The emerging role of microRNAs in resistance to lung cancer treatments

One of the major challenges in the treatment of lung cancer is the development of drug resistance. This represents a major obstacle in the treatment of patients, limiting the efficacy of both conventional chemotherapy and biological therapies. Deciphering the mechanisms of resistance is critical to further understanding the multifactorial pathways involved, and in developing more specific targeted treatments. To date, numerous studies have reported the potential role of microRNAs (miRNAs) in resistance to various cancer treatments. MicroRNAs are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing translational repression or mRNA degradation. More than 1200 validated human miRNAs have been identified to date. While as little as one miRNA can regulate hundreds of targets, a single target can also be affected by multiple miRNAs. Evidence suggests that dysregulation of specific miRNAs may be involved in the acquisition of resistance to a number of cancer treatments, thereby modulating the sensitivity of cancer cells to such therapies. Therefore, targeting miRNAs may be an attractive strategy for developing novel and more effective individualized therapies, improving drug efficiency, and for predicting patient response to different treatments. In this review, we provide an overview on the role of miRNAs in resistance to current lung cancer therapies and novel biological agents.

Topography of the combining region of a Thomsen-Friedenreich-antigen-specific lectin jacalin (Artocarpus integrifolia agglutinin). A thermodynamic and circular-dichroism spectroscopic study

Thermodynamic analysis of carbohydrate binding by Artocarpus integrifolia (jackfruit) agglutinin (jacalin) shows that, among monosaccharides, Me alpha GalNAc (methyl-alpha-N-acetylgalactosamine) is the strongest binding ligand. Despite its strong affinity for Me alpha GalNAc and Me alpha Gal, the lectin binds very poorly when Gal and GalNAc are in alpha-linkage with other sugars such as in A- and B-blood-group trisaccharides, Gal alpha 1-3Gal and Gal alpha 1-4Gal. These binding properties are explained by considering the thermodynamic parameters in conjunction with the minimum energy conformations of these sugars. It binds to Gal beta 1-3GalNAc alpha Me with 2800-fold stronger affinity over Gal beta 1-3GalNAc beta Me. It does not bind to asialo-GM1 (monosialoganglioside) oligosaccharide. Moreover, it binds to Gal beta 1-3GalNAc alpha Ser, the authentic T (Thomsen-Friedenreich)-antigen, with about 2.5-fold greater affinity as compared with Gal beta 1-3GalNAc. Asialoglycophorin A was found to be about 169,333 times stronger an inhibitor than Gal beta 1-3GalNAc. The present study thus reveals the exquisite specificity of A. integrifolia lectin for the T-antigen. Appreciable binding of disaccharides Glc beta 1-3GalNAc and GlcNAc beta 1-3Gal and the very poor binding of beta-linked disaccharides, which instead of Gal and GalNAc contain other sugars at the reducing end, underscore the important contribution made by Gal and GalNAc at the reducing end for recognition by the lectin. The ligand-structure-dependent alterations of the c.d. spectrum in the tertiary structural region of the protein allows the placement of various sugar units in the combining region of the lectin. These studies suggest that the primary subsite (subsite A) can accommodate only Gal or GalNAc or alpha-linked Gal or GalNAc, whereas the secondary subsite (subsite B) can associate either with GalNAc beta Me or Gal beta Me. Considering these factors a likely arrangement for various disaccharides in the binding site of the lectin is proposed. Its exquisite specificity for the authentic T-antigen, Gal beta 1-3GalNAc alpha Ser, together with its virtual non-binding to A- and B-blood-group antigens, Gal beta 1-3GalNAc beta Me and asialo-GM1 should make A. integrifolia lectin a valuable probe for monitoring the expression of T-antigen on cell surfaces.

Measurement of the top quark mass in the dilepton channel using mT2 at CDF

We present measurements of the top quark mass using the \mT2, a variable related to the transverse mass in events with two missing particles. We use the template method applied to t\tbar dilepton events produced in p\pbar collisions at Fermilab's Tevatron and collected by the CDF detector. From a data sample corresponding to an integrated luminosity of 3.4 \invfb, we select 236 t\tbar candidate events. Using the \mT2 distribution, we measure the top quark mass to be M_{Top} = 168.0^{+4.8}_{-4.0} $\pm$ {2.9} GeV/c^{2}. By combining the \mT2 with the reconstructed top mass distributions based on a neutrino weighting method, we measure M_{top}=169.3 $\pm$ 2.7 $\pm$ 3.2 GeV/c^{2}. This is the first application of the \mT2 variable in a mass measurement at a hadron collider.

