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Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers. Finding biomarkers for targeted therapy is a promising approach to treat cancer. Here, the authors show that in breast cancer preclinical models and patients, CDK12 promotes tumourigenesis but induces selective vulnerability to therapies that target folate one-carbon metabolism. [ABSTRACT FROM AUTHOR]

Gaussian Process (GP) models are extensively used in data analysis given their flexible modeling capabilities and interpretability. The fully Bayesian treatment of GP models is analytically intractable, and therefore it is necessary to resort to either deterministic or stochastic approximations. This paper focuses on stochastic-based inference techniques. After discussing the challenges associated with the fully Bayesian treatment of GP models, a number of inference strategies based on Markov chain Monte Carlo methods are presented and rigorously assessed. In particular, strategies based on efficient parameterizations and efficient proposal mechanisms are extensively compared on simulated and real data on the basis of convergence speed, sampling efficiency, and computational cost. [ABSTRACT FROM AUTHOR]

The pepper Bs2 gene confers resistance to Xanthomonas campestris pv. vesicatoria ( Xcv) pathogenic strains containing the avrBs2 avirulence gene in susceptible pepper and tomato. The avrBs2 gene is highly conserved in the Xanthomonas genus and when bacteria lack this gene their growth in a susceptible host is diminished, indicating that the avrBs2 gene product could confer an adaptive advantage to the pathogen. The avrBs2 of Xanthomonas citri subsp. citri ( Xcc), cause of citrus canker, shares 96% homology with avrBs2 of Xcv. To evaluate if Bs2 could recognize avrBs2 of Xcc in citrus plants and thereby activate plant defence mechanisms to increase resistance to canker, transient expression experiments were conducted using Agrobacterium tumefaciens in lemon plants subsequently challenged with wildtype Xcc. The results showed that transient expression of Bs2 reduced canker formation in lemon and induced plant defence mechanisms, as shown by callose deposition and PR-1 expression. Moreover, when an avrBs2 mutant of Xcc was used, no decrease in disease symptoms was observed. This work shows that the Bs2 gene from Solanaceae is functional in lemon, a member of the Rutaceae family. Therefore, Bs2 is a potential candidate gene for stable expression in transgenic citrus plants in order to improve resistance to canker disease. [ABSTRACT FROM AUTHOR]

Sugarcane is known for its highly complex genetics and more knowledge is needed for better use and conservation of genetic materials. In order to identify genotypes and to assess genetic diversity, diverse data sets such as morphological and molecular markers are used as a general approach. To evaluate the usefulness of different markers, important sugarcane genotypes in Argentina were characterized by AFLP, SSR and morphological traits. All genotypes characterized were grouped in one main cluster in dendrograms using two independent softwares. Interestingly, local genotypes grouped together with USA varieties and no clear genetic differentiation could be found probably due to intensive germplasm exchange between these breeding programs. The molecular markers tested were useful for genetic diversity assessment as well as for genotype identification. These markers should be included in the internationally established characters for sugarcane variety protection as they give a better view on whole genome complexity. Additionally, genetic similarities obtained from molecular markers will provide more accurate information to breeders than the pedigree method, especially when considering the asymmetric genetic inheritance of sugarcane. Morphological traits are valuable tools to identify genotypes since they reflect external resemblance more than genetic relatedness. When they were combined with molecular markers the dendogram obtained revealed genetic relationships and the genetic diversity was better estimated. In summary, both methods appear to be useful, complementing each other and should be used together to assist sugarcane breeders in estimating genetic diversity, electing parents for crossings, identifying superior lines and to protect intellectual property rights. [ABSTRACT FROM AUTHOR]

