Modulation of neuropeptide growth factor signalling by anti-cancer substance-P analogues

Widespread metastases are characteristic of the most aggressive form of lung cancer, small cell lung cancer (SCLC). Although initially sensitive to treatment by radio- and chemotherapy, SCLC develops chemoresistance so the 2-year survival rate remains less than 5%. The aberrant proliferation of SCLC is sustained by multiple autocrine and paracrine growth loops involving calcium mobilising neuropeptides such as vasopressin (AVP) and gastrin releasing peptide (GRP). The expression of these neuropeptides and their receptors are a hallmark of the disease and present an important target for therapeutic intervention. Analogues of substance-P, including [D-ArgI,D-Phe5,D-Trp7-9,Leu11]-substance-P (SP-D) and [Arg6,D-Trp7-9,NmePhe8]-substance-P (6-11) (SP-G), are novel anti-cancer agents which inhibit the growth of SCLC cells. Investigations into the mechanism of action of substance- P analogues on bombesin receptors revealed that in addition to blocking bombesin-induced mitogenesis and signal transduction they also have agonist activity. This unique pharmacological activity of 'biased agonism' may be centred to the growth inhibitory effects of these agents.The aim of this study was to determine whether these agents exhibit 'biased agonist' activity at receptors other than the bombesin/GRP receptor and investigate factors influencing their ability to modulate neuropeptide signalling. Model cell systems consisting of CHO-K1 cell-lines stably expressing GRP or Via receptors were therefore established and the effect of SP-D and SP-G tested. Expression of GRP and Via receptors led to the development of a transformed phenotype as cells showed increased cloning efficiency and survival in soft-agar and suspension growth respectively. GRP and Via receptor expressing cells were less adherent, more migratory and not contact inhibited. Neuropeptide receptor stimulation provided some protection from the cytotoxic effects of etoposide suggesting a role in chemoresistance. Substance-P analogues inhibited normal and anchorageindependent growth of receptor expressing cells. In receptor binding studies on GRP and Via receptor expressing cells, analogue inhibited radioligand binding noncompetitively. Transfected GRP and Via receptors effectively coupled to Ga.q to increase intracellular calcium and the analogues were effective antagonists of this response. Neuropeptide and analogues stimulated ERK activity in GRP and Via receptor expressing cells. Activation of ERK by neuropeptide was rapid and transient while analogue induced activation was delayed and sustained. Analoguestimulated ERK activity was pertussis toxin sensitive whereas neuropeptidestimulated ERK activation was not. In addition, analogue induced ERK activity was blocked by inhibition of EGF receptor kinase. This indicates that SP-D and SP-G facilitate receptor coupling to G-protein Gj/Gq subunits for subsequent calciumindependent ERK activation via EGFR transactivation. Stable cell-lines expressing different levels of Via receptor were used to examine the effect of altering the ratio of receptor to G-protein on the ability of the analogues to direct receptor signalling. There appeared to be little receptor reserve for calcium and ERK responses stimulated by neuropeptide as the efficacy of the response increased with increasing receptor numbers. In contrast, analogue-induced ERK activation occurred with a higher receptor reserve for activated Gj as the magnitude of the response did not increase between medium and high expressing cells. Chimeric Via receptors containing the second (Vjj2) or third intracellular (Vii3) loop of the V2 receptor were used to investigate the influence of substance-P analogues on G-protein selectivity. Both receptors were still capable of binding AVP and SP-G but had altered ability to activate PLC and ERK. The second intracellular loop of VIAR was essential for AVP-stimulated PLC and ERK activation but not for SP-G-induced ERK activation. This confirms that the effects of the agents cause an alteration in the receptor-Gprotein coupling domains of receptors. These findings demonstrate that substance-P analogues are biased agonists of receptors other than GRP receptors, activating downstream signals which differ from those stimulated by the natural agonist through promoting an alternative agonist state of the receptor. This pathway selectivity combined with the receptor specificity of different substance-P analogues offers great potential for the tailored treatment of neuropeptide-dependent tumours

Pakistan’s Electricity Demand Analysis 1975-2016

The problem of energy is one that has plagued the economic growth of Pakistan for decades; the resulting domestic pressure has often led to the misallocation of resources, and therefore should be studied extensively for evidence based policy recommendation. The study in hand aims to envelope and analyze approximate factors responsible for determining electricity demand in the country. The study analyzes the aggregate demand for electricity in Pakistan from 1975-2016, by considering log-run climatic variable affecting electricity demand. The ADF, the Johansen Cointegration, and the ARDL techniques have been applied for the estimation of parameters and analysis. The scientific analysis found that in the short run and long run number of consumers, income (real GDP per capita) square of income and stock of appliances have a significant relationship with the demand of electricity. Where all significant relationships in the long run have a positive relationship with the demand apart from the square of income which may suggest a shift towards alternate means of energy production with a long term sustained growth in income. While, price is found to be insignificant determinant of electricity demand in both short run and long run, which reveals that electricity is considered a necessity by Pakistan’s electricity consumers. In the short run number of consumers, income, squared income, and stock of appliances, all have significant positive relationships with demand, and temperature has an insignificant positive relationship in the short run, but a significant positive relationship in the long run