Interrelations of micro-organisms and mulberry III. The beneficial influence of certain heterotrophs on the nitrifiers in rhizosphere

Evidence has been presented to show that the autotrophic nitrifying organisms get stimulated in the mulberry rhizosphere. Three species of Pseudomonas, one each of Achromobacter and Bacillus capable of degrading methionine were shown to be stimulated in the rhizosphere. These bacteria were capable of reversing the inhibitory effect of methionine on soil nitrification. Two of them were able to form nitrite from methionine. The possibility that the increased nitrifying activity in the mulberry rhizosphere in the presence of methionine found in mulberry root exudations was the result of the activity of these organisms was suggested.

Measurement of the top quark mass in the dilepton channel using mT2 at CDF

We present measurements of the top quark mass using the \mT2, a variable related to the transverse mass in events with two missing particles. We use the template method applied to t\tbar dilepton events produced in p\pbar collisions at Fermilab's Tevatron and collected by the CDF detector. From a data sample corresponding to an integrated luminosity of 3.4 \invfb, we select 236 t\tbar candidate events. Using the \mT2 distribution, we measure the top quark mass to be M_{Top} = 168.0^{+4.8}_{-4.0} $\pm$ {2.9} GeV/c^{2}. By combining the \mT2 with the reconstructed top mass distributions based on a neutrino weighting method, we measure M_{top}=169.3 $\pm$ 2.7 $\pm$ 3.2 GeV/c^{2}. This is the first application of the \mT2 variable in a mass measurement at a hadron collider.

Raman and infra-red spectra of crystalline potassium sulphamate

Raman spectrum of a single crystal of potassium sulphamate has been recorded for the first time using λ 2536 radiation of mercury as the exciter. Thirty-three Raman lines have been observed of which nine belong to the lattice oscillations. The infra-red absorption spectrum of the substance was taken in the powder form in potassium bromide disc using Carl Zeiss UR 10 IR spectrometer. Thirty-six absorption maxima could be identified of which twenty-five have been recorded for the first time. The analysis clearly shows that the N-H bond in the crystalline potassium sulphamate is not hydrogen-bonded to any appreciable extent.

Understanding Human Drug Conjugating Enzymes; Regio- and Stereoselectivity in Sulfotransferase 1A3 and the UDP-Glucuronosyltransferases

Sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs) are important detoxification enzymes and they contribute to bioavailability and elimination of many drugs. SULT1A3 is an extrahepatic enzyme responsible for the sulfonation of dopamine, which is often used as its probe substrate. A new method for analyzing dopamine-3-O-sulfate and dopamine-4-O-sulfate by high-performance liquid chromatography was developed and the enzyme kinetic parameters for their formation were determined using purified recombinant human SULT1A3. The results show that SULT1A3 strongly favors the 3-hydroxy group of dopamine, which indicates that it may be the major enzyme responsible for the difference between the circulating levels of dopamine sulfates in human blood. All 19 known human UGTs were expressed as recombinant enzymes in baculovirus infected insect cells and their activities toward dopamine and estradiol were studied. UGT1A10 was identified as the only UGT capable of dopamine glucuronidation at a substantial level. The results were supported by studies with human intestinal and liver microsomes. The affinity was low indicating that UGT1A10 is not an important enzyme in dopamine metabolism in vivo. Despite the low affinity, dopamine is a potential new probe substrate for UGT1A10 due to its selectivity. Dopamine was used to study the importance of phenylalanines 90 and 93 in UGT1A10. The results revealed distinct effects that are dependent on differences in the size of the side chain and on the differences in their position within the protein. Examination of twelve mutants revealed lower activity in all of them. However, the enzyme kinetic studies of four mutants showed that their affinities were similar to that of UGT1A10 suggesting that F90 and F93 are not directly involved in dopamine binding in the active site. The glucuronidation of β-estradiol and epiestradiol (α-estradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. The results show that there are clear differences in the regio- and stereoselectivities of UGTs. The most active isoforms were UGT1A10 and UGT2B7 demonstrating opposite regioselectivity. The stereoselectivities of UGT2Bs were more complex than those of UGT1As. The amino acid sequences of the human UGTs 1A9 and 1A10 are 93% identical, yet there are large differences in their activity and substrate selectivity. Several mutants were constructed to identify the residues responsible for the activity differences. The results revealed that the residues between Leu86 and Tyr176 of UGT1A9 determine the differences between UGT1A9 and UGT1A10. Phe117 of UGT1A9 participated in 1-naphthol binding and the residues at positions 152 and 169 contributed to the higher glucuronidation rates of UGT1A10. In summary, the results emphasize that the substrate selectivities, including regio- and stereoselectivities, of UGTs are complex and they are controlled by many amino acids rather than one critical residue.