Archiving of documents and specimens generated during a non-clinical laboratory study is a basic Good Laboratory Practice (GLP) requirement. The records and materials that should be archived as well as the characteristics and the organisation of archive facilities are addressed in the OECD Series on Principles of Good Laboratory Practice No. 1 ( OECD Principles of Good Laboratory Practice (as revised in 1997) [1]. However, in recent years, questions concerning archiving have been raised and the need for a more detailed guidance on this matter has become evident The aim of the Society for Applied Pharmacological Sciences/Italian Group of Quality Assurance in Research (SSFA/GIQAR) working group on 'Archiving according to GLP' was to issue a position paper, present it for discussion in an ad hoc round table with representatives of the Italian GLP monitoring authority to promote common standards and to provide additional recommendations on storage and retention of records. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, may be associated with long-term airflow limitation. Survivors of BPD may develop asthma-like symptoms in childhood, with a variable response to ß[2]-agonists. However, the pathologic pathways underlying these respiratory manifestations are still unknown. The aim of this study was to measure exhaled nitric oxide (FE[NO]) and lung function in a group of 31 school-age survivors of BPD. They showed variable degrees of airflow obstruction (mean FEV[1] 77.8 +/- 2.3% predicted) unresponsive to ß[2]-agonists in 72% of the subjects. Their FE[NO] values (geometric mean [95% confidence interval]: 7.7 [+/- 1.1] ppb) were significantly lower than in a group of healthy matched control subjects born at term (10.7 [+/- 1.1] ppb, p < 0.05) and a group of preterm children without BPD (9.9 [+/- 1.1] ppb, p < 0.05). The children with BPD were also compared with a group of 31 patients with asthma with a comparable airflow limitation (FEV[1] 80.2 +/- 2.1% predicted) and showed FE[NO] values four times lower than in those with asthma (24.9 [+/- 1.2] ppb, p < 0.001). In conclusion, unlike children with asthma, school-age survivors of BPD have airflow limitation associated with low FE[NO] values and lack of reversibility to ß[2]-agonists, probably as a result of mechanisms related to early life structural changes in the airways. [ABSTRACT FROM AUTHOR]

Background: Methylxanthines are often administered to preterm infants for the treatment of apnoea.Aims: To study the effects of theophylline on energy metabolism, physical activity, and lung mechanics in preterm infants.Methods: Indirect calorimetry was performed for six hours before and after administration of a bolus of theophylline (5 mg/kg) in 18 preterm infants while physical activity was recorded with a video camera. Lung mechanics measurements were performed at baseline and 12 and 24 hours after theophylline treatment.Results: Theophylline increased mean (SEM) energy expenditure by 15 (5) kJ/kg/day and augmented carbohydrate utilisation from 6.8 to 8.0 g/kg/day, but fat oxidation was unchanged. After theophylline treatment, preterm infants had faster respiration, lower transcutaneous CO2, and improved static respiratory compliance without increased physical activity.Conclusions: A bolus of 5 mg/kg theophylline increased energy expenditure independently of physical activity, increased carbohydrate utilisation, and improved respiratory compliance. The increased energy expenditure could be detrimental to the growth of the preterm infant. [ABSTRACT FROM AUTHOR]

We followed the clinical course of 21 infants with bronchopulmonary dysplasia enrolled in a prospective home O[sub 2] therapy programme during a 4-year-period. Mean gestational age was 28.5 weeks (range, 25–36 weeks) and mean birth weight 1093 g (range 630–2750 g). Infants were regularly monitored to maintain pulse oximeter O[sub 2] saturation over 94%–95%. The source of O[sub 2] was liquid oxygen and was delivered by nasal cannula. During the follow up oxygenation was assessed by SatO[sub 2] measurement, cardiac function by Doppler echocardiography and respiratory function by the occlusion technique. All patients had an ophthalmological follow up. The mean age of the infants at discharge was 3.7 months (range 1.7–8.6) and mean weight 2830 g (range 2150–3780 g). At discharge 8 infants had right ventricular hypertrophy (RVH) and four of them had pulmonary hypertension. Mean duration of home O[sub 2] therapy was 97 days (range 15–320 days) and the mean age of discontinuation of O[sub 2] was 6.9 months (range 3–14.7 months). The cardiological follow up was benign: the ECG signs of RVH disappeared by 12 months of age in six out of eight infants and the right ventricular pulmonary pressure, as measured by the Doppler method, normalised in the four patients in whom it was detected. No relationship was found between respiratory mechanics and the duration of O[sub 2] therapy. Weight gain was poor with mean growth at the 3rd percentile for females and just below the 3rd percentile for males. Twelve of the 21 infants required 25 rehospitalizations. No one presented deterioration of retinopathy of prematurity that was present in 16 infants at discharge; at 12 months retinopathy was resolved in 14 infants. A total of 2025 hospital days were saved, representing a significant financial saving.Conclusion Home O[sub 2] therapy permits the safe early discharge of O[sub 2] -dependent BPD infants and it reduces significantly the... [ABSTRACT FROM AUTHOR]