One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation.

The coupling of carboxylic acids and amines to form amide linkages is the most commonly performed reaction in the pharmaceutical industry. Herein, we report a new strategy that merges these traditional amide coupling partners to generate sulfonamides, important amide bioisosteres. This method leverages copper ligand-to-metal charge transfer (LMCT) to convert aromatic acids to sulfonyl chlorides, followed by one-pot amination to form the corresponding sulfonamide. This process requires no prefunctionalization of the native acid or amine and extends to a diverse set of aryl, heteroaryl, and s-rich aliphatic substrates. Further, we extend this strategy to the synthesis of (hetero)aryl sulfonyl fluorides, which have found utility as "click" handles in chemical probes and programmable bifunctional reagents. Finally, we demonstrate the utility of these protocols in pharmaceutical analogue synthesis.

Decarboxylative Borylation and Cross-Coupling of (Hetero)aryl Acids Enabled by Copper Charge Transfer Catalysis.

We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp2)-C(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.

A Unified Approach to Decarboxylative Halogenation of (Hetero)aryl Carboxylic Acids.

Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo(hetero)arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.

The effect of air temperature, velocity and humidity on respiration rate and rectal temperature as an expression of heat stress in gestating sows.

Global warming combined with increased production (i.e. more piglets, more milk and consequently more heat) means that sows are more often challenged by heat stress. The objective was to develop an effective temperature (ET) equation to predict how air temperature, velocity and humidity affect the respiration rate (RR), rectal temperature (RT) and skin temperature (ST) as an expression of heat stress in gestating sows in order to elucidate the relationship between the thermal parameters and the sows' perception of the environment. The experimental room was equipped with a negative pressure ventilation system with diffuse air inlet through the ceiling, electrical heaters, steam generators and dehumidifiers. An air distribution unit was constructed to generate vertical air velocity. A total of 16 gestating sows were exposed to three temperatures (25°C, 29°C and 33°C), two levels of relative humidity (30% and 70%) and three levels of air velocity (0.2 ms-1, 1 ms-1 and 2.5 ms-1). The RR, RT and ST were recorded every 30 min throughout the three 2-h test periods. The estimated effects of humidity and velocity in relation to effect of temperature was nearly independent of whether it was determined from RR or RT, whereas the effect of humidity was much smaller when determined from ST. High coefficients of determination (>0.97) were found for the second order relationship between the estimated ET and RR, RT and ST. An increase in relative humidity from 50 to 70% corresponded to an increase in ET of 0.9°C, while an increase in air velocity from 0.2 to 1.0 ms-1 corresponded to a decrease in ET of 1.2°C. The applied ET equation was useful for expressing the combined effect of temperature, humidity and velocity on animals exposed to heat stress. However, multiplying the effect of velocity by the temperature gradient between the animal and the surrounding air did not improve the estimation.

Comparing patient-reported outcomes entered at home versus at hospital, and testing touch screens for initial recruitment to scientific trials in arthritis patients.

OBJECTIVES: Touch screens for entering patient-reported outcomes (PROs) are available at all Danish departments of rheumatology reporting to the nationwide DANBIO registry. This project comprises two substudies in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (AxSpA), aiming to (A) investigate the feasibility of first line patient recruitment for research via touch screens, and (B) compare PROs collected at hospital versus at home, including patient preferences. METHOD: Substudy A: using a touch screen, patients answered whether we could contact them about a clinical research project (yes/no). Characteristics of patients who accepted/declined were explored using chi-squared and Mann-Whitney U-tests. Substudy B (randomized crossover agreement study): a random sample of patients from the accepting group in substudy A was contacted by telephone. According to prespecified power and sample size estimation, 56 patients were included. After randomization, 50% of patients entered PROs and information on comorbidities and lifestyle from home and then at hospital, and 50% first from hospital and then at home. Finally, they stated their preference for data entry (hospital/home/equally good). Differences in PROs entered from home and in the hospital were compared (limits of agreement, 95% confidence intervals, and intraclass correlation coefficients). RESULTS: The touch-screen invitation was accepted by 428/952 patients (45%). Patients who accepted and those who declined had similar PROs and demographics. Substudy B was completed by 42 patients (22 RA, 20 AxSpA). They had no significant differences between PROs and lifestyle/comorbidity data entered from home and hospital, except for AxSpA patients on the Bath Ankylosing Spondylitis Functional Index and Bath Ankylosing Spondylitis Disease Activity Index item 5. The preferred method of data entry was hospital (10%), home (50%), and equally good (40%). CONCLUSION: Touch screens seem feasible for first line research recruitment. PROs collected from home were similar to the touch-screen solution. Patients preferred data entry from home.