Pajala–Kolarin ja Soklin kaivoshankkeisiin liittyvien rautatie- ja tieinvestointien ja Kemin satamainvestointien aluetaloudelliset vaikutukset

Lappiin suunnitteilla olevat Pajala–Kolarin rauta- ja Soklin fosforikaivos ovat megaluokan hankkeita. Kaivosten rakentaminen ei voi kuitenkaan toteutua jos niiden tarvitsemia rautatie-, satama- ja tieinvestointeja ei voida toteuttaa. Tutkimuksen tavoitteena oli arvioida näiden väyläinvestointien aluetaloudellisia vaikutuksia. Tutkimus on jatkoa Ruraliassa juuri valmistuneelle yhdeksää Pohjois- ja Itä-Suomen kaivoshanketta koskevalle tutkimukselle, jossa keskitytään itse kaivosinvestointien vaikutuksiin. Tutkimuksen on rahoittanut Liikenne- ja viestintäministeriö yhdessä Työ- ja elinkeinoministeriön kanssa. Työvälineenä oli Ruraliassa kehitetty RegFinDyn-aluemalli. Simuloinnit suoritettiin vuosille 2008–2030 ja raportoitiin Lapin seutukuntien tasolla. Tulosten mukaan kaikki, mutta erityisesti mittavat rautatieinvestoinnit olisivat merkittäviä seutukuntien taloudelliselle kasvulle. Äkäsjoki–Ajos radan rakentaminen auttaisi Tunturi-Lapin, Torniolaakson ja Kemi–Tornion seutukuntia taantuman yli. Taloudellinen kasvu voisi lisääntyä läntisen Lapin seutukunnissa yhteensä 0,6–2,2% vuoteen 2011 ja yhteensä 1,3–4,3% vuoteen 2016 mennessä. Tämä olisi keskimäärin 0,1–0,5% vuodessa. Soklin kaivoksen tapauksessa Kemijärvi–Kelloselkä–Sokli rautatien vaikutukset Itä- ja Pohjois-Lapin seutukuntiin olisivat merkittäviä. Investointien edetessä Itä-Lapin seutukunnan taloudellinen kasvu voisi vahvistua kumulatiivisesti tarkasteltuna 8,3% vuoteen 2013 mennessä. Vuosikeskiarvona tämä olisi 2,8%. Radan vaikutus Pohjois-Lapin taloudelliseen kasvuun olisi pienempi, vuoteen 2014 mennessä yhteensä 3% eli keskimäärin 0,8% vuodessa. Väyläinvestointien työllisyysvaikutukset olisivat myönteisiä. Pajala–Kolarin kaivoksen rautatieinvestoinnit toisivat läntiseen Lappiin uusia työpaikkoja vuoteen 2015 mennessä yhteensä 418. Tästä Tunturi-Lapin osuus olisi 147, Torniolaakson 114 ja Kemi–Tornion seutukunnan 157. Vastaavat vuosikeskiarvot olisivat 52, 18, 14 ja 20. Soklin kaivoksen rautatieinvestoinnit toisivat jonkun verran enemmän uusia työpaikkoja Pajala–Kolariin verrattuna koska investoinnit olisivat suuremmat. Radan rakentaminen voisi tuoda Itä-Lappiin yhteensä 506 uutta työpaikkaa vuoden 2013 loppuun mennessä. Pohjois-Lapin työllisyys voisi lisääntyä 153 uudella työpaikalla. Yhteensä voisi siten syntyä 660 uutta työpaikkaa. Vastaavat vuosikeskiarvot olisivat 169, 51, 220 uutta työpaikkaa. Kun kaivoksia tarkastellaan yhdessä, työllisyysvaikutukset olisivat suurimmat vuonna 2015, jonka loppuun mennessä väyläinvestoinnit voisivat luoda yhteensä 1288 uutta työpaikkaa. Vastaava vuosikeskiarvo olisi 161. Taloudellisen kasvun ohella työllisyystulokset korostavat analysoitujen väyläinvestointien myönteistä aluetaloudellista merkitystä. Ruralia-instituutin arvioinnin perusteella molempien kaivosten rautatie-, satama- ja tieinvestoinnit olisivat toteuttamiskelpoisia aluetaloudellisin perustein. Ne lisäisivät tuotantoa, työllisyyttä, tuloja, kulutusta ja verotuloja useissa Lapin seutukunnissa.

