior in semiconductor cavities and open the way for single-growth-run manufacturing the devices comprising an active region and a cavity with tunable mode frequencies.

Gene therapy of pancreatic cancer targeting the K-Ras oncogene.

Ras mutations are present in ∼95% of pancreatic cancer (PC) cases leading to increased proliferation and apoptosis resistance. The aim of this study is to selectively kill Ras-transformed cells by overexpressing the pro-apoptotic protein, p53 upregulated modulator of apoptosis (PUMA) under a Ras-responsive promoter. Colo357, Panc1 and MiaPaca, PC cell lines harboring K-Ras mutations, normal rat IEC18 enterocytes, and their K-Ras transformed R1 counterparts, were tested. We constructed adenoviral vectors containing the PUMA gene downstream to: (1) Four or five repetitive Ras-responsive elements (Ad-PY4/PY5-PUMA) and (2) a negative control (Ad-SV40-PUMA). Cell viability was estimated by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis was evaluated by FACS. In vivo potency of the adenoviruses was evaluated in athymic nude mice. Infection with Ad-PY4/PY5-PUMA markedly inhibited cell growth (∼40-50%), and apoptosis was detected in all cells with high Ras activity, whereas IEC18 cells remained unaffected. The control vector, Ad-SV40-PUMA, did not induce any cell death. Selective and high expression of PUMA was detected in Ad-PY4-PUMA-infected cells. In vivo, Ad-PY4-PUMA inhibited by ∼35% the growth of established tumors compared with the Ad-SV40-PUMA. Selective overexpression of PUMA efficiently inhibits the growth of Ras-transformed cells while sparing the normal ones. This treatment modality may become a useful, effective and safe approach to selectively target Ras-mutated tumor cells.

Risk of colorectal neoplasia associated with the adenomatous polyposis coli E1317Q variant.

BACKGROUND: Reports of the risk of colorectal neoplasia associated with a variant of the adenomatous polyposis coli (APC E1317Q) gene are conflicting. Using a case-control design, we investigated this relationship within a clinic-based cohort followed through the Integrated Cancer Prevention Center and the Tel-Aviv Sourasky Medical Center. MATERIALS AND METHODS: All study subjects were tested for the APC E1317Q variant at enrollment. Subjects underwent colonoscopic evaluation (+/-biopsy and/or polypectomy) and had cancer history and colorectal neoplasia risk factors assessed. The crude and adjusted risks of neoplasia associated with the E1317Q variant were calculated. RESULTS: The prevalence of the E1317Q variant was 1.4% in the entire study sample and 3.2% in Sephardic Jews. E1317Q was more prevalent among cases: 15 of 458 (3.3%) cases were carriers compared with 11 of 1431 (0.8%) controls [odds ratio (OR) 4.4, 95% CI 2.0-9.6]. When stratified by neoplasia type, adenoma risk was significantly elevated in carriers (OR 4.1, 95% CI 1.8-9.4) but colorectal cancer risk was not (OR 2.1, 95% CI 0.8-5.3). After adjustment, the E1317Q variant remained a significant predictor of colorectal adenoma (OR 4.6, 95% CI 2.0-10.8). CONCLUSIONS: The APC E1317Q variant is associated with colorectal neoplasia, particularly colorectal adenomas, but further studies are still needed. Variant prevalence is elevated in Sephardic Jews.

CD24 plays an important role in the carcinogenesis process of the pancreas.

Patients with pancreatic adenocarcinoma have a doom prognosis these tumors were previously proved to express high level of CD24. The current study was aimed to demonstrate that the treatment with monoclonal antibodies to CD24 is effective, in vitro, in pancreatic cancer cells, similar to what we had previously shown in the setting of colorectal cancer. Three human pancreatic cancer cell lines, Colo357, Panc1 and MIA-PaCa, were analyzed for their expression levels of CD24 by Western blot analysis. The correlation for the protein available on the cytoplasmic membrane was assessed by ELISA assay to plates coated with fixed cells using anti-CD24 Ab as the first binder. Human cancer cell lines were tested for their response to two different anti-CD24 monoclonal antibodies and a control antibody (mouse anti-GFP). Human pancreatic adenocarcinomas cell lines that express CD24 (Colo357 and Panc1 cells) showed growth inhibition in dose and time dependent manners. These results were repetitive for the two different antibodies. Growth rate was not affected in MIA-PaCa cells that do not express CD24, or when cells were treated with a control antibody. CD24 may play an important role in the carcinogenesis process of pancreatic cancer. It may serve as a useful target in the therapy of pancreatic cancer.

Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells.

OBJECTIVES: Osteoarthritis (OA) is the Western world's leading cause of disability. Cyclo-oxygenase-2 (COX-2) inhibitors are efficient anti-inflammatory agents commonly used in the treatment of osteoarthritis. However, recent studies have shown that their long-term use may be limited due to cardiovascular toxicity. The anti-inflammatory efficacy of the phytochemical curcumin has been demonstrated in several in vitro and animal models. This study was undertaken to investigate whether curcumin augments the growth-inhibitory and pro-apoptotic effects of celecoxib in OA synovial adherent cells. METHODS: OA synovial adherent cells were prepared from human synovial tissue collected during total knee replacement surgery. The cells were exposed to different concentrations of celecoxib (0-40 mum), curcumin (0-20 mum) and their combination. Flow cytometric analysis was used to measure the percentage of cells with a subdiploid DNA content, the hallmark of apoptosis. COX-2 activity was assessed by measuring production of prostaglandin E(2) by enzyme-linked immunoassay. RESULTS: A synergistic effect was observed in inhibition of cell growth when the cells were exposed to various concentrations of celecoxib combined with curcumin. The inhibitory effect of the combination on cell growth was associated with an increased induction of apoptosis. The synergistic effect was mediated through a mechanism that involves inhibition of COX-2 activity. CONCLUSIONS: This effect may enable the use of celecoxib at lower and safer concentrations, and may pave the way for a novel combination treatment in osteoarthritis and other rheumatological disorders.

Ha-ras(val12) induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-ras(val12)-transformed cells.

Heat shock proteins (Hsps) are overexpressed in many tumors, but are downregulated in some tumors. To check for a direct effect of Ha-Ras(val12) on HSP70 transcription, we transiently expressed the oncoprotein in Rat1 fibroblasts and monitored its effect on HSP70b promoter-driven reporter gene. We show that expression of Ha-Ras(val12) induced this promoter. Promoter analysis via systematic deletions and point mutations revealed that Ha-Ras(val12) induces HSP70b transcription via heat shock elements (HSEs). Also, Ha-Ras(val12) induction of HSE-mediated transcription was dramatically reduced in HSF1-/- cells. Yet, residual effect of Ha-Ras(val12) that was still measured in HSF1-/- cells suggests that some of the Ha-Ras(val12) effect is Hsf1-independent. When HSF1-/- cells, stably expressing Ha-Ras(val12), were grown on soft agar only small colonies were formed suggesting a role for heat shock factor 1 (Hsf1) in Ha-Ras(val12)-mediated transformation. Although Ha-ras(Val12) seems to be an inducer of HSP70's expression, we found that in Ha-ras(Val12-)transformed fibroblasts expression of this gene is suppressed. This suppression is correlated with higher sensitivity of Ha-ras(val12)-transformed cells to heat shock. We suggest that Ha-ras(Val12) is involved in Hsf1 activation, thereby inducing the cellular protective response. Cells that repress this response are perhaps those that acquire the capability to further proliferate and become transformed clones.

Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells.

BACKGROUND AND AIM: Adenocarcinoma of the Pancreas is a leading cause of cancer-related mortality, accounting for an estimated 30,000 deaths per year in the United States. Multiple studies have indicated that specific cyclooxygenase-2 (COX-2) inhibitors may serve in the prevention and treatment of a variety of malignancies including pancreatic adenocarcinoma. Recent studies had shown that the long-term use of high concentration of COX-2 inhibitors is not toxic free and may be limited due to serious gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. In this study we investigated whether curcumin potentiates the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human pancreatic cancer cells. METHODS: P-34 (expressing high levels of COX-2), and MIAPaCa (expressing low levels of COX-2) and Panc-1 (no expression of COX-2) evaluated cell lines were exposed to different concentrations of celecoxib (0-40 microM), curcumin (0-20 microM) and their combination. Cell viability was by XTT assay. Apoptosis was assessed by flow cytometry and COX-2 expression was measured by Western blotting analysis. RESULTS: In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Western blot analysis showed that COX-2 expression was down-regulated by the combination therapy. CONCLUSION: Curcumin synergistically augments the growth inhibition inserted by celecoxib in pancreatic cancer cells expressing COX-2. The synergistic effect was mediated through inhibition of COX-2. This may enable the use of celecoxib at lower and safer concentrations and may pave the way for a more effective treatment in this devastating disease.

