Gap opening in graphene by shear strain

We exploit the concept of strain-induced band structure engineering in graphene through the calculation of its electronic properties under uniaxial, shear, and combined uniaxial-shear deformations. We show that by combining shear deformations to uniaxial strains it is possible modulate the graphene energy gap value from zero up to $0.9$ eV. Interestingly enough, the use of a shear component allows for a gap opening at moderate absolute deformation, safely smaller than the graphene failure strain.Comment: to appear on PRB - Rapid Communicatio

Human Ovarian Cancer Tumor Formation in Severe Combined Immunodeficient (SCID) Pigs

Ovarian cancer (OvCa) is the most lethal gynecologic malignancy, with two-thirds of patients having late-stage disease (II-IV) at diagnosis. Improved diagnosis and therapies are needed, yet preclinical animal models for ovarian cancer research have primarily been restricted to rodents, for data on which can fail to translate to the clinic. Thus, there is currently a need for a large animal OvCa model. Therefore, we sought to determine if pigs, being more similar to humans in terms of anatomy and physiology, would be a viable preclinical animal model for OvCa. We injected human OSPC-ARK1 cells, a chemotherapy-resistant primary ovarian serous papillary carcinoma cell line, into the neck muscle and ear tissue of four severe combined immune deficient (SCID) and two non-SCID pigs housed in novel biocontainment facilities to study the ability of human OvCa cells to form tumors in a xenotransplantation model. Tumors developed in ear tissue of three SCID pigs, while two SCID pigs developed tumors in neck tissue; no tumors were detected in non-SCID control pigs. All tumor masses were confirmed microscopically as ovarian carcinomas. The carcinomas in SCID pigs were morphologically similar to the original ovarian carcinoma and had the same immunohistochemical phenotype based on expression of Claudin 3, Claudin 4, Cytokeratin 7, p16, and EMA. Confirmation that OSPC-ARK1 cells form carcinomas in SCID pigs substantiates further development of orthotopic models of OvCa in pigs

Evaluation of a novel human IgG1 anti-claudin3 antibody that specifically recognizes its aberrantly localized antigen in ovarian cancer cells and that is suitable for selective drug delivery

Membrane protein claudin3 has been recently suggested as a marker for biologically aggressive tumors and a possible target for the therapeutic delivery of active anti-cancer compounds. Claudin3-binding molecules such as the Clostridium perfringens enterotoxin (CPE), CPE-related molecules, and murine and chimeric antibodies have shown promising antitumor efficacy in preclinical oncological settings. We first engineered a fully human anti-claudin3 IgG1 antibody (IgGH6) by fusing the human IgG1 Fc-domain to the anti-claudin3 scFvH6 previously isolated from a pre-immune phage display library. The construct was expressed in mammalian cells and specifically targeted claudin3 endogenously expressed on the surface of different human ovarian cancer cell lines. No detectable cross-reactivity with other homologous claudins was observed. The epitope recognized by IgGH6 is located within the minor extracellular domain of claudin3 and becomes accessible only in tumor cells characterized by incomplete junction formation. Confocal microscopy experiments demonstrated that IgGH6 was actively internalized in tumor cells after binding to native claudin3 and co-localized, likely within intracellular vesicles, with the C-CPE peptide. Preliminary results indicate that IgGH6 accumulated in vivo in free claudin3 ovarian carcinoma xenografts. For its selective uptake in tumor cells and its human nature, IgGH6 represents a valuable candidate for antibody-drug conjugate therapeutic applications in ovarian cancer patients

Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

<p>Abstract</p> <p>Background</p> <p>Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology.</p> <p>Methods</p> <p>Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the <it>in vitro </it>expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs-⁵¹chromium-release-assays against cervical cancer cell lines <it>in vitro</it>.</p> <p>Results</p> <p>Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (<it>p </it>= 0.0023 qRT-PCR; <it>p </it>= 0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing ± SD, 56.2% ± 15.9%, range, 32.4%-76.9%, <it>p </it>< 0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (<it>p </it>= 0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (<it>p </it>= 0.597).</p> <p>Conclusions</p> <p>TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities.</p

Advanced Cellular Models for Preclinical Drug Testing: From 2D Cultures to Organ-on-a-Chip Technology

Cancer is a complex disease arising from a homeostatic imbalance of cell-intrinsic and microenvironment-related mechanisms. A multimodal approach to treat cancer that includes surgery, chemotherapy, and radiation therapy often fails in achieving tumor remission and produces unbearable side effects including secondary malignancies. Novel strategies have been implemented in the past decades in order to replace conventional chemotherapeutics with targeted, less toxic drugs. Up to now, scientists have relied on results achieved in animal research before proceeding to clinical trials. However, the high failure rate of targeted drugs in early phase trials leaves no doubt about the inadequacy of those models. In compliance with the need of reducing, and possibly replacing, animal research, studies have been conducted in vitro with advanced cellular models that more and more mimic the tumor in vivo. We will here review those methods that allow for the 3D reconstitution of the tumor and its microenvironment and the implementation of the organ-on-a-chip technology to study minimal organ units in disease progression. We will make specific reference to the usability of these systems as predictive cancer models and report on recent applications in high-throughput screenings of innovative and targeted drug compounds