Lack of focus on nutrition and documentation in nursing homes, home care- and home nursing: the self-perceived views of the primary care workforce.

BACKGROUND: Malnutrition is a comprehensive challenge for the nursing home, home care- and home nursing sector. Nutritional care and the subsequent documentation are a common and multifaceted healthcare practice that requires that the healthcare professionals possess complex combinations of competencies in order to deliver high-quality care and treatment. The purpose of this study was to investigate how a varied group of healthcare professionals' perceive their own competencies within nutrition and documentation and how organizational structures influence their daily work and the quality of care provided. METHODS: Two focus groups consisting of 14 healthcare professionals were conducted. The transcribed focus group interviews was analyzed using the qualitative content analysis approach. RESULTS: Six categories were identified: 1) Lack of uniform and systematic communication affect nutritional care practices 2) Experience-based knowledge among the primary workforce influences daily clinical decisions, 3) Different attitudes towards nutritional care lead to differences in the quality of care 4) Differences in organizational culture affect quality of care, 5) Lack of clear nutritional care responsibilities affect how daily care is performed and 6) Lack of clinical leadership and priorities makes nutritional care invisible. CONCLUSIONS: The six categories revealed two explanatory themes: 1) Absent inter- and intra-professional collaboration and communication obstructs optimal clinical decision-making and 2) quality deterioration due to poorly-established nutritional care structure. Overall, the two themes explain that from the healthcare professionals' point of view, a visible organization that allocates resources as well as prioritizing and articulating the need for daily nutritional care and documentation is a prerequisite for high-quality care and treatment. Furthermore, optimal clinical decision making among the healthcare professionals are compromised by imprecise and unclear language and terminology in the patients' healthcare records and also a lack of clinical guidelines and standards for collaboration between different healthcare professionals working in nursing homes, home care or home nursing. The findings of this study are beneficial to support organizations within these settings with strategies focusing on increasing nutritional care and documentation competencies among the healthcare professionals. Furthermore, the results advocate for the daily involvement and support of leaders and managers in articulating and structuring the importance of nutritional care and treatment and the subsequent documentation.

Effects of trimethoprim-sulfadiazine and detomidine on the function of equine Kv 11.1 channels in a two-electrode voltage-clamp (TEVC) oocyte model.

The long QT syndrome (LQTS) is a channelopathy that can lead to severe arrhythmia and sudden cardiac death. Pharmacologically induced LQTS is caused by interaction between drugs and potassium channels, especially the Kv 11.1 channel. Due to such interactions, numerous drugs have been withdrawn from the market or are administered with precautions in human medicine. However, some compounds, such as trimethoprim-sulfonamide combinations are still widely used in veterinarian medicine. Therefore, we investigate the effect of trimethoprim-sulfadiazine (TMS), trimethoprim, sulfadiazine, and detomidine on equine-specific Kv 11.1 channels. Kv 11.1 channels cloned from equine hearts were heterologously expressed in Xenopus laevis oocytes, and whole cell currents were measured by two-electrode voltage-clamp before and after drug application. TMS blocked equine Kv 11.1 current with an IC50 of 3.74 mm (95% CI: 2.95-4.73 mm) and affected the kinetics of activation and inactivation. Similar was found for trimethoprim but not for sulfadiazine, suggesting the effect is due to trimethoprim. Detomidine did not affect equine Kv 11.1 current. Thus, equine Kv 11.1 channels are also susceptible to pharmacological block, indicating that some drugs may have the potential to affect repolarization in horse. However, in vivo studies are needed to assess the potential risk of these drugs to induce equine LQTS.