A Comparative Study of Personality Dynamics of Family and Non-Family Entrepreneurs and their Impact on Organizational Effectiveness

The current research focuses on the exploration of the big five personality traits model and its impact on organizational effectiveness in the restaurant industry entrepreneurs of Lahore, Pakistan. The personality traits of different entrepreneurs working in family and non-family owned enterprises are analyzed along with their effectiveness. Data collection mode was survey and data was collected through structured questionnaire. Purposive non-probability sampling technique was used for sample selection. Questionnaire was responded by 110 entrepreneurs (55 family entrepreneurs and 55 non-family entrepreneurs) of restaurant industry. The research findings reveal that all of the personality items have a positive correlation with the organizational effectiveness except neuroticism, yet these personality traits have variable impact on the effectiveness of restaurants. For family entrepreneurs, the traits of extrovert, neuroticism, openness to experience and agreeableness have significant impact on the effectiveness of restaurants whereas for non-family restaurants only conscientiousness trait has a significant impact on restaurants’ effectiveness. Keywords: family entrepreneurs, non-family entrepreneurs, conscientiousness, extrovert, neuroticism, openness to experience, agreeableness, organizational effectiveness.

Does Intelligence Always Guarantee Performance?

Abstract: The current research is intended to explore the individuals' cognitive intelligence and its impact on their performance. The study examines the intellectual capabilities of employees in reference to the problems that arises due to the interaction with varying job related tasks. Raven's progressive matrices were used to measure the IQ level of employees. This IQ test was intended to measure the non-verbal intelligence, spatial intelligence, mathematical and logical intelligence of employees. It was hypothesized that individuals' intelligence does not always guarantee performance. The final data was collected on 300 employees from different organizations of Telecom sector in the city of Lahore, Pakistan. Outcome of the analysis revealed interesting findings that Intelligence Quotient is found to be insignificantly related with individuals' performance. It shows that IQ alone is not a strong predictor of employees' performance. Intelligence may ensure a reach to entry level position in an organization but for a sustained position other competencies are of utmost importance. This study may provoke new lines of research in the field of positive psychology specifically

Economic Impact of Climate Change on the Agricultural Sector of Punjab

As back as the Industrial Revolution, anthropogenic activities namely, power generation from fossil fuels and deforestation activities have been continuously increasing the atmospheric concentration of GHGs beyond their natural limits resulting in an enhanced greenhouse effect, vis-à-vis, an increase in global temperature. The rise in temperature could be coupled with changes in rainfall pattern, rise in sea level, and frequency and severity of extreme events namely, cyclones and droughts etc. The sum of all these changes is referred to as climate change. Climate change affects economic development in many ways, especially the agrarian economies have always depended on vagaries of nature and climate. Change in temperature, precipitation averages and extreme climate events can alter yield, income, health, sociology and physical safety. Climate change is a global phenomenon and no country is immune to it. The disappearing of the Himalayan glaciers at a fast pace would increase the probability of extreme water flows, rendering it uncontrolled will bring heavy floods, loss of life, livestock, crops and infrastructural facilities in Pakistan, India, Nepal and Bangladesh. Climate change will affect all sectors of the economy not alone agricultural sector the most as well as health, forests, energy, coastal area, biodiversity and ecology all over the globe. In this connection, it will be pertinent to give the most recent events which have taken place across Asia

Evaluation of anti-nociceptive, anti-inflammatory and hepatoprotective effects of methanol extract of Mazus pumilus (Burm. f.) Steenis (Mazaceae) herb

Purpose: This study was designed to investigate the anti-nociceptive, anti-inflammatory and hepatoprotective activities of the methanol extract of Mazus pumilus (Mazaceae) herb. Methods: Anti-nociceptive activity was determined using hot plate, tail flick and acetic acid-induced writing methods. Carrageenan-induced rat paw edema (0.1 mL of 1 %) model was used for the assessment of anti-inflammatory activity. The methanol extract was administered orally at three different doses (150, 300 and 600 mg/kg) to three separate groups in all the experiments. Diclofenac sodium (50 mg/kg) was used as standard drug while control group received DMSO (1 %, 10 mL/kg). The hepatocurative effect of methanol extract of M. pumilus (400 mg/kg) was determined in isoniazid (50 mg/kg) and rifampicin (100 mg/kg) induced liver injury. Silymarin (100 mg/kg) was used as standard drug for comparison. The control group received distilled water (10 mL/kg). Preliminary phytochemical screening was also carried out. Results: The methanol extract of M. pumilus significantly (p < 0.05) augmented latency time and reduced the number of writhes in the pain models at all doses used for the assessment of antinociceptive actions. The anti-inflammatory activity of different doses of extract was evaluated by measuring the reduction in the size of the paw. A significant (p < 0.05) hepatocurative effect was observed when administered after anti-tuberculosis drugs. Histopathological analysis of the liver tissues also revealed restored hepatocellular architecture. Conclusion: The results demonstrate the anti-nociceptive, anti-inflammatory and hepatoprotective effects of the methanol extract of M. pumilus, thus substantiating the ethnomedical claims associated with the herb

