Identification of the biochemical signalling mechanisms underlying CD40 killing in colorectal cancer cells

CD40 is a member of the tumour necrosis factor receptor (TNFR) superfamily and ligation by membrane- presented CD40 ligand (mCD40L), but not soluble agonists, causes extensive apoptosis in malignant epithelial cells, including colorectal carcinoma (CRC) cells. This thesis aimed to unravel the precise cell signalling pathways responsible for mCD40L-mediated apoptosis in CRC cells. This study has provided evidence that CRC cell death by mCD40L is rapid. mCD40L activated MOMP, cytochrome c release from mitochondria and induction of Bak/Bax within <6 hours post ligation. The pro- apoptotic role of Bax was confirmed by shRNA-mediated Bax knockdown as this attenuated apoptosis and decreased caspase 3/7 activity. mCD40L triggered rapid TRAIL induction and a caspase-dependent pathway that involved caspase-10 (but not caspase-8) and caspase-9 to cause CRC cell death. Thus CD40 cross-talks with the extrinsic pathway by inducing TRAIL-mediated, caspase-10 activation, mitochondrial disruption, tBid activation, Bak/Bax induction, and activation of caspase-9 and -3/7 to cause CRC cell death. When the signalling pathways triggered by CD40 were studied further, we found that CD40 induced both p- JNK and p-p38 in CRC cells which is necessary for apoptosis, and that JNK might be acting downstream of p38. p38 and JNK directly regulated Bak/Bax and TRAIL induction at the transcriptional level. We also showed that TRAF1, -3, and 6 were induced in CRC cells as early as 1.5 hours post ligation. Our studies not only demonstrated a novel pattern of TRAF regulation in CRC cells but revealed for the first time that TRAF3 has an essential role in CD40-mediated CRC cells death. TRAF3 is central in the induction of apoptosis as its knockdown attenuates apoptosis, by abrogating p38 and JNK activation, induction of Bak/Bax and caspase-3/7 activation. Therefore, despite the existence to a dual apoptotic pathway being engaged in CRC cells, TRAF3 appears to be central in both signalling axes. ROS are rapidly induced in CRC cells by CD40 in a Nox-dependent fashion and this plays an important role in CD40-mediated killing. More specifically, CD40 activation appears to result in TRAF3-dependent p40phox activation. CD40 also regulates directly ROS scavenging mediators, as we detected reduction in Trx-1 expression. Moreover, CD40 triggered activation of the Trx-regulated pro-apoptotic kinase ASK-1, which provided direct molecular explanation for the importance of ROS in CD40 signalling and downstream activation of MKKs and p38/JNK. Thus, the mCD40L-CD40-TRAF3-NOX axis utilises ROS for the activation of ASK-1/MKK/p38/JNK pro-apoptotic pathways in CRC cells. Based on observations in this thesis and more recent findings following completion of this work, we hypothesise that at some point the MAPK/p38/JNK pathway diverges to drive on one hand transcriptional upregulation of TRAIL, activation of tBid and cross talk to the mitochondria, whilst the other p38/JNK pathway directly induces Bak/Bax to also induce MOMP and mitochondrial death, the latter being more reminiscent of CD40-mediated cell death in UCC cells. However, unlike UCC cells were the operation of only the latter pathway takes place means apoptosis requires a minimum of 24-36 hours to occur, in CRC cells there is rapid amplification of the apoptotic signal and quick induction of death. To our knowledge, this is the first demonstration of such extensive and rapid carcinoma cell apoptosis triggered by CD40 ligation. Overall, this study has identified the intracellular signalling cascade triggered by CD40 ligation and results in extensive apoptosis in CRC cells. It has identified a TRAF3-Nox-ROS-ASK1-MKK-p38/JNK pathway (that activates caspase-10 and caspase-9) as the driving force that triggers both a TRAIL-associated extrinsic as well as the intrinsic apoptotic pathways. Thus, in CRC cells CD40 induces apoptosis by pathway cross talk which permits strikingly rapid apoptosis. These findings not only provided novel observations on the mechanisms of apoptosis triggered by the TNSRF member CD40, and also reinforced the importance of the quality of CD40 signal in determining functional outcome, but they have also raised interesting hypotheses for further biological studies. Equally importantly, the findings have also assisted in the formulation of a novel combinatorial therapeutic approach that may exploit CD40 for anticancer therapy

Pragmatic Explicitation Strategy in Rendering of Tayeb Salih's Season of Migration to the North into English: A Socio-cultural Study