The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside.

At the beginning of the twenty-first century, 3-bromopyruvate (3BP), a simple alkylating chemical compound was presented to the scientific community as a potent anticancer agent, able to cause rapid toxicity to cancer cells without bystander effects on normal tissues. The altered metabolism of cancers, an essential hallmark for their progression, also became their Achilles heel by facilitating 3BP's selective entry and specific targeting. Treatment with 3BP has been administered in several cancer type models both in vitro and in vivo, either alone or in combination with other anticancer therapeutic approaches. These studies clearly demonstrate 3BP's broad action against multiple cancer types. Clinical trials using 3BP are needed to further support its anticancer efficacy against multiple cancer types thus making it available to more than 30 million patients living with cancer worldwide. This review discusses current knowledge about 3BP related to cancer and discusses also the possibility of its use in future clinical applications as it relates to safety and treatment issues.

Preparation of Ultracold Atom Clouds at the Shot Noise Level.

We prepare number stabilized ultracold atom clouds through the real-time analysis of nondestructive images and the application of feedback. In our experiments, the atom number N∼10^{6} is determined by high precision Faraday imaging with uncertainty ΔN below the shot noise level, i.e., ΔN

The effect of alcohol consumption on periodontitis in older Danes.

OBJECTIVES: To examine the association of alcohol consumption measured at different points in time and periodontitis at 20 years follow-up and to investigate whether long-term alcohol consumption is related to periodontitis in old age. DESIGN: Participants aged 65 years or older in 2003, from the longitudinal study Copenhagen City Heart Study (CCHS), were invited to participate in the Copenhagen Oral Health Senior Study. METHODS: Clinical periodontal attachment loss was calculated to determine the progress of periodontitis. Alcohol consumption was measured at CCHS follow-ups in 1981-1983, 1991-1994 and 2001-2003, using a standard questionnaire. Alcohol consumption was defined as light, moderate and heavy drinking and used individually for each follow-up. The three follow-ups were summarized into long-term alcohol consumption. Logistic regression analysis was used to estimate the relation between alcohol consumption measured at different points in time and periodontitis and to assess the effect of long-term alcohol consumption on periodontitis. RESULTS: The results show that heavy drinkers in 1981-1983 had a higher odds ratio for having periodontitis compared to light drinkers (OR = 4.64 95% CI = [1.1; 19.42]). CONCLUSION: Early consumption of alcohol may increase the odds of having periodontitis 20 years later. There is a need for further studies including larger populations to investigate both alcohol consumption measured at different points in time, and long-term alcohol consumption and periodontitis progression over time.

Role of vesicular nucleotide transporter VNUT (SLC17A9) in release of ATP from AR42J cells and mouse pancreatic acinar cells.

ATP is released from cells in response to various stimuli. Our previous studies on pancreas indicated that pancreatic acini could be major stores of secreted ATP. In the present study, our aim was to establish the role of the vesicular nucleotide transporter (VNUT), SLC17A9, in storage and release of ATP. Freshly prepared acini from mice and AR42J rat acinar cells were used in this study. We illustrate that in AR42J cells, quinacrine (an ATP store marker) and Bodipy ATP (a fluorescent ATP analog) co-localized with VNUT-mCherry to vesicles/granules. Furthermore, in acini and AR42J cells, a marker of the zymogen granule membranes, Rab3D, and VNUT co-localized. Dexamethasone treatment of AR42J cells promoted formation of acinar structures, paralleled by increased amylase and VNUT expression, and increased ATP release in response to cholinergic stimulation. Mechanical stimulus (pressure) and cell swelling also induced ATP release, but this was not influenced by dexamethasone, most likely indicating different non-zymogen-related release mechanism. In conclusion, we propose that VNUT-dependent ATP release pathway is associated with agonist-induced secretion process and downstream purinergic signalling in pancreatic ducts.

