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Several clinical practice guidelines (CPGs), consensus statements, and recommendations currently exist for the diagnosis and management of breakthrough cancer pain (BTcP). These documents have considerable variability amongst them, and to date, their quality and methodologic rigor have not been appraised.We aim to identify and perform a quality appraisal of CPGs for the diagnosis and management of BTcP using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.A comprehensive literature search was performed in MEDLINE (via PubMed), EMBASE, and SCOPUS databases up until January 1, 2021. Four reviewers independently evaluated each guideline using the AGREE II instrument. Scaled domain scores were generated and the threshold used for satisfactory quality was60%. Additionally, intraclass correlation coefficients (ICC) were calculated to determine level of agreement between reviewers.Eleven guidelines were selected for final evaluation based on inclusion/exclusion criteria. Only one guideline was classified of "average" quality while the rest were classified as "low" quality. The "Editorial Independence" (70.46 ± 35.7) and "Scope and Purpose" (64.78 ± 12.5) domains received the highest mean scores, while the "Applicability" (32.58 ± 13.5) and "Rigor of Development" (35.04 ± 9.0) domains received the lowest mean scores. ICC statistical analysis showed high magnitude of agreement between reviewers with a range of (0.790-0.988).Reflecting upon our quality appraisal, it is evident that the quality and methodologic rigor of BTcP guidelines can be improved upon in the future. Our findings also elucidate the existing variability/discrepancies among guidelines in diagnostic criteria and management of BTcP.

Nanofluids have already proven great potential in the thermal amplification of several manufacturing industries and have been widely employed in energy technologies in recent times. Therefore, the current framework investigates the characteristics of the Jeffrey nanofluid flow with the influence of activation energy and motile microorganisms over a sheet is considered. The influence of the magnetic field is another important physical parameter in the flow analysis and has been regarded in this review. The remarkable properties of nanofluid are demonstrated by thermophoresis and Brownian motion characteristics. Thermophoresis has relevance in mass transport processes in many higher temperature gradient operating systems. An appropriate similarities transformation is utilized make convenient to partial differential equation into ordinary differential equations. The well-known shooting tactic is utilized to estimate numerical outcomes of obtained ordinary system of flow. The governing dimensionless equations are integrated subject to the aid of the bvp4c scheme in the built-in software of MATLAB to find out the solution. The procedure assumed employing MATLAB. The characteristics of physical parameters against the velocity of fluid, temperature, concentration, and motile microorganisms are elaborated through graphs and tables. The dynamic physical declaration of attained results reveals that buoyancy ratio parameter and bioconvection Rayleigh number plays a vibrant role in the declining flow of Jeffery nanofluid while contrasting nature is analyzed for mixed convection parameter. The increasing behavior of temperature is observed for larger variations of heat sink/source parameters and thermophoresis parameter while it shows conflicting nature for increasing values of Prandtl number. The concentration of nanoparticle is reduced with the advanced values of Prandtl number, Lewis number and Brownian motion, perceived from the results. The mounting valuation of the Peclet number and Bioconvection Lewis number caused a reduction in motile microorganism concentration. The envisaged hypotheses could be beneficial for modifications to extrusion systems, bio-mimetic systems, efficient energy generation, bio-molecules and improved production systems.

الملخص: أهداف البحث: يهدف هذا البحث إلى تقييم الآثار قبل السريرية المضادة للسرطان للميتفورمين في نموذج طُعم أجنبي لسرطان الثدي. طرق البحث: أجريت هذه التجربة التداخلية خلال فترة محددة مدتها خمسة أشهر (أغسطس ٢٠١٦ - يناير ٢٠١٧). حيث استخدمنا نموذج طُعم أجنبي من الفئران بلب/ج عارية. وكان حجم العينة ٥٠ فأرا، وُزعت لمجموعتين المجموعة أ والمجموعة ب لمجموعتي الميتفورمين والتحكم السلبية، على التوالي. وتم تقييم النشاط السرطاني للميتفورمين من خلال مقارنة حجم الورم، ووزن الورم، ونسبة تراجع الورم، ونسبة التراجع المئوية ومعدل البقاء على قيد الحياة. النتائج: بالمقارنة مع مجموعة التحكم، خفض الميتفورمين بشكل كبير تطور الورم في نموذج الطُعم الأجنبي لسرطان الثدي الناجم حسب مؤسسة ميتشغان للسرطان-٧. وقد انعكس ذلك من خلال اختلافات كبيرة في حجم الورم في المتابعة النهائية. وقد تم دعم النتائج التي توصلنا إليها من خلال انخفاض كبير في معدل نمو الورم ووزن الورم في مجموعة الميتفورمين مقارنة بمجموعة التحكم. وبالمثل، كان معدل البقاء الكلي وتراجع الورم مرتبطين بشكل أكبر في مجموعة الميتفورمين. الاستنتاجات: أثبتت هذه الدراسة أن الميتفورمين يمكن أن يقلل بشكل كبير من نمو الورم ويمكن أن يزيد من معدل البقاء على قيد الحياة في نموذج الطُعم الأجنبي لسرطان الثدي. Abstract: Objective: This research aims to evaluate the preclinical meritorious and anticancer effects of Metformin in a Xenograft model of breast cancer. Methods: This interventional trial was conducted during a defined period of 5 months (August 2016 January 2017). We used a Xenograft model of nude BALB/c mice. A sample size of 50 mice, allocated into two groups and designated as Group A and Group B for Metformin and negative control groups, respectively. The anticancer activity of Metformin has been evaluated by comparing the tumour volume, tumour weight, tumour regression ratio, percentage regression, and survival rate. Results: Compared with the control group, Metformin can significantly reduce the progression of tumour in the Xenograft model of breast cancer induced by MCF-7. This is reflected by significant differences in tumour volume at the final follow-up (p =

