Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis

This work is licensed under a Creative Commons Attribution 4.0 International License.Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is upregulated in breast cancer, and elevated cytoplasmic HuR correlates with high-grade tumors and poor clinical outcome of breast cancer. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, and cytokines that support major tumor hallmarks including invasion and metastasis. Here, we report a HuR inhibitor KH-3, which potently suppresses breast cancer cell growth and invasion. Furthermore, KH-3 inhibits breast cancer experimental lung metastasis, improves mouse survival, and reduces orthotopic tumor growth. Mechanistically, we identify FOXQ1 as a direct target of HuR. KH-3 disrupts HuR–FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion. Our study suggests that inhibiting HuR is a promising therapeutic strategy for lethal metastatic breast cancer

Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases

Protein kinases are the most common protein domains implicated in cancer, where somatically acquired mutations are known to be functionally linked to a variety of cancers. Resequencing studies of protein kinase coding regions have emphasized the importance of sequence and structure determinants of cancer-causing kinase mutations in understanding of the mutation-dependent activation process. We have developed an integrated bioinformatics resource, which consolidated and mapped all currently available information on genetic modifications in protein kinase genes with sequence, structure and functional data. The integration of diverse data types provided a convenient framework for kinome-wide study of sequence-based and structure-based signatures of cancer mutations. The database-driven analysis has revealed a differential enrichment of SNPs categories in functional regions of the kinase domain, demonstrating that a significant number of cancer mutations could fall at structurally equivalent positions (mutational hotspots) within the catalytic core. We have also found that structurally conserved mutational hotspots can be shared by multiple kinase genes and are often enriched by cancer driver mutations with high oncogenic activity. Structural modeling and energetic analysis of the mutational hotspots have suggested a common molecular mechanism of kinase activation by cancer mutations, and have allowed to reconcile the experimental data. According to a proposed mechanism, structural effect of kinase mutations with a high oncogenic potential may manifest in a significant destabilization of the autoinhibited kinase form, which is likely to drive tumorigenesis at some level. Structure-based functional annotation and prediction of cancer mutation effects in protein kinases can facilitate an understanding of the mutation-dependent activation process and inform experimental studies exploring molecular pathology of tumorigenesis

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Determination of resource mobilization during seedling growth ofpalmyra palm, Borassus flabellifer L.

Asian palmyra palm (Borassus flabellifer L.) is a multipurpose tree with year round products as food for the dependentsociety. Besides edible items the tree offers around 801 useful goods which are economically important. Such a plant’sseedling bilogy has not been fully understood. Hence, the present study was aimed at understanding seedling developmentalstages and resource mobilisation in Palmyra palm and further to determine the role of cotyledonary sheath (CS) during entireseedling growth. We investigated the developmental changes throughout growth of seedlings by providing different sets ofgrowth conditions. Artificial seed bed made of coconut coir was compared with that of soil conditions to study germinationand establishment of seedlings. Phloem loading dye was used to track the flow of nutrients from embryo to cotyledonarysheath. Seed germination in palmyra palm is hypogeal by forming ligular and tubular structures remotely in soil. Eight neworgans differentiate from the seed embryo that includes haustorium, ligule, cotyledonary sheath, cataphyll, eophyll,mesocotyle (junction), primary root and mesocotyl roots during seed germination. Among these the first four are temporaryorgans and they disentegrate once the seedling is well established. The last four organs are responsible for developing acomplete plantlet at later stages. The seed and seedling organs of Palmyra palm have four major storage reserves to supportsuccessful germination and firm establishment of seedling. Palmyra has evolved to control the solubilisation, movement andregulation of food among transient seedling organs and carry out translocation of food to the developing and differentiatingorgans. Seedlings also have developed physiological functions and strategies to mobilise the stored food without losing themat any point of their growth and developmental stages. Water required for seed germination permeates laterally only viacotyledonary sheath which has spongy tissues and lenticels all over. These tissues are the primary mode of water supply asthe seedlings lack major root organs in the early stages of development. Flourescent microscopic and anatomical studieswere carried out to observe the transport and storage of food substances required during seedling growth. Histochemicalstudies of seedling organs have revealed the presence of various type of nutrients such as simple sugars, carbohydrates,proteins, amino acids and lipids