Synthetic investigation on the building of ring A of steroids

Methyl 7-keto-1,2,3,4,4a,5,6,7-octahydronaphthoate (Va) has been prepared by the reduction of 7-methoxy-1,2,3,4-tetrahydronaphthoic acid (III) with lithium and ammonia followed by hydrolysis of the enol ether, esterification and migration of the double bond. Alkylation of Va has led to the substitution at the expected 8-position. Methyl 4-keto-7-methoxy-1,2,3,4-tetrahydronaphthoate (X), an intermediate in the preparation of III, has been converted into methyl 3-methyl-3-cyano-4-keto-7-methoxy-1,2,3,4-tetrahydronaphthoate (XIII).

Finnish cattle as reservoir of Campylobacter spp.

The reported incidence of human campylobacteriosis in Finland is higher than in most other European countries. A high annual percentage of sporadic infections is of foreign origin, although a notable proportion of summer infections is domestically acquired. While chickens appear to be a major source of campylobacters for humans in most countries, the prevalence of campylobacters is very low in chicken slaughter batches in Finland. Data on other potential animal reservoirs of human pathogenic campylobacters in Finland are scarce. Consequently, this study aimed to investigate the status of Finnish cattle as a potential source of thermophilic Campylobacter spp. and antibiotic-resistant Campylobacter jejuni for human sporadic campylobacter infections of domestic origin. A survey of the prevalence of thermophilic Campylobacter spp. in Finnish cattle studied bovine rectal faecal samples (n=952) and carcass surface samples (n=948) from twelve Finnish slaughterhouses from January to December 2003. The total prevalence of Campylobacter spp. in faecal samples was 31.1%, and in carcass samples 3.5%. Campylobacter jejuni, the most common species, was present in 19.5% of faecal samples and in 3.1% of carcasses. In addition to thermophilic Campylobacter spp., C. hyointestinalis ssp. hyointestinalis was present in bovine samples. The prevalence of campylobacters was higher among beef cattle than among dairy cattle. Using the enrichment method, the number of positive faecal samples was 7.5 times higher than that obtained by direct plating. The predominant serotypes of faecal C. jejuni, determined by serotyping with a set of 25 commercial antisera for heat-stable antigens (Penner), were Pen2 and Pen4-complex, which covered 52% of the samples. Genotyping with pulsed-field gel electrophoresis (PFGE) using SmaI restriction yielded a high diversity of C. jejuni subtypes in cattle. Determining the minimum inhibitory concentrations of ampicillin, enrofloxacin, erythromycin, gentamicin, nalidixic acid, and oxytetracycline among bovine C. jejuni isolates using a commercial broth microdilution method yielded 9% of isolates resistant to at least one of the antimicrobials examined. No multiresistant isolates were found among the bovine C. jejuni strains. The study of the shedding patterns of Campylobacter spp. among three Finnish dairy cattle herds included the examination of fresh faecal samples and tank milk samples taken five times, as well as samples from drinking troughs taken once during the one-year study. The semiquantitative enrichment method detected C. jejuni in 169 of the 340 faecal samples, mostly at low levels. In addition, C. jejuni was present in one drinking trough sample. The prevalence between herds and sampling occasions varied widely. PFGE, using SmaI as restriction enzyme, identified only a few subtypes in each herd. In two 2 of the herds, two subtypes persisted throughout the sampling. Individual animals presented various shedding patterns during the study. Comparison of C. jejuni isolates from humans, chickens and cattle included the design of primers for four new genetic markers selected from completely sequenced C. jejuni genomes 81-176, RM1221 and NCTC 11168, and the PCR examination of domestic human isolates from southern Finland in 1996, 2002 and 2003 (n=309), chicken isolates from 2003, 2006 and 2007 (n=205), and bovine isolates from 2003 (n=131). The results revealed that bovine isolates differed significantly from human and chicken isolates. In particular, the - glutamyl transpeptidase gene was uncommon among bovine isolates. The PFGE genotyping of C. jejuni isolates, using SmaI and KpnI restriction enzymes, included a geographically representative collection of isolates from domestic sporadic human infections, chicken slaughter batches, and cattle faeces and carcasses during the seasonal peak of campylobacteriosis in the summer of 2003. The study determined that 55.4% of human isolates were indistinguishable from those of chickens and cattle. Temporal association between isolates from humans and chickens was possible in 31.4% of human infections. Approximately 19% of the human infections may have been associated with cattle. However, isolates from bovine carcasses and human cases represented different PFGE subtypes. In conclusion, this study suggests that Finnish cattle is a notable reservoir of C. jejuni, the most important Campylobacter sp. in human enteric infections. Although the concentration of these organisms in bovine faeces appeared to be low, excretion can be persistent. The genetic diversity and presence or absence of marker genes support previous suggestions of host-adapted C. jejuni strains, and may indicate variations in virulence between strains from different hosts. In addition to chickens, Finnish cattle appeared to be an important reservoir and possible source of C. jejuni in domestic sporadic human infections. However, sources of campylobacters may differ between rural and urban areas in Finland, and in general, the transmission of C. jejuni of bovine origin probably occurs via other routes than food.