Cells are exposed to several environmental or chemical stressors that may cause DNA damage. DNA damage alters the normal functioning of the cell and contributes to several diseases, including cancer. Cells either induce DNA damage repair pathways or programmed cell death pathways to prevent disease formation depending on the severity of the stress and the damage caused. The DNA repair mechanisms are crucial to maintaining genome stability. During this adaptive response, the heat shock proteins (HSPs) are the key players. HSPs are overexpressed during genotoxic stress, but the role of different molecular players in the interaction between HSPs and DNA repair proteins is still poorly understood. As DNA damage promotes genomic instability and proteotoxic stress, modulating the protein quality control systems like the HSPs network could be a promising strategy for targeting disease pathologies associated with genomic instability, such as cancer. Hence, this review highlights the role of HSPs in DNA repair pathways. Further, the review also provides an outlook on the role of genomic instability and protein homeostasis in cancer, which is crucial to understanding the mechanisms behind its survival and developing novel targeted therapies.

Green synthesis approach to manufacture metal oxide nanoparticles (MONPs) have gained attention due to marvelous properties governed by the synergistic effects of metal and phyto-constituents. We report green chemistry method for extracellular synthesis of Copper (CuO), Magnesium (MgO) and Iron oxide (FeO) nanoparticles using Clematis orientalis leaves extract. Copper acetate, magnesium sulfate and ferric chloride (0.25 and 0.5 M each separately) were reduced by leaves extract of C. orientalis to synthesize respective MONPs. The theoretical size of MONPs calculated using XRD data was 13–53 nm. The purity of MONPs was confirmed through EDS while SEM analysis confirmed crystalline nature of CuO and FeO NPs, however MgO NPs were crystalline cum amorphous in nature. MONPs synthesized at low salt concentration (0.25 M) revealed better free radical scavenging activity, reducing power potential, and total antioxidative capacity. While phenolic and flavonoid like activities on MNOPs were better when synthesized at 0.5 M salt concentration. MONPs exhibited significant antibacterial activity (10–23 mm) against Gram-positive and Gram-negative bacterial strains. The study concludes that concentration of salt used for synthesis of MONPs has the influential role in determining physiological and biological properties of MONPs. Furthermore, C. orientalis functionalized MONPs can be used for medical applications due to antibacterial and antioxidative capabilities.

Recent advances indicate a possible role of phytochemicals as modulatory factors in signaling pathways. We have previously demonstrated PHLPP2-mediated suppression of Nrf2 responses during oxidant attack. The present study was designed to explore Nrf2-potentiating mechanism of morin, a flavonol, via its possible role in intervening PHLPP2-regulated Akt/GSK3β/Fyn kinase axis. Efficacy of morin was evaluated against oxidative stress-mediated damage to primary hepatocytes by tert-butyl hydroperoxide (tBHP) and acetaminophen. The anti-cytotoxic effects of morin were found to be a consequence of fortification of Nrf2-regulated antioxidant defenses since morin failed to sustain activities of redox enzyme in Nrf2 silenced hepatocytes. Morin promoted Nrf2 stability and its nuclear retention by possibly modulating PHLPP2 activity which subdues cellular Nrf2 responses by activating Fyn kinase. Pull-down assay using morin-conjugated beads indicated the binding affinity of morin towards PHLPP2. Molecular docking also revealed the propensity of morin to occupy the active site of PHLPP2 enzyme. Thus, dietary phytochemical morin was observed to counteract oxidant-induced hepatocellular damage by promoting Nrf2-regulated transcriptional induction. The findings support the novel role of morin in potentiating Nrf2 responses by limiting PHLPP2 and hence Fyn kinase activation. Therefore, morin may be exploited in developing novel therapeutic strategy aimed at enhancing Nrf2 responses., Graphical abstract fx1, Highlights • Cytoprotection against tBHP-evoked oxidative stress by morin is Nrf2-regulated. • Morin prevents Nrf2-destabilization via PHLPP2-Akt-GSK3β-Fyn kinase pathway. • In silico docking studies confirmed PHLPP2 activity inhibition by morin. • Morin mitigates APAP induced cytotoxicity by suppressing PHLPP2 pathway.