Immobilization of Rose Waste Biomass for Uptake of Pb(II) from Aqueous Solutions

Rosa centifolia and Rosa gruss an teplitz distillation waste biomass was immobilized using sodium alginate for Pb(II) uptake from aqueous solutions under varied experimental conditions. The maximum Pb(II) adsorption occurred at pH 5. Immobilized rose waste biomasses were modified physically and chemically to enhance Pb(II) removal. The Langmuir sorption isotherm and pseudo-second-order kinetic models fitted well to the adsorption data of Pb(II) by immobilized Rosa centifolia and Rosa gruss an teplitz. The adsorbed metal is recovered by treating immobilized biomass with different chemical reagents (H2SO4, HCl and H3PO4) and maximum Pb(II) recovered when treated with sulphuric acid (95.67%). The presence of cometals Na, Ca(II), Al(III), Cr(III), Cr(VI), and Cu(II), reduced Pb(II) adsorption on Rosa centifolia and Rosa gruss an teplitz waste biomass. It can be concluded from the results of the present study that rose waste can be effectively used for the uptake of Pb(II) from aqueous streams

Evaluation of Safety of Stewart’s Wood Fern (Dryopteris stewartii) and Its Anti-Hyperglycemic Potential in Alloxan-Induced Diabetic Mice

Diabetes has become a critical challenge to the global health concerns. Cytotoxicity and development of resistance against available drugs for management of diabetes have shifted the focus of global scientific researchers from synthetic to herbal medications. Therefore, the current study was conducted to investigate the possible anti-hyperglycemic potential of Dryopteris stewartii using Swiss albino mice. To evaluate any possible toxic effect of the plant, acute oral toxicity test was performed while the anti-diabetic effects of aqueous and ethanol extracts at 500 mg/kg, positive, negative and normal control were assessed simultaneously. The anti-diabetic study revealed that aqueous extract has higher anti-diabetic potential than ethanol extract while lowered blood glucose level at second week reaching 150 mg/dL, exerting stronger anti-diabetic effects, compared to ethanol extract (190 mg/dL). Oral glucose tolerance findings revealed that aqueous extract decreased blood glucose level by −0.41-fold, compared to ethanol extract showing a decrease by only −0.29-folds. The histopathological evaluation of liver and pancreas of all groups revealed normal cell architecture with no morphological abnormalities. These results suggested the possible use of D. stewartii as anti-diabetic herbal drug in near future. However, these recommendations are conditioned by deep mechanistic studies

A multicenter case control study of association of vitamin D with breast cancer among women in Karachi, Pakistan

Background: The prevalence of vitamin D inadequacy and breast cancer are both high among women living in Karachi, Pakistan. Methods: A matched case control study was conducted in two hospitals of Karachi, Pakistan to evaluate the association of vitamin D (serum 25-hydroxyvitamin D) concentrations, vitamin D supplementation and sun exposure with breast cancer among Pakistani women. A total of 411 newly diagnosed histologically confirmed primary breast cancer cases were enrolled and 784 controls, free of breast and any other cancers, were matched by age (year of birth ± 5 years), residence in the same geographic area and study site. Information was collected on sociodemographic history, history of vitamin D supplementation, past medical and obstetrical history, family history of breast cancer, sun exposure history, histopathology reports and anthropometric measurement and venous blood was collected to measure serum 25-hydroxyvitamin D (25(OH)D) concentration. Results: Compared to patients with sufficient serum vitamin D (\u3e30 ng/ml), women with serum vitamin D deficiency (\u3c20ng/ml), had a higher risk of breast cancer (OR = 1.65, 95%CI: 1.10, 2.50). Women with history of vitamin D supplementation one year prior to enrollment, had significant protective effect against breast cancer (OR = 0.32, 95% CI: 0.24, 0.43). Conclusions and Recommendation: Serum vitamin D deficiency was associated with increased risk of breast cancer, while vitamin D supplementation was associated with decreased risk of breast cancer. In Pakistani women, where vitamin D deficiency is common, raising and maintaining serum vitamin D at population level is a safe and affordable strategy. It may play a role in reducing the incidence of both vitamin D deficiency and breast cancer, particularly among poor women where the breast cancer mortality is highest due to limited resources for early detection, diagnosis, and treatment. The effects of vitamin D with regard to breast cancer risk in Karachi Pakistan should be further evaluated