The current paper aims to  study critically how the translator(Denys Johnson-Davies) has employed  explicitation strategy in rendering the novel of Tayeb Salih's'' Season of Migration to the North into English''. The objective of the study is to examine the usage of explicitation strategy by the intended  translator in rendering the novel  from Arabic into English. The novel has many complicated symbols  and  many literary and thematic techniques such as the reference to the Nile, the sand, the palm tree which may pose  some  lexical and cultural challenges for the translator to reproduce the text into the target language. The data to be analyzed here is a set of  selected expressions chosen randomly from various pages  of the intended  novel. The selected data were then classified on the basis of reasons for which explicitation strategy was used and the effectiveness of explicitation strategy in rendering  some cultural expressions into English . The result of the study reveals  that the translator (Denys Johnson-Davies)has resorted to some  types of explicitation strategy categorized by Klaudy. They are : the obligatory, optional and pragmatic  explicitation such as (addition ,substitution ,  recasts and  narrowing ( specification). Keywords: Explicitation Strategy, symbols, challenges, pragmatic, addition, substitution DOI: 10.7176/JLLL/57-05 Publication date:June 30th 201

Investigating Methods of Generating Meanings and Derivation of Words in Arabic and Hausa Languages: A Comparative Analytical Linguistic Study

The current study aims at identifying the methods of generating meanings and derivational words in Arabic and Hausa Languages and possible inconsistencies and incongruities that exist between the two languages. The study also aimed at exploring the areas of similarities and differences between the two languages. The study revealed that both Arabic and Hausa languages are similar in ways of: derivation, compounding, functional change and borrowing in varying degrees. Whereas the differences include backformation which is existed in Hausa but is not found in Arabic, consequently, commonalities in the two languages are confirmed in the origins, impact and effect resulting from the direct contact

TRAF3/p38-JNK Signalling Crosstalk with Intracellular-TRAIL/Caspase-10-Induced Apoptosis Accelerates ROS-Driven Cancer Cell-Specific Death by CD40

The capacity to induce tumour-cell specific apoptosis represents the most unique feature of the TNF receptor (TNFR) family member CD40. Recent studies on the signalling events triggered by its membrane-presented ligand CD40L (mCD40L) in normal and malignant epithelial cells have started to unravel an exquisite context and cell type specificity for the functional effects of CD40. Here, we demonstrate that, in comparison to other carcinomas, mCD40L triggered strikingly more rapid apoptosis in colorectal carcinoma (CRC) cells, underpinned by its ability to entrain two concurrently operating signalling axes. CD40 ligation initially activates TNFR-associated factor 3 (TRAF3) and subsequently NADPH oxidase (NOX)/Apoptosis signal-regulating kinase 1 (ASK1)-signalling and induction of reactive oxygen species (ROS) to mediate p38/JNK- and ROS-dependent cell death. At that point, p38/JNK signalling directly activates the mitochondrial pathway, and triggers rapid induction of intracellular TNF-related apoptosis-inducing ligand (TRAIL) that signals from internal compartments to initiate extrinsic caspase-10-asscociated apoptosis, leading to truncated Bid (tBid)-activated mitochondrial signalling. p38 and JNK are essential both for direct mitochondrial apoptosis induction and the TRAIL/caspase-10/tBid pathway, but their involvement follows functional hierarchy and temporally controlled interplay, as p38 function is required for JNK phosphorylation. By engaging both intrinsic and extrinsic pathways to activate apoptosis via two signals simultaneously, CD40 can accelerate CRC cell death. Our findings further unravel the multi-faceted properties of the CD40/mCD40L dyad, highlighted by the novel TNFR crosstalk that accelerates tumour cell-specific death, and may have implications for the use of CD40 as a therapeutic target

Effects of Atmospheric Turbulence on Optical Wireless Communication in NEOM Smart City