Mammalian forkhead-box family members belonging to the 'O' category (FoxO) manipulate a plethora of genes modulating a wide array of cellular functions including cell cycle regulation, apoptosis, DNA damage repair, and energy metabolism. FoxO overexpression and nuclear accumulation have been reported to show correlation with hindered tumor growth in vitro and size in vivo, while FoxO's downregulation via phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway has been linked with tumor promotion. In this study, we have explored for the first time intervention of berberine, a plant-derived isoquinoline alkaloid, with FoxO family proteins in hepatoma cells. We observed that berberine significantly upregulated the mRNA expression of both FoxO1 and FoxO3a. Their phosphorylation-mediated cytoplasmic sequestration followed by degradation was prevented by berberine-induced downmodulation of the PI3K/Akt/mTOR pathway which promoted FoxO nuclear retention. PTEN, a tumor suppressor gene and negative regulator of the PI3K/Akt axis, was upregulated while phosphorylation of its Ser380 residue (possible mechanism of PTEN degradation) was significantly decreased in treated HepG2 cells. Exposure to berberine induced a significant increase in transcriptional activity of FoxO, as shown by GFP reporter assay. FoxO transcription factors effectively heightened BH3-only protein Bim expression, which in turn, being a direct activator of proapoptotic protein Bax, altered Bax/Bcl-2 ratio, culminating into mitochondrial dysfunction, caspases activation, and DNA fragmentation. The pivotal role of Bim in berberine-mediated cytotoxicity was further corroborated by knockdown experiments where Bim-silencing partially restored HepG2 cell viability during berberine exposure. In addition, a correlation between oxidative overload and FoxO's nuclear accumulation via JNK activation was evident as berberine treatment led to a pronounced increase in JNK phosphorylation together with enhanced ROS generation, lipid peroxidation, decreased activities of superoxide dismutase and catalase, and diminished glutathione levels. Thus, our findings suggest that the antiproliferative effect of berberine may in part be due to mitochondria-mediated apoptosis with Bim acting as a pivotal downstream factor of FoxO-induced transcriptional activation.

Haloxylon stocksii is a perennial halophytic shrub found in saline arid habitats. Ecophysiology of this xero-halophyte was studied to better understand its adaptations to survive under saline conditions (0–300 mM NaCl). Growth parameters remained unaffected at 100 mM NaCl compared to non-saline control and declined at 300 mM; root biomass however, increased in 100 mM NaCl. Shoot water potential, osmotic potential and turgor decreased under saline conditions. Gas exchange parameters such as rate of photosynthesis, rate of transpiration and stomatal conductance decreased in 300 mM NaCl with a decline in intercellular carbon dioxide concentration suggesting stomatal limitation of photosynthesis. Water use efficiency increased significantly in 300 mM NaCl compared to 0 and 100 mM NaCl. Chlorophyll content decreased progressively with increasing salinity while chlorophyll a/b ratio remained unaffected. Potential photochemical quantum yield of PSII (Fv/Fm) and the effective quantum yield [Y (II)] were not affected by salinity; however, there was a constitutive increase in non-photochemical quenching under saline conditions (100 and 300 mM) and decrease in relative electron transport rate in 300 mM NaCl as a protective measure to reduce oxidative stress at cellular level. Total soluble sugars increased by ≈25% in 300 mM NaCl possibly indicating a lower energy demand for growth. Anti-nutritive secondary metabolites such as polyphenols, tannins, flavonoids, saponins and nitrates decreased under saline conditions except for some increase in oxalates in 100 mM NaCl. This study indicates that Haloxylon stocksii is a moderately salt tolerant plant with adaptations to down- regulate its photosynthetic machinery to avoid oxidative stress and could be a palatable animal feed.