Employment status in cancer patients the first five years after diagnosis-a register-based study.

PURPOSE: Work is important for identity formation, social status, and economic independency. Although some evidence within the field of work and cancer survivorship exists, no study has so far investigated employment status across all cancer diagnoses. Thus, the aim of the present study was to investigate the impact of all cancer diagnoses on employment status. METHODS: Danish cancer patients aged 20-60 years, diagnosed between 2000 and 2015, were identified through Danish registers and matched 1:5 with cancer-free controls. Logistic and linear regression was performed separately in 11 cancer types to assess and compare work status and work participation between cancer patients and cancer-free controls one, three, and five years after diagnosis. RESULTS: A total of 111,770 cancer patients and 507,003 cancer-free controls were included. All cancer types had lower chances of working one year after diagnosis (ORs between 0.05 and 0.76), with lung, colorectal, upper gastrointestinal, and blood cancer patients having the lowest chances. After three years, 10 of 11 cancer types had lower chances (ORs between 0.39 and 0.84). After five years, there were minimal differences between cancer patients and controls among most cancer types (ORs between 0.75 and 1.36). CONCLUSION: Most cancer patients had lower chances of working compared with the general population until five years after diagnosis. However, patients with certain cancer types experienced lower chances of working all years, despite improvement over time. IMPLICATIONS FOR CANCER SURVIVORS: The knowledge will help increase awareness on challenges regarding work-life after cancer. Furthermore, the distinguishing between diagnoses can inform to more targeted vocational rehabilitation.

Basal and T3-induced ROS production in lymphocyte mitochondria is increased in type 2 diabetic patients.

Mitochondrial function, including production of reactive oxygen species (ROS), is important in the pathogenesis of diabetes and its complications. Thyroid hormones are major regulator of these processes. Hence, the aim of this study was to examine the thyroid hormone regulation of ROS production in human lymphocytes in patients with diabetes mellitus type 2 (T2DM). Lymphocytes from 10 controls and 10 persons with T2DM were examined. Mitochondrial membrane potential (MMP) was examined by flow cytometry after staining with MitoTracker Green (MTG). Similarly ROS was measured following staining with carboxy-H2DCFDA. MMP was increased in T2DM patients and T3 stimulation increased MMP in controls [1398 a.u. (979-4094) vs. 2156 a.u. (1611-15189), p=0.04, median and quartiles] as well as in T2DM patients [9167 a.u. (7387-11746) vs. 20274 a.u. (17183-27839 p=0.004, median and quartiles]. Basal ROS concentration was increased in lymphocytes from T2DM and T3 significantly stimulated ROS concentration in controls [3691 a.u. (2584-6396) vs. 5650 a.u. (3001-7802) p=0.013, median and quartiles] and in T2DM patients [19271 a.u. (6288-25282) vs. 23178 a.u. (10004-28857) p=0.013, median and quartiles]. The ratio of ROS production related to MMP was significantly higher in T2DM, unstimulated as well as T3-stimulated in T2DM. Unstimulated and T3 stimulated ROS production and MMP were higher in lymphocytes from diabetic patients. An altered balance between ROS production and MMP, favoring ROS production in T2DM patients, was found suggesting that an increased mitochondrial sensitivity for T3 may be a significant factor responsible for increased ROS activity in diabetic patients.

Feasibility of self-directed learning in clerkships.