International audienceThe foundation of any smart city requires an innovative and robust communication infrastructure. Many research communities envision free-space optical communication (FSO) as a promising backbone technology for the services and applications provided by such cities. However, the channel through which the FSO signal travels is the atmosphere. Therefore, the FSO performance is limited by the local weather conditions. The variation in meteorological variables leads to variations of the refractive index along the transmission path. These index inhomogeneities (i.e., atmospheric turbulence) can significantly degrade the performance of FSO systems. Thus, a practical implementation of the FSO link must carefully consider the atmospheric turbulence effect. This paper aims to investigate the feasibility of FSO communication for NEOM, a promising smart city in Saudi Arabia. We study the effect of weather conditions on FSO links using the micrometeorology model, taking into account actual weather data. The FSO performance in winter and summer was compared in terms of the bit error rate, signal-to-noise ratio (SNR), link availability, and transmission distance. The study shows that the atmospheric turbulence strength is moderate and strong in winter and summer, respectively. The temperature has the biggest impact on the FSO system when compared to the other meteorological elements included in this study. Furthermore, at transmission distances less than 300 m, atmospheric turbulence does not significantly affect the FSO for the operating wavelength of 1550 nm. Furthermore, it has been shown that at transmission distances greater than 300 m, the SNR in summer is more than 18% higher than in winter. The findings of this research enable understanding of the effect of turbulence caused by NEOM weather on the FSO link, thus assisting engineers in establishing a reliable FSO backbone link by adjusting the relevant parameters

Investigating Methods of Generating Meanings and Derivation of Words in Arabic and Hausa Languages: A Comparative Analytical Linguistic Study

The current study aims at identifying the methods of generating meanings and derivational words in Arabic and Hausa Languages and possible inconsistencies and incongruities that exist between the two languages.&nbsp;&nbsp; The study also aimed at exploring the areas of similarities and differences between the two languages. The study revealed that both Arabic and Hausa languages are similar in ways of: derivation, compounding, functional change and borrowing in varying degrees. Whereas the differences include backformation which is existed in Hausa but is not found in Arabic, consequently, commonalities in the two languages are confirmed in the origins, impact and effect resulting from the direct contact

Emergence of ischemic cardiomyopathy as the main cause of heart failure in urban Sudanese population

Heart failure is a rapidly growing cardiovascular (CV) problem in Sudan due to affluence and lifestyle changes producing high rates of CV risk factors and consequent coronary heart disease in addition to the historical causes of hypertension and rheumatic heart disease. This study is intended to measure the prevalence of heart failure (HF) among hospital admissions and study the recent trends in etiology, clinical features and methods of treatment. Methods: All admissions at Sudan Heart Institute between January 2000 and June 2011 were studied. Patients went through detailed history taking and physical examination. Investigations included 12 lead ECG and chest X-ray, echocardiography and cardiac catheterization was also carried out where indicated. Results: A total of 12453 cases were collected and 1073 case of HF were verified by the authors and an independent cardiologist, constituting 8.6% of CV disease admissions. Female to male ratio was 1:1.6 and age 15 to 96 years (median 58 years). 74.6 % of all patients were urban dwellers. Left ventricular (LV) systolic dysfunction accounted for 71.6% and preserved systolic function 28.4%. Ischemic aetiology accounted for 44.6% of cases, hypertension 24.8 %, RHD 14.4% and idiopathic 12.4%. Conclusion: Ischemic cardiomyopathy emerged as the main cause of HF among urban population probably due to changes in lifestyle. Treatment and prevention of these risk may reduce the prevalence of heart failure

Hereditary Hemorrhagic Telangiectasia in a Sudanese Patient

Background. Hereditary hemorrhagic telangiectasia (HHT) also known as Osler–Weber–Rendu syndrome is a rare autosomal dominant disorder, which results in vascular dysplasia affecting mainly visceral and mucocutaneous organs. Case Presentation. A 65-year-old woman with a 12-year history of recurrent spontaneous epistaxis presented with shortness of breath, easy fatigability, and bilateral lower limb edema. Her family history was significant for definite hereditary hemorrhagic telangiectasia in first-degree relatives. During the previous 15 days, she has experienced three episodes of recurrent nasal bleeding. She has a background of chronic mitral regurgitation. Physical examination revealed telangiectases in her tongue, lower lip, and hand in addition to signs of congestive heart failure. The patient met 3\4 Curacao criteria and had a definite HHT. Her laboratory workup revealed a hemoglobin count of 5.4 g/dl. Echocardiography revealed a left systolic ejection fraction of 51% with left atrial dilatation and severe mitral regurgitation. Chest X-ray showed features of cardiomegaly and pulmonary edema. The abdominal ultrasonography showed enlarged liver size with homogenous texture and congested hepatic veins without features of hepatic AVMs. She was treated with intravenous frusemide, iron supplement, tranexamic acid, blood transfusion, and nasal packing. Conclusions. HTT usually passes unnoticed in Sudan. The rarity of HHT, difficulties in affording diagnostic imaging studies, and low clinical suspicion among doctors are important contributing factors. Anemia resulting from recurrent epistaxis might have an influential role in precipitating acute heart failure in those with chronic rheumatic valvular disease