The Interleukin-11/IL-11 Receptor Promotes Glioblastoma Survival and Invasion under Glucose-Starved Conditions through Enhanced Glutaminolysis.

Glioblastoma cells adapt to changes in glucose availability through metabolic plasticity allowing for cell survival and continued progression in low-glucose concentrations. However, the regulatory cytokine networks that govern the ability to survive in glucose-starved conditions are not fully defined. In the present study, we define a critical role for the IL-11/IL-11Rα signalling axis in glioblastoma survival, proliferation and invasion when cells are starved of glucose. We identified enhanced IL-11/IL-11Rα expression correlated with reduced overall survival in glioblastoma patients. Glioblastoma cell lines over-expressing IL-11Rα displayed greater survival, proliferation, migration and invasion in glucose-free conditions compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα reversed these pro-tumorigenic characteristics. In addition, these IL-11Rα-over-expressing cells displayed enhanced glutamine oxidation and glutamate production compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα or the pharmacological inhibition of several members of the glutaminolysis pathway resulted in reduced survival (enhanced apoptosis) and reduced migration and invasion. Furthermore, IL-11Rα expression in glioblastoma patient samples correlated with enhanced gene expression of the glutaminolysis pathway genes GLUD1, GSS and c-Myc. Overall, our study identified that the IL-11/IL-11Rα pathway promotes glioblastoma cell survival and enhances cell migration and invasion in environments of glucose starvation via glutaminolysis.

Carfilzomib Promotes the Unfolded Protein Response and Apoptosis in Cetuximab-Resistant Colorectal Cancer.

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.

Highly stable graphene-assisted tunable dual-wavelength erbium-doped fiber laser.

A highly stable tunable dual-wavelength fiber laser (TDWFL) using graphene as a means to generate a highly stable output is proposed and generated. The TDWFL comprises a 1 m long, highly doped erbium-doped fiber (EDF) acting as the linear gain medium, with a 24-channel arrayed waveguide grating acting as a wavelength slicer as well as a tuning mechanism to generate different wavelength pairs. The tuned wavelength pairs can range from 0.8 to 18.2 nm. A few layers of graphene are incorporated into the laser cavity to induce the four-wave-mixing effect, which stabilizes the dual-wavelength output by suppressing the mode competition that arises as a result of homogenous broadening in the EDF.

Quantification of mesenchymal stem cell growth rates through secretory and excretory biomolecules in conditioned media via Fresnel reflection.

An efficient and low cost optical method for directly measuring the concentration of homogenous biological solutes is proposed and demonstrated. The proposed system operates by Fresnel reflection, with a flat-cleaved single-mode fiber serving as the sensor probe. A laser provides a 12.9 dBm sensor signal at 1,550 nm, while a computer-controlled optical power meter measures the power of the signal returned by the probe. Three different mesenchymal stem cell (MSC) lines were obtained, sub-cultured and trypsinized daily over 9 days. Counts were measured using a haemocytometer and the conditioned media (CM) was collected daily and stored at -80 °C. MSCs release excretory biomolecules proportional to their growth rate into the CM, which changes the refractive index of the latter. The sensor is capable of detecting changes in the number of stem cells via correlation to the change in the refractive index of the CM, with the measured power loss decreasing approximately 0.4 dB in the CM sample per average 1,000 cells in the MSC subculture. The proposed system is highly cost-effective, simple to deploy, operate, and maintain, is non-destructive, and allows reliable real-time measurement of various stem cell proliferation parameters.

OsGERLP: A novel aluminum tolerance rice gene isolated from a local cultivar in Indonesia.

There is a decrease in the land available for rice cultivation due to the rapid conversion to urban uses. Subsequently, acid soil could be an alternative land cultivating rice, but will require the use of aluminum (Al)-tolerant rice varieties. This Al tolerance trait is genetically controlled, and there is a need to discover more genes needed to develop Al-tolerant rice. Therefore, the objective of this study was to clone and characterize a novel Al tolerance gene isolated from a local cultivar of Indonesian rice. The gene cloning was conducted based on the rye/rice microsynteny relationship. In addition, the root growth and gene expression analyses were performed to verify the role of the gene on Al tolerance in gene-silenced rice and in overexpressed transgenic tobacco. The results showed an Al tolerance candidate gene, OsGERLP, was successfully cloned from rice cv. Hawara Bunar, with its gene encoding a protein similar to a bacterial ribosomal L32 protein. Additionally, the analysis showed that low gene expression caused the gene-silenced rice to be sensitive to Al, while high expression induced the Al tolerance in transgenic tobacco. Furthermore, it was discovered that the gene expression level in both plants was in line with the lower expression of the OsFRDL4 gene in the silenced rice and the high expression of the MATE gene in transgenic tobacco also with the higher citrate secretion from transgenic tobacco roots. In conclusion, the OsGERLP gene could act as a regulator for other Al tolerance genes, with the potential to develop Al-tolerant rice varieties.

EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism.

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

Reduced EGFR and increased miR-221 is associated with increased resistance to temozolomide and radiotherapy in glioblastoma.

Despite aggressive treatment with temozolomide and radiotherapy and extensive research into alternative therapies there has been little improvement in Glioblastoma patient survival. Median survival time remains between 12 and 15 months mainly due to treatment resistance and tumor recurrence. In this study, we aimed to explore the underlying mechanisms behind treatment resistance and the lack of success with anti-EGFR therapy in the clinic. After generating a number of treatment resistant Glioblastoma cell lines we observed that resistant cell lines lacked EGFR activation and expression. Furthermore, cell viability assays showed resistant cells were significantly less sensitive to the anti-EGFR agents when compared to parental cell lines. To further characterise the resistance mechanism in our cells microRNA prediction software identified miR-221 as a negative regulator of EGFR expression. miR-221 was up-regulated in our resistant cell lines, and this up-regulation led to a significant reduction in EGFR expression in both our cultured cell lines and a large cohort of glioblastoma patient tumor tissue.

STAT3 signaling mediates tumour resistance to EGFR targeted therapeutics.

Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC). In this mini-review, we specifically focus on the role of the STAT3 signaling axis in providing both intrinsic and acquired resistance to inhibitors of the EGFR. We also focus on STAT3 pathway targeting in an attempt to overcome resistance to anti-EGFR therapeutics.

Composite fluorocarbon membranes by surface-initiated polymerization from nanoporous gold-coated alumina.

This manuscript describes the versatile fabrication and characterization of a novel composite membrane that consists of a porous alumina support, a 100 nm thick nanoporous gold coating, and a selective poly(5-(perfluorohexyl)norbornene) (pNBF6) polymer that can be grown exclusively from the nanoporous gold or throughout the membrane. Integration of the three materials is achieved by means of silane and thiol chemistry, and the use of surface-initiated ring-opening metathesis polymerization (SI-ROMP) to grow the pNBF6. The use of SI-ROMP allows tailoring of the extent of polymerization of pNBF6 throughout the structure by varying polymerization time. Scanning electron microscopy (SEM) images indicate that the thin polymer films cover the structure entirely. Cross-sectional SEM images of the membrane not only corroborate growth of the pNBF6 polymer within both the porous alumina and the nanoporous gold coating but also show the growth of a pNBF6 layer between these porous substrates that lifts the nanoporous gold coating away from the alumina. Advancing contact angle (θ(A)) measurements show that the surfaces of these composite membranes exhibit both hydrophobic (θ(A) = 121-129)° and oleophobic (θ(A) = 69-74)° behavior due to the fluorocarbon side chains of the pNBF6 polymer that dominate the surface. Results from electrochemical impedance spectroscopy (EIS) confirm that the membranes provide effective barriers to aqueous ions, as evidenced by a resistive impedance on the order of 1 × 10(7) Ω cm(2). Sulfonation of the polymer backbone substantially enhances ion transport through the composite membrane, as indicated by a 40-60 fold reduction in resistive impedance. Ion transport and selectivity of the membrane change by regulating the polymerization time. The fluorinated nature of the sulfonated polymer renders the membrane selective toward molecules with similar chemical characteristics.