BACKGROUND: Self-directed learning has been well described in preclinical settings. However, studies report conflicting results when self-directed initiatives are implemented in clinical clerkships. AIM: To explore the feasibility of self-directed learning stimulated by clinical encounter-cards (CECs) in clinical clerkships. METHODS: Two focus groups of year-four and year-five students were interviewed about the usefulness of CECs to their learning in clerkships. The CECs were then introduced in two cohorts of 248 year-four and 250 year-five medical students and evaluated on a nine-point scale with regard to usefulness and feasibility. RESULTS: The pilot groups reported that the CECs had positive effects in terms of engaging in diagnostic reasoning, reflection on management plans, and professional identity formation. However, the two large cohorts of students rated the usefulness of the CECs on learning in clerkship low (year-four: mean 2.92, SD 1.54; year-five: mean 2.28, SD 1.06) along with preceptor support (year-four: mean 2.68, SD 1.62; year-five: mean 2.59, SD 1.78, p = 0.34). CONCLUSION: Self-directed CECs can have a positive effect on participation and clinical reasoning but are highly dependent on the context of use. Self-directed learning initiatives that aim to increase participation in communities of practice may not be feasible without major faculty development initiatives.

In vitro inhibition of Clostridium difficile and Clostridium perfringens by commercial probiotic strains.

Probiotics have gained importance in human and veterinary medicine to prevent and control clostridial enteric disease. Limited information is available on the ability of different probiotic bacteria used in food products to inhibit Clostridium difficile and Clostridium perfringens. The objective of this study was to examine the in vitro inhibitory effects of selected commercial bacterial strains on pathogenic clostridia and their growth characteristics under simulated gastrointestinal conditions. The inhibitory effects of 17 commercial strains of Lactobacillus (n = 16) and Bifidobacterium (n = 1) on the reference strains of C. difficile and C. perfringens were assessed by an agar well diffusion assay and by a broth culture inhibition assay using cell-free supernatant harvested at different growth phases, with and without pH neutralization. To study growth characteristics, probiotic strains were cultivated in different acid and bile environments, and growth in the modified media was compared to growth in standard medium. In the agar well diffusion assay, supernatant obtained from two probiotic strains inhibited the growth of both reference and clinical strains of C. perfringens. This effect as seen when supernatant was assessed with and without pH neutralization. Supernatants obtained from 10 probiotic strains inhibited C. difficile only when supernatant was added without pH neutralization. In the broth culture inhibition assay, growth of C. perfringens and C. difficile was inhibited by supernatant without pH neutralization from 5 and 10 probiotic strains, respectively. All potential probiotic strains were able to grow at pH 4.0 and in the presence of 0.15% and 0.3% bile but none were able to grow or survive at pH 2.0. Altogether five probiotic strains [Lactobacillus plantarum (n = 2), Lactobacillus rhamnosus (n = 2), Bifidobacterium animalis lactis (n = 1)] were shown to inhibit all strains of C. difficile and C. perfringens. The inhibitory effect was probiotic strain-specific. Two strains showed a pH-independent inhibitory effect likely due to production of either antibiotics or bacteriocins inhibiting C. perfringens only. These strains have favourable growth characteristics for use as probiotics and their efficacy as prophylactic or therapeutic measures against clostridial enteric disease should be further evaluated by clinical trials in animals.

The development of medical infographics to raise symptom awareness and promote communication to patients with cancer: A co-creation study.

Objective: The study aims to develop medical infographics that have a potential to raise symptom awareness and promote symptom communication between patients diagnosed with cancer and healthcare professionals. Methods: This study comprised four phases: 1) development of medical infographics, 2) user testing with healthcare professionals and patients, 3) selection of specific medical infographics, and 4) interviews on these specific medical infographics with patients using the think-aloud method. Results: Design students created 22 medical infographics conveying information about six symptoms and concerns. Patients (n = 28) with cancer said that the colourful infographics evoked individual emotional responses and associations, and they facilitated their narratives of experiences with symptoms. Healthcare professionals (n = 29) thought the infographics were eye-catching and may promote dialogue on symptoms. Conclusions: The design of medical infographics must target a specific population. When introduced, the use of medical infographics may be influenced by the physical surroundings. Medical infographics can facilitate symptom communication by creating symptom awareness and providing patients with the vocabulary to describe their symptoms and concerns. Innovation: Medical infographics are engaging visual messages with the potential to help prepare cancer patients to communicate their symptom experiences and reduce the feeling of being alone in experiencing certain symptoms.

A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.

The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly.

