Targeting SHP-1,2 and SHIP pathways – a novel strategy for cancer treatment?

Well balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, however, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in lymphocytes and other haematopoietic cells are SHP-1 and SHP-2 (SH2 domain-containing phosphatases 1 and 2), SHP-1,2 have been shown to promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP (SH2 domain-containing inositol phosphatase) is another inhibitory phosphatase that is rather specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and, as a result, a SHIP defiency results in myeloproliferation and B cell lymphoma in mice. This strong validation of SHP-1,2 and SHIP as oncology targets has generated considerable interest in the development of small molecule inhibitors as potential therapeutic agents for haematologic malignancies and solid tumours, however, SHP-1,2 and SHIP have proven to be an extremely difficult target for drug discovery, due primarily to the highly conserved and positively charged nature of its PTP active site. The majority of reported PTP inhibitors lack either appropriate selectivity or membrane permeability, limiting their utility in modulating the activity of the intracellular PTPs. In order to overcome these caveats novel techniques have been employed to synthesise new inhibitors that specifically attentuate the PTP-dependent signaling inside the cell and amongst them some are already in clinical development (e.g., SHP-1 inhibitor sodium stibogluconate; SHP-2 inhibitor TNO155; SHIP-1 activator AQX-1125). In this review the mechanisms of action and the clinical development of newly available SHP-1,2 and SHIP inhibitors and activators are decribed and the major issues facing this rapidly evolving field are discussed

Targeting developmental pathways: the Achilles Heel of cancer?

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways

Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells

The COX-2 protein is frequently overexpressed in human malignant gliomas. This expression has been associated with their aggressive growth characteristics and poor prognosis for patients. Targeting the COX-2 pathway might improve glioma therapy. In this study, the effects of the selective COX-2 inhibitor meloxicam alone and in combination with irradiation were investigated on human glioma cells in vitro. A panel of three glioma cell lines (D384, U87 and U251) was used in the experiments from which U87 cells expressed constitutive COX-2. The response to meloxicam and irradiation (dose-range of 0–6 Gy) was determined by the clonogenic assay, cell proliferation was evaluated by growth analysis and cell cycle distribution by FACS. 24–72 h exposure to 250–750 μM meloxicam resulted in a time and dose dependent growth inhibition with an almost complete inhibition after 24 h for all cell lines. Exposure to 750 μM meloxicam for 24 h increased the fraction of cells in the radiosensitive G2/M cell cycle phase in D384 (18–27%) and U251 (17–41%) cells. 750 μM meloxicam resulted in radiosensitization of D384 (DMF:2.19) and U87 (DMF:1.25) cells, but not U251 cells (DMF:1.08). The selective COX-2 inhibitor meloxicam exerted COX-2 independent growth inhibition and radiosensitization of human glioma cells

O ensino das ciências experimentais no liceu, em Portugal, na I República (1910-1926)

O ensino das ciências experimentais (ECE) em Portugal ficou, como pretendemos demonstrar, fortemente marcado pela instauração da República, que comemorou no ano transacto o seu centenário. A República de 1910 pretendeu reformar toda a mentalidade portuguesa, através do pilar base – a educação – pela qual seria capaz de sacudir a nossa maneira de ser, lançando desta forma o país para um progresso de nível europeu. O estudo a que nos propomos, uma investigação documental no domínio da História da Ciência1, visa aprofundar os conhecimentos existentes sobre esta época e perceber o impacto da reforma do ECE, principalmente nos Liceus, caracterizando as principais figuras, políticas e docentes responsáveis pela sua conceptualização e aplicação. Através desta investigação procuraremos lançar as primeiras bases para descobrir as origens deste pensamento, querendo ainda comparar os fundamentos psicopedagógicos, epistemológicos e sociológicos da época com as principais ideias actualmente presentes no ensino da Ciência. Com este trabalho pretendemos, num primeiro momento, apresentar e divulgar o desenho da investigação e os seus objectivos, na procura de estabelecer parcerias e receber contributos da comunidade académica interessada por esta problemática

Efficacy and Safety of Approved First-Line Tyrosine Kinase Inhibitor Treatments in Metastatic Renal Cell Carcinoma: A Network Meta-Analysis

Introduction This network meta-analysis aims to deliver an up-to-date, comprehensive efficacy and toxicity comparison of the approved first-line tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) in order to provide support for evidence-based treatment decisions. Previous NMAs of first-line mRCC treatments either predate the approval of all the first-line TKIs currently available or do not include evaluation of safety data for all treatments. Methods We performed a systematic literature review and network meta-analysis of phase II/III randomised controlled trials (RCTs) assessing approved first-line TKI therapies for mRCC. A random effects model with a frequentist approach was computed for progression-free survival (PFS) data and for the proportion of patients experiencing a maximum of grade 3 or 4 adverse events (AEs). Results The network meta-analysis of PFS demonstrated no significant differences between cabozantinib and either sunitinib (50 mg 4/2), pazopanib or tivozanib. The network meta-analysis indicated that in terms of grade 3 and 4 AEs, tivozanib had the most favourable safety profile and was associated with significantly less risk of toxicity than the other TKIs. Conclusion These network meta-analysis data demonstrate that cabozantinib, sunitinib, pazopanib and tivozanib do not significantly differ in their efficacy, but tivozanib is associated with a more favourable safety profile in terms of grade 3 or 4 toxicities. Consequently, the relative toxicity of these first-line TKIs may play a more significant role than efficacy comparisons in treatment decisions and in planning future RCTs