Characterisation and pathological variability of Exserohilum turcicum responsible for causing northern corn leaf blight (NCLB) disease in Malaysia

Aims: Corn is grown primarily for human consumption. It is considered as the second most important cereal crop after rice in Asia. Many diseases affect this crop due to planting of susceptible hybrids. This research is aimed to characterize the causative agent of northern corn leaf blight disease in Malaysia, caused by Exserohilum turcicum. Methodology and results: Leaf samples were collected from infected farms of 2 corn growing areas of Peninsular Malaysia in 2015. A total of 5 fungal isolates were examined for cultural, morphological and molecular properties, and based on the results, the five isolates were identified as E. turcicum. The conidial shapes were observed to be elongated and spindle. Cultural characteristics showed that variation existed among the isolates in colony growth and colour. Mycelia growth rates of the isolates were significantly different on potato dextrose agar (PDA), corn meal agar (CMA) and potato sucrose agar (PSA) media, growth on CMA was faster than on PSA and PDA. The isolates were grouped into three groups based on colony colour i.e. light gray, gray and dark gray. The isolates were categorized into 2 groups based on growth namely, moderate growth and profused growth. The number of septa ranged from 5-7 to 7-10 representing isolates ET002 and ET003, respectively. Similarly, conidial length varied from 56.7 µm to 89.44 µm for isolates ET002 and ET003, respectively. The pathogenic variability tested on Thai Super Sweet (TSS) corn variety, showed that isolates ET001 and ET003 were more aggressive while isolate ET005 was less aggressive among the isolates tested. Conclusion, significance and impact of the study: Both morphology and molecular results showed that, the isolates were identified as E. turcicum. The findings of this study will serve as a baseline for future studies and will help to minimize losses in yield.

Awareness of oral cancer and precancer among final year medical and dental students of Universiti Sains Malaysia (USM), Malaysia

The objective of this survey was to evaluate the knowledge of final year dental and medical students of Universiti Sains Malaysia concerning epidemiology, aetiology, clinical aspects, prevention, early detection and treatment of oral cancer and oral potentially malignant disorders (OPMD). A pre-tested, self-administered questionnaire with 36 questions was used. Forty five dental students and 147 medical students participated in the study. Dental students were relatively better informed than their medical colleagues concerning most issues addressed in the questionnaire. Yet, in some areas of knowledge, the dental students did not differ significantly from their medical colleagues. Only a small proportion of both groups of students expressed confidence in their knowledge and skills in oral cancer prevention and detection. This study revealed areas of deficiency in the awareness of these students concerning oral cancer and OPMD. It points to a necessity to strengthen these aspects of medical and dental undergraduate curricula.

Prevalence and pattern of use of herbal medicines during pregancy in Tumpat District,Kelantan

The objective of this cross -sectional study is to determine the prevalence and pattern of herbal medicines use during pregnancy among women in Tumpat district, Kelantan. A total of 210 mothers were interviewed using a structured questionnaire. There were 108 mothers (51.4%) who used at least one type of herbal medicines during pregnancy. The most common herbal medicines used (63.9%) was coconut oil which was ingested during the third trimester of pregnancy only. The most common indication was (89.8%) to facilitate labour. The majority of users (79.6%) used herbal medicines during the third trimester of pregnancy only. Many of them (81.5%) believed that herbal medicines were effective to solve their health problems and fulfilled the indications for use. The older generation like parents and in laws (63.9%) were the most common persons who suggested using herbal medicines. The majority of them used the herbs only once (56.5%) and one type (87.0%) throughout the pregnancy. Further research focusing on local commonly used herbal medicines is to be carried out to evaluate the safety and efficacy of the herbs.

Effectiveness of nutrition education vs. non-nutrition education intervention in improving awareness pertaining iron deficiency among anemic adolescents

This study was carried out to compare the effect between nutrition education intervention and non-nutrition education intervention on awareness regarding iron deficiency among schooling adolescents in Tanah Merah, one of rural district in Kelantan, Malaysia. This study which was started in year 2010 involved 280 respondents [223 girls, 57 boys, age: 16 yr] from schools in Tanah Merah. The selection criteria were based on hemoglobin level [Hb = 7 - 11.9 g/dL for girls; Hb = 7 - 12.9 g/dL for boys]. They were divided into 2 groups. The first group received nutrition education package [Nutrition education, NE], whereas another group was entitled to receive non-nutrition education intervention [Non-Nutrition Education, NNE] [supplement only]. Both interventions were implemented for 3 months. The changes in awareness among respondents of both groups were evaluated using multi-choices questionnaire. Nutrition education receiver group [NE] demonstrated improvement in awareness at post-intervention. No substantial improvement was demonstrated by the counterpart group [NNE]. Multimedia nutrition education program conducted at school setting was in fact practical and effective in improving awareness on iron deficiency among anemic adolescents