Mass Transfer Coefficients in Mixer-Settlers

Mass transfer coefficients have been determined for transfer into a highly viscous phase in a stirred tank involving high Schmidt numbers. The results have been used to compute mass transfer coefficients in the extraction of free fatty acids from oils using alcohol and show good agreement with experimental results

Charge-order driven multiferroic and magneto-dielectric properties of rare earth manganates

Charge-order driven magnetic ferroelectricity is shown to occur in several rare earth manganates of the general formula, Ln(1-x)A(x)MnO(3) (In = rare earth, A = alkaline earth). Charge-ordered manganates exhibit dielectric constant anomalies around the charge-ordering or the antiferromagnetic transition temperature. Magnetic fields have a marked effect on the dielectric properties of these compounds, indicating the presence of coupling between the magnetic and electrical order parameters. Magneto-dielectric properties are retained in small particles of the manganates. The observation of magneto-ferroelectricity in these manganates is in accordance with theoretical predictions.

Charge-order driven multiferroic and magneto-dielectric properties of rare earth manganates

Charge-order driven magnetic ferroelectricity is shown to occur in several rare earth manganates of the general formula, Ln(1-x)A(x)MnO(3) (In = rare earth, A = alkaline earth). Charge-ordered manganates exhibit dielectric constant anomalies around the charge-ordering or the antiferromagnetic transition temperature. Magnetic fields have a marked effect on the dielectric properties of these compounds, indicating the presence of coupling between the magnetic and electrical order parameters. Magneto-dielectric properties are retained in small particles of the manganates. The observation of magneto-ferroelectricity in these manganates is in accordance with theoretical predictions.

Adaptation in a Business Network Cooperation Context (summary section only)

In today’s business one can say that competition does not take place inside the network, but between networks. Change and dynamics are central issues in network studies, and a company, due its changing environment, can identify opportunities and threats and respond to them accordingly. These opportunities are vital, but also complex and demanding for the management. Earlier research has identified a shortcoming in explanations of how the micro-level interactions to macro-level patterns are connected. The IMP-group has been trying to fill this research gap with research on interactions within business networks. In this area of research lies the focus of research on relationships between organizations. Adaptation in cooperation is a central concept within business network research. Adaptation has been dealt with in previous literature, but the focus of the studies has mainly been outside this phenomenon, and it has mostly had a supporting role. Most literature has also described the buyers' point of view in studied supply networks, whereas much less attention has been paid to the suppliers' view on them. This study focuses on this research gap. The results of the study stress that adaptation should be included to a greater extent in the strategy work of companies. The adaptations should be carefully planned and, as far as possible, made consciously. Conscious, well-planned adaptations can be seen as investments into present and future relationships, and resources should be invested into something that does not increase the company’s dependence, but divides the power in the relationship between the companies. Adaptations should be planned so that they result in a more offensive way of responding to the demands that are placed upon the companies. In this way, the actions can be viewed and analyzed in accordance with whether the actions make the company weaker or stronger.