Gene targeting approach to selectively kill colon cancer cells, with hyperactive K-Ras pathway.

BACKGROUND: Ras mutations are present in approximately 50% of human colorectal tumors. We have previously shown that transfection of a non-tumorigenic rat intestinal epithelial cell line, IEC18, by the K-Ras oncogene (R1 cells), resulted in malignant cell transformation. Utilizing the constantly active Ras signaling pathway to selectively target transformed but not normal cells is a plausible goal. AIM: To selectively kill Ras transformed cells by over expressing a lethal gene using a Ras-responsive promoter. MATERIAL AND METHODS: IEC18, R1 and a number of colon cancer cell lines were transfected with luciferase (Luc) reporter gene under the control of different Ras-responsive elements. The Ras-responsive promoter Py2 contains two copies of adjacent Ets and AP I binding sites followed by a minimal promoter. Apoptotic genes (bax, caspase-8 and PKG) were cloned into the Py2 plasmids. RI cells co-transfected with expression constructs and a selected vector and then grown for 3 weeks under selection. RESULTS: R1, SW480 and HCT116 with mutated c-K-Ras expressed high level of Luc activity following transfection with the Py2 element. IEC18 cell lines that do not contain this mutation expressed negligible low Luc activity. Following transfection of SW480 and R1 cells with Py2-bax, caspase-8 and PKG, there was a significant reduction in the number of colony formation. CONCLUSIONS: 1. Selective over-expression of pro-apoptotic genes, inhibits the growth of Ras transformed cells, and not normal cells. 2. This gene approach therapy may become a useful, effective and safe to target Ras mutated tumor cells with sparing of the normal cells.

Prospective assessment of microsatellite instability in gastrointestinal neoplasia in Ashkenazi and non-Ashkenazi Jews.

BACKGROUND: Microsatellite instability (MSI) is a useful marker of replication errors in neoplasia, resulting from mutations in the mismatch repair (MMR) genes. Nearly all hereditary non-polyposis colorectal cancer (HNPCC) and about 15% of sporadic colorectal cancers (CRC) exhibit high MSI (MSI-H). The use of the Amsterdam criteria for HNPCC diagnosis may fail to identify many HNPCC cases. Genetic screening of mutations in the MMR genes is laborious, time-consuming, expensive and limited by a low detection rate. Hence, MSI testing is a feasible and cost-effective method to select suspected HNPCC patients for genetic analysis. MSI has not been used routinely or prospectively in the assessment of newly diagnosed CRC. AIMS: To prospectively evaluate MSI status in a cohort of patients seen at the Gastrointestinal Oncology Unit of the Tel Aviv Medical Center. METHODS: Ninety-eight consecutive patients with colonic or gastric neoplasia were included. Samples from neoplastic and normal mucosa were obtained at the time of diagnostic endoscopy. MSI was determined based on five Bethesda markers using standard polymerase chain reaction procedures. RESULTS: The overall incidence of MSI was 20.4%. MSI-H was detected in 22.2% of CRC, 20% of colonic adenomas and 18.2% of gastric neoplasia. MSI-positive neoplasia tended to display multiple colonic sites, moderate-well differentiated tumors, and a higher rate of familial gastrointestinal neoplasia. CONCLUSIONS: MSI may be involved in the early stages of some colorectal tumorigenesis pathways since it may be detected in adenomas. MSI may serve as a cost-effective, reliable and important tool in the selection of HNPCC-suspected families for genetic testing. A small study population, referral bias or ethnic variation might explain the higher MSI rate. It is suggested that, similar to familial adenomatous polyposis, a state of attenuated HNPCC may exist. Hence, the clinical approach in positive patients, and their family members, should be conducted as for families with genetically proven HNPCC.