A new reagent for selective reduction of nitro group

1315-1318The nitro group in aromatic nitro compounds containing reducible substituents such as methyl, carboxylic acids and phenols, and halogens are selectively and rapidly reduced at room temperature to the corresponding amines in good yield by employing hydrazine glyoxylate in the presence of zinc powder or magnesium powder. It has been observed that hydrazine glyoxylate is more effective than hydrazine, glyoxylic acid, hydrazinium monoformate or ammonium monoformate and reduction of the nitro group occurs without hydrogenolysis in the presence of low-cost magnesium compared to expensive metals like palladium, platinum, ruthenium, etc. The products have been characterized by comparison of their TLC, infrared spectra and melting point

Determination of resource mobilization during seedling growth of palmyra palm, Borassus flabellifer L.

498-509Asian palmyra palm (Borassus flabellifer L.) is a multipurpose tree with year round products as food for the dependent society. Besides edible items the tree offers around 801 useful goods which are economically important. Such a plant’s seedling bilogy has not been fully understood. Hence, the present study was aimed at understanding seedling developmental stages and resource mobilisation in Palmyra palm and further to determine the role of cotyledonary sheath (CS) during entire seedling growth. We investigated the developmental changes throughout growth of seedlings by providing different sets of growth conditions. Artificial seed bed made of coconut coir was compared with that of soil conditions to study germination and establishment of seedlings. Phloem loading dye was used to track the flow of nutrients from embryo to cotyledonary sheath. Seed germination in palmyra palm is hypogeal by forming ligular and tubular structures remotely in soil. Eight new organs differentiate from the seed embryo that includes haustorium, ligule, cotyledonary sheath, cataphyll, eophyll, mesocotyle (junction), primary root and mesocotyl roots during seed germination. Among these the first four are temporary organs and they disentegrate once the seedling is well established. The last four organs are responsible for developing a complete plantlet at later stages. The seed and seedling organs of Palmyra palm have four major storage reserves to support successful germination and firm establishment of seedling. Palmyra has evolved to control the solubilisation, movement and regulation of food among transient seedling organs and carry out translocation of food to the developing and differentiating organs. Seedlings also have developed physiological functions and strategies to mobilise the stored food without losing them at any point of their growth and developmental stages. Water required for seed germination permeates laterally only via cotyledonary sheath which has spongy tissues and lenticels all over. These tissues are the primary mode of water supply as the seedlings lack major root organs in the early stages of development. Flourescent microscopic and anatomical studies were carried out to observe the transport and storage of food substances required during seedling growth. Histochemical studies of seedling organs have revealed the presence of various type of nutrients such as simple sugars, carbohydrates, proteins, amino acids and lipids

Exponential Stability Analysis of Stochastic Semi-Linear Systems With Lèvy Noise

The exponential stability of semi-linear stochastic partial differential equations (SPDEs) involving Lèvy type noise is investigated in this paper. By constructing an appropriate Lyapunov function, a new set of sufficient conditions are established in terms of linear matrix inequalities (LMIs) which ensures the mean-square exponentially stability (MSES) of given system with Neumann boundary conditions. Then the $H_\infty$ performance index is introduced to eliminate the disturbance which occurs in the considered system. The boundary control gain is obtained by solving the LMI conditions using the standard MATLAB software. Finally, a numerical example is provided to demonstrate the usefulness of the proposed methods

Tensile Strength Improvement Using Human Hair Reinforcement in Recycled High Density Polyethylene

410-413One way to reduce the harmful destruction of our ecosystem is to have policies encouraging the use of natural fiber. Human hair disposal has become a growing concern as it is non-degradable. Considerable research is being done regarding the alternative uses of the same. But the high tensile strength of human hair can be harnessed in productive ways. Another area of study aims at increasing the productivity of recycled plastics. This work aims at making use of this non-degradable material for increasing the strength of recycled plastic. Human hair (HH) is used as reinforcement in high density polyethylene (HDPE) forming a polymer matrix composite. Composite samples were made using 3%, 5% and 10% of human hair by weight and the mechanical properties of them were evaluated. The fabricated HH-HDPE polymer matrix composite samples have given encouraging results of improved tensile strength and tensile modulus