Efficacy evaluation of surgery combined with chemotherapy for stage IIIA small cell lung cancer patients: a retrospective analysis

Background: The efficacy of surgery in combination of chemotherapy for stage IIIA small cell lung cancer (IIIA-SCLC) is controversial. The aim of the present study was to analyze the efficacy of surgery combined with chemotherapy, especially in the setting of neoadjuvant chemotherapy (NAC) followed by surgery for IIIA-SCLC.Methods: Between 2004 and 2015, we reviewed 2,199 chemotherapy-treated stage IIIA (N1/2) SCLC cases in the Surveillance, Epidemiology, and End Results (SEER) database, and 32 NAC + intentional radical resection treated, centrally-located IIIA-SCLC cases at Shanghai Pulmonary Hospital (SPH). Outcomes were compared between surgically and non-surgically treated patients from the SEER database after propensity score matching (PSM), and comparing lobectomy/bi-lobectomy and pneumonectomy patients from SPH. Prognostic factors were evaluated by Kaplan-Meier method and the Cox proportional hazards regression model.Results: There was significantly higher overall survival (OS) in surgically treated IIIA-SCLC patients (OS, 44.8 vs. 21.2 months, P=0.048), and similar efficacy was observed between sub-lobectomy and lobectomy/ bi-lobectomy patients (OS: 55.6 vs. 30.3 months, P=0.167) in SEER database. At SPH, significantly higher OS was associated with T1 stage (before NAC: T1 vs. T2-4, 48.7 vs. 32.2 months, P=0.025; after NAC: T1 vs. T2-4, 42.7 vs. 21.3 months, P=0.048). Female sex [hazard ratio (HR): 0.078, P=0.009], T1 stage (HR: 13.048, P=0.026), and pneumonectomy (HR: 0.095, P=0.009) were independent prognostic factors for IIIASCLC patients who received NAC + intentional radical resection.Conclusions: For stage IIIA SCLC patients, complete resection combined with chemotherapy might improve the prognosis than patients without surgery. Post-NAC lobectomy was not found to be superior to sub-lobectomy, while pneumonectomy was considered suitable for central-type IIIA-SCLC patients after NAC treatment

Local recurrence and distant metastases 18 years after resection of the greater omentum hemangiopericytoma

<p>Abstract</p> <p>Background</p> <p>Hemangiopericytoma occurs with increasing frequency in 5^thdecade of life and has prediction for retroperitoneum and extremities. A case of a local recurrence and metastases of hemangiopericytoma is described.</p> <p>Case presentation</p> <p>Recurrence of hemangiopericytoma in the greater omentum and the jejunal mesentery as well as metastases in the retroperitoneal space were diagnosed in a 61-year-old patient who had a hemangiopericytoma of the greater omentum excised 18 years before.</p> <p>Conclusion</p> <p>Because of the rarity of this disease and its typical clinical course associated with late recurrence and metastases, the authors decided to present this case emphasizing the necessity of systematic oncological follow-up after the end of treatment.</p

β-Catenin stabilizes Cyclooxygenase-2 mRNA by interacting with AU-rich elements of 3′-UTR

Cyclooxygenase-2 (COX-2) mRNA is induced in the majority of human colorectal carcinomas. Transcriptional regulation plays a key role in COX-2 expression in human colon carcinoma cells, but post-transcriptional regulation of its mRNA is also critical for tumorigenesis. Expression of COX-2 mRNA is regulated by various cytokines, growth factors and other signals. β-Catenin, a key transcription factor in the Wnt signal pathway, activates transcription of COX-2. Here we found that COX-2 mRNA was also substantially stabilized by activating β-catenin in NIH3T3 and 293T cells. We identified the β-catenin-responsive element in the proximal region of the COX-2 3′-untranslated region (3′-UTR) and showed that β-catenin interacted with AU-rich elements (ARE) of 3′-UTR in vitro and in vivo. Interestingly, β-catenin induced the cytoplasmic localization of the RNA stabilizing factor, HuR, which may bind to β-catenin in an RNA-mediated complex and facilitate β-catenin-dependent stabilization of COX-2 mRNA. Taken together, we provided evidences for β-catenin as an RNA-binding factor and a regulator of stabilization of COX-2 mRNA

Cyclin D1 Expression and the Inhibitory Effect of Celecoxib on Ovarian Tumor Growth in Vivo

The report aims to investigate the relationship between the expression of cyclin D1 and Cyclooxgenase-2 (COX-2), thus to explore the molecular mechanisms of the antitumor efficacy of Celecoxib, a COX-2 inhibitor. Human ovarian SKOV-3 carcinoma cell xenograft-bearing mice were treated with Celecoxib by infusing gaster (i.g.) twice/day for 21 days. The mRNA levels of COX-2 and cyclin D1 were determined by RT-PCR. The expression of cyclin D1 at the protein level was detected by immunohistochemistry, while COX-2 protein expression was determined by Western blot. A high-dose of Celecoxib (100 mg/kg) significantly inhibited tumor growth (P < 0.05), and the expression of cyclin D1 was reduced by 61%. Celecoxib decreased the proliferation cell index by 40% (P < 0.001) and increased apoptotic index by 52% (P < 0.05) in high-dose Celecoxib treated group. Our results suggest that the antitumor efficacy of Celecoxib against ovarian cancer in mice may in part be mediated through suppression of cyclin D1, which may contribute to its ability to suppress proliferation