Oral status and the need for oral health care among patients hospitalised with acute medical conditions.

AIMS AND OBJECTIVES: To investigate the prevalence of oral health problems in patients hospitalised with acute medical conditions. BACKGROUND: Increases in our knowledge of oral health and its effects on overall well-being have helped us elucidate the relationship between oral health, disease and treatment. Currently, little is known regarding the number of patients requiring oral care at the time of hospitalisation. DESIGN: This was a cross-sectional study that assessed patients hospitalised with acute medical conditions using the Revised Oral Assessment Guide (ROAG). METHODS: The ROAG was translated into Danish, and three experienced nurses performed the assessments. A visual guide was used to calibrate the assessments. The data were analysed with spss to determine the percentage of participants who exhibited specific clinical characteristics. RESULTS: Ninety-one per cent of the newly admitted patients in this study had one or more oral health problems. Common oral problems, listed in order of the most frequent first, included the following: local plaque or debris, decayed teeth or damaged dentures and dryness and/or changes in the colour of the tongue. There was a correlation between age and the number of oral health problems. CONCLUSIONS: In this study, oral health was severely affected at the time that patients were hospitalised for acute medical issues. RELEVANCE TO CLINICAL PRACTICE: Highlights the need for standardised oral health assessments of acutely hospitalised patients, which should begin as soon as the patient's condition allows. Without these oral health assessments, a number of oral problems may not be detected and may increase in severity.

Cytoskeleton disruption by the metabolic inhibitor 3-bromopyruvate: implications in cancer therapy.

The small molecule 3-bromopyruvate (3BP), is an anticancer molecule that acts by hindering glycolysis and mitochondrial function leading to energy depletion and consequently, to cell death. In this work we have focused on understanding how the glycolytic inhibition affects cancer cell structural features. We showed that 3BP leads to a drastic decrease in the levels of ß-actin and α-tubulin followed by disorganization and shrinkage of the cytoskeleton in breast cancer cells. 3BP inhibits cell migration and colony formation independently of the activity of metalloproteinases. To disclose if these structural alterations occurred prior to 3BP toxic effect, non-toxic concentrations of 3BP were used and we could observe that 3BP was able to inhibit energy production and induce loss of ß-actin and α-tubulin proteins. This was accompanied with alterations in cytoskeleton organization and an increase in E-cadherin levels which may indicate a decrease in cancer cells aggressiveness. In this study we demonstrate that 3BP glycolytic inhibition of breast cancer cells is accompanied by cytoskeleton disruption and consequently loss of migration ability, suggesting that 3BP can potentially be explored for metastatic breast cancer therapy.

A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients.

AIMS: brain metastasis is a common cause of mortality in cancer patients, and associated with poor prognosis. Our objective was to develop a clinically relevant animal model by transplanting human biopsy spheroids derived from metastatic lesions into brains of immunodeficient rats. METHODS: nine different patient brain metastases from four different primary cancers were implanted into brains of immunodeficient rats. The xenografts were compared with patient tumours by magnetic resonance imaging, histochemistry, immunohistochemistry and DNA copy number analysis. RESULTS: after transplantation, tumour growth was achieved in seven out of nine human brain metastases. Spheroids derived from four of the metastases initiated in the rat brains were further serially transplanted into new animals and a 100% tumour take was observed during second passage. Three of the biopsies were implanted subcutaneously, where no tumour take was observed. The animal brain metastases exhibited similar radiological features as observed clinically. Histological comparisons between the primary tumours from the patients, the patient brain metastases and the derived xenografts showed striking similarities in histology and growth patterns. Also, immunohistochemistry showed a strong marker expression similarity between the patient tumours and the corresponding xenografts. DNA copy number analysis between the brain metastases, and the corresponding xenografts revealed strong similarities in gains and losses of chromosomal content. CONCLUSION: we have developed a representative in vivo model for studying the growth of human metastatic brain cancers. The model described represents an important tool to assess responses to new treatment modalities and for studying mechanisms behind metastatic growth